OVERVIEW OF THE DIAGNOSIS AND MANAGEMENT OF BRAIN, SPINE, AND MENINGEAL METASTASES

OVERVIEW OF THE DIAGNOSIS AND MANAGEMENT OF BRAIN, SPINE, AND MENINGEAL METASTASES INITIAL See end of artile for authors affiliations Correspondene to: Dr K N Franks, Cookridge Hospital, Leeds Teahing Hospitals NHS Trust, Hospital Lane, Leeds LS16 6QB, UK; knfranks@hotmail.om T G E Gerrard, K N Franks J Neurol Neurosurg Psyhiatry 2004; 75(Suppl II):ii37 ii42. doi: 10.1136/jnnp.2004.040493 en to 50% of patients with systemi malignany develop brain metastases during the ourse of their disease and metastases aount for more than half of all brain tumours in adults. The major originating primary tumours are arinomas typially arising from sites shown in fig 1. The majority of patients have multiple metastases. A long disease-free interval, with absent systemi metastati disease and presentation of brain metastases of unknown primary, may require biopsy of the brain lesion if ative treatment is appropriate. However, in the ontext of known metastati disease histologial onfirmation is not usually neessary. Up to one third of brain metastases are disovered on routine staging investigations, the majority presenting with varying linial features. The diagnosis of brain tumours should be suspeted in any aner patient who develops any new neurologial symptoms. Brain metastases present with headahes in 40 50% of patients, with inreased frequeny with multiple metastases or posterior fossa metastases. Seizures and behavioural symptoms are also ommon while, in omparison, foal neurologial signs are rare as presenting symptoms. In patients suspeted to have brain metastases, ontrast enhaned magneti resonane imaging (MRI) is the best diagnosti test. However, urrent pratie in the UK is to investigate initially with omputed tomography (CT). If the CT san shows multiple metastases then an MRI would not usually add any further information. However, in good performane status patients if a single metastasis is seen on CT imaging an MRI should be performed to exlude multiple metastases before more radial treatment (fig 2). MEDICAL MANAGEMENT OF BRAIN METASTASES Initial medial management is with ortiosteroids to treat peri-tumour oedema. Cortiosteroids are effetive for symptom ontrol with the majority of patients improving in the first few days. Dexamethasone has been used sine 1961 and ats in part by reduing the permeability of tumour apillaries. Potential advantages over other ortiosteroids inlude redued ognitive impairment and less mineraloortioid ativity, reduing the risk of fluid retention and hypokalaemia. Conventionally the dose of dexamethasone is 16 mg/day and, due to the long biologial half-life of dexamethasone, there is no advantage in divided dosing over the 24 hour period. A small double blind randomised ontrol study (RCT) showed that using 4 mg, 8 mg, or 16 mg of dexamethasone in 89 patients with brain metastases produed no differene in Karnofsky performane status after one week of treatment. 1 Toxiity was dose dependent and more prevalent in patients reeiving 16 mg/24hour dexamethasone. In longer term use of ortiosteroids patients have inreased risk of gastritis, hyperglyaemia, immunosuppression, insomnia, mood hanges, oral andidiasis, proximal myopathy, and weight gain. Therefore the lowest dose of dexamethasone should be used for adequate symptom ontrol to redue the risk of ortiosteroid ompliations. Standard antionvulsants are given if the patient presents with fits but there is no evidene that they are benefiial prophylatially. 2 However, ase reports have suggested that a ombination of phenytoin and ranial irradiation is assoiated with a small inreased risk of severe skin reations inluding erythema multiforme and Stevens-Johnson syndrome. Ative treatment is only appropriate in patients who have a reasonable quality of life and a meaningful life expetany. ONCOLOGICAL TREATMENT OF PATIENTS WITH MULTIPLE BRAIN METASTASES Whole brain radiotherapy Whole brain radiotherapy (WBRT) remains the treatment of hoie though the impat of WBRT on survival and quality of life ompared to best supportive are has not been tested in randomised ontrol trials. Current pereption based on phase II studies is that WBRT ahieves improvement in intraranial disease ontrol with funtional improvement in two thirds of patients. This relatively high response rate is from older studies and two reent papers have shown a muh lower response www.jnnp.om ii37 J Neurol Neurosurg Psyhiatry: first published as 10.1136/jnnp.2004.040493 on 14 May 2004. Downloaded from http://jnnp.bmj.om/ on 2 Otober 2018 by guest. Proteted by opyright.

ii38 Figure 1 Common auses of brain metastases. with less than a third of patients deriving benefit. However, the redued response rate may only reflet a differene in omparing physiian and patient questionnaire assessment. In patients with two or more poor prognosti features whole brain radiotherapy may not provide effetive palliation for the majority of these patients. Gaspar and olleagues performed a retrospetive analysis of 1200 patients and suggested three lasses of patients: lass 1 with a Karnofsky performane status (KPS) > 70,, 65 years of age with ontrolled primary and no extraranial metastases; lass 3 KPS, 70; lass 2 all others. Class 1 patients had a median survival of 7.1 months ompared with lass 3 with median survival of 2.3 months. 3 WBRT an also have signifiant aute and late effets whih should be taken into onsideration when deiding whether to treat a patient palliatively. Aute effets inlude alopeia, skin erythema, erebral oedema with transient worsening bak to pre-radiotherapy neurologial defiit, and very small risk of death. Late side effets inlude somnolene syndrome, neuroendorine dysfuntion, neuroognitive deline, and normal pressure hydroephalus. Neuroognitive deline is an important ause of morbidity and there is urrently a phase II study looking at the effiay of methylphenidate (Ritalin), a pyhostimulant used in the treatment of psyhiatri onditions, as a treatment of neuroognitive effets post-radiotherapy. Fators that predit for late effets are total dose, dose per fration (higher dose per fration results in greater late effets), pre-morbid ondition, and extent of disease. Studies in whih patients were given one week of radiotherapy versus, two, three, and four or five weeks of radiotherapy showed no survival differene and hene there is no onsensus for the ideal dose and shedule. In the UK the standard treatment is either 20 Gy in five frations over one week or 30 Gy in 10 frations over two weeks to the whole brain. Currently there is no evidene that in patients with multiple brain metastases any additional treatment to WBRT ontributes further linial benefit. However, trials with addition of biologial agents are planned and may prove to at synergistially with radiotherapy. Systemi treatments Systemi treatments are being inreasingly used in patients presenting with brain metastases. It would seem logial to use systemi agents as more than half of the patients treated Figure 2 (A) Single metastasis visible on omputed tomographi (CT) head san. (B) Multiple metastases visible in the same patient on magneti resonane imaging (MRI). with surgery or radiotherapy for their brain metastases will die as a result of systemi disease. Chemotherapy has been used in a variety of tumour types with disappointing results. It had been thought that the blood brain barrier prevented hemotherapy agents rossing into the erebrospinal fluid, but hemotherapy responsiveness of enhaning brain metastases is similar to systemi disease metastases. Therefore hemotherapy is appropriate in patients with hemosensitive tumours suh as small ell lung aner, non-hodgkin s lymphoma, and germ ell tumours. Chemotherapy has also produed responses in brain metastases from breast aner and non-small ell lung aner (NSCLC), though no RCTs have ompared hemotherapy to WBRT. Prognosti fators in patients with brain metastases Performane status Age Presene of other metastati disease Status of primary disease J Neurol Neurosurg Psyhiatry: first published as 10.1136/jnnp.2004.040493 on 14 May 2004. Downloaded from http://jnnp.bmj.om/ on 2 Otober 2018 by guest. Proteted by opyright. www.jnnp.om

Despite inreasing numbers of studies examining the additional role of hemotherapy agents the potential linially meaningful benefit is likely to be small. Chemotherapy may have a role in patients relapsed after WBRT and in patients with systemi disease and small asymptomati brain metastases. In patients with poor performane status (KPS, 70), advaned non-ranial disease, and poor life expetany, best supportive are is likely to be the best option with dexamethasone, at the lowest symptom ontrolling dose, and palliative are support. ONCOLOGICAL TREATMENT OF PATIENTS WITH SOLITARY BRAIN METASTASES Patients with radiologially proven solitary brain metastases should be onsidered for either primary surgial exision or radiosurgery. 4 Surgery Surgery is the primary treatment option in patients with an MRI verified surgially aessible solitary brain metastasis, providing the patient is of good performane status and has minimal or no evidene of extraranial disease. Surgial removal of single brain metastasis followed by radiotherapy has been ompared to radiotherapy alone in prospetive randomised ontrol trials. Pathell and olleagues randomised 48 patients to either biopsy of the lesion plus WBRT or omplete resetion of the metastasis plus WBRT. Both groups reeived 36 Gy in 12, 3 Gy frations over 12 days. Reurrene at the site of the original metastasis was less frequent in the surgially reseted group (20% v 52%; p, 0.02) and the overall survival was longer in the surgially reseted group (median, 40 weeks v 15 weeks; p, 0.01). 5 A seond RCT of 63 patients performed in the Netherlands onfirmed these results with a signifiant inrease in overall survival in the surgially reseted followed by WBRT ompared with WBRT alone (10 months v 6 months; p = 0.04). This was more pronouned in patients with stable extraranial disease (median overall survival 12 months v 7 months). They also measured funtionally independent survival (FIS) whih was also improved in the ombined arm. However, they used a non-standard radiation dose with two frations per day up to a total dose of 40 Gy; patients who were randomised to radiotherapy alone did not have histologial onfirmation and MRI imaging was not performed to exlude multiple small metastases. 6 A third larger RCT showed that there was no benefit from surgery plus radiotherapy ompared with radiotherapy alone, though Abbreviations ASCO: Amerian Soiety of Clinial Onology CNS: entral nervous system CSF: erebrospinal fluid CT: omputerised tomography GP: general pratitioner KPS: Karnofsky performane status ICP: intraranial pressure MRI: magneti resonane imaging NSCLC: non-small ell lung aner RCT: randomised ontrol trial SCC: spinal ord ompression WBRT: whole brain radiotherapy extraranial metastases were an important preditor for overall survival. 7 Surgery annot be performed in all patients with solitary brain metastases beause of the proximity of lesions to salient areas of the brain and those areas that are not aessible. Stereotati radiosurgery Stereotati radiosurgery is a non-invasive alternative to surgery and should be onsidered in patients with tumours ( 3.5 m in diameter. It delivers high dose radiation to a foal area in the brain by delivering multiple onvergent beams. These beams an be produed by using a dediated multisoure obalt unit (gamma knife), stereotati multiple ar radiotherapy from a linear aelerator, or protons produed by ylotron. Beause of the degree of auray neessary to treat lesions with radiosurgery, speial immobilisation devies to prevent patient movement and CT or MRI imaging with omputer planning systems are required. In unontrolled studies the effiay of stereotati radiosurgery is similar to surgery, though no diret omparison RCT has been performed. It produes loal ontrol rates of 73 94% though it is assoiated with a signifiant inidene of radiation nerosis of 5 10%. Other side effets inlude dizziness, nausea, and new onset headahe that an our within the first two days following radiosurgery, whih tends to be relatively mild. Fitting an our within the first week following radiosurgery and is more ommon in patients whose lesions lie in the motor ortex. Late side effets inlude radiation nerosis and treatment indued ranial neuropathies. The role of WBRT following radiosurgery or following omplete resetion of solitary brain metastases is unlear. An RCT is to ommene in the UK shortly to attempt to answer this question. SPINAL METASTASES Spinal metastases are a ommon onsequene of malignant disease and approximately 10% of patients with aner will develop spinal ord ompression (SCC). Bony spinal metastases an arise from any primary malignany but our ommonly from prostate, breast, and lung aner. Other less ommon auses are renal ell arinoma, plasmaytoma/multiple myeloma, and non- Hodgkin s lymphoma. Spinal metastases without neurologial ompromise are more ommon than SCC though 20% of patients with spinal metastases will develop SCC. One fifth of ases of SCC present in patients without a known primary site. Two thirds of SCC are in the thorai region beause of the narrower spinal anal. SCC presents with pain in over 80% of patients whih often develops over 7 15 weeks before the onset of neurologial symptoms. The pain an be loalised or radiular, it an be exaerbated by lying down and usually progressively worsens over a period of weeks. Motor weakness is present in 60 85% of patients with SCC, usually produing bilateral leg weakness. Sensory signs are less ommon than motor weakness, often with a sensory level, but an our in a radiular distribution, with asending numbness or paresthesia. Bowel and bladder disturbanes are late features but may develop in up to 50% of patients. Neither the site of pain nor the sensory level often orrelate with the atual level of ord ompression. Unfortunately, ii39 J Neurol Neurosurg Psyhiatry: first published as 10.1136/jnnp.2004.040493 on 14 May 2004. Downloaded from http://jnnp.bmj.om/ on 2 Otober 2018 by guest. Proteted by opyright. www.jnnp.om

ii40 beause of delay in presentation and diagnosis malignant SCC is a signifiant ause of morbidity and mortality. Therefore liniians need to be aware of the possibility of SCC to aid early diagnosis and urgently arrange appropriate investigations. In a prospetive study, most patients reported early symptoms to their general pratitioner (GP), though the diagnosis was delayed for approximately two months from the GP visit. At diagnosis 82% of patients were unable to walk unaided. 8 In patients with a known diagnosis of aner, SCC should be suspeted in patients with severe bak or radiular pain. The investigation of hoie is an MRI san of the spine, as plain x ray and isotope bone sans are inadequate for diagnosis and prediting the level of ompression. One a diagnosis is suspeted the patient should be ommened on steroids, usually dexamethasone 16 mg/24 hours though higher doses, typially 96 mg/24 hours, have been used. However, there is only one RCT trial of dexamethasone versus no steroids in patients treated with radiotherapy. 9 This showed an improvement in gait funtion in the dexamethasone arm (81% v 63%) and at six months a signifiant improvement in those patients still ambulatory (59% v 33%) in the dexamethasone arm. Treatment with high dose steroids (96 mg/24 hours) may be slightly more effetive, but have a higher inidene of side effets. Surgery Surgery for spinal metastases an be onsidered and, with advanes in surgial tehniques, symptomati and funtional outomes have improved. Traditionally a posterior deompression via laminetomy was the surgial tehnique in a patient with symptomati SCC. However, the majority of metastati deposits are in the anterior part of the vertebral body and this approah does not give neurologial improvement if the anterior body of the vertebra has ollapsed. In view of the poor outome from laminetomy, more radial surgial approahes are now used with the aim of omplete exision of the metastases and immediate deompression of the spinal anal. This an be done via a retroperitoneal approah or thoraotomy depending on the site of metastasis, providing extensive exposure for omplete resetion and enabling anterior stabilisation. Bone grafting or the use of instrumentation and methylmetharylate are used to ahieve stabilisation. This has been reported in small retrospetive studies to show an advantage over radiotherapy alone. In a reent abstrat presented at the annual meeting of the Amerian Soiety of Clinial Onology (ASCO) in 2003, patients were randomised to radiotherapy alone or surgery followed by radiotherapy. The trial was stopped prematurely when planned interim analysis at 50% arual showed a signifiant differene in the number of days the patient remained ambulatory in the surgery following radiotherapy arm (126 v 35 days; p = 0.005). There were also improvements in levels of ontinene, daily steroid dose, and opiate use for pain ontrol. The differene in overall survival between the two groups was not signifiant though there was a trend towards better survival in the surgial arm. Crossover from the radiotherapy arm to surgery was allowed in the trial if there was progressive weakness despite radiotherapy. Twenty per ent of patients who were nonambulatory after radiotherapy reeived surgery. Although there was a higher surgial ompliation rate (40% ompared with 12% in surgery initially), three of the 10 patients were ambulatory post-surgery. The trial exluded patients with haematologial and germ ell malignanies, both being hemotherapy and radiotherapy sensitive and primary spinal tumours. This trial suggested that patients who reeived surgery followed by radiotherapy had better funtional and symptomati outomes and surgery should be onsidered before radiotherapy for suitable patients. 10 Radiotherapy Radiotherapy is the urrent standard treatment for patients with metastati spinal ord ompression. Unfortunately, multiple levels of ompression our in approximately one third of patients with metastati SCC, and the poor prognosis of many patients (mean survival 4 6 months) exludes a surgial option. Radiotherapy is typially given from a posterior field to the affeted vertebra(e), enompassing one vertebral body above and below to aount for daily variations in patient setup. Doses used range from 8 Gy in a single fration to up to 30 40 Gy over 3 4 weeks. Although there are no randomised ontrol trials omparing dose regimens, there is some evidene that lower doses may be as effetive. The most ommonly used regimen in the UK is 20 Gy in five frations. Radiotherapy is most effetive for improving pain and this is ahieved in the majority of patients. Funtional outome is determined by the pretreatment neurologial status of the patient. Radiotherapy preserves neurologial funtion in the majority of patients and 80 100% of patients treated when still walking remain ambulatory. In ontrast, only a minority with initial inability to walk improve in funtion enough to return to walking unaided, though this fration improves in more radiosensitive tumours suh lymphoma and myeloma. The duration of symptoms also influenes post-treatment funtion. The longer the duration of symptoms the better the result from radiotherapy. Chemotherapy Chemotherapy is not routinely used in the treatment of malignant SCC. It may be appropriate for hemosensitive tumours and has been used to good effet in germ ell tumours and lymphoma, and an be onsidered if surgery and radiotherapy are ontraindiated. In highly hemosensitive tumours a response may be seen in days though in less sensitive tumours a response may take weeks, potentially allowing time for further damage to our and reduing funtional outome. Other treatments inlude embolisation, partiularly in vasular tumours for example, renal ell aner and Indiations for onsideration of surgery for spinal metastases Life expetany greater than three months Single site of ompression Not ompletely paraplegi or paraplegia less than 12 24 hours Deterioration despite radiotherapy Bony deformity Radio-resistant tumours J Neurol Neurosurg Psyhiatry: first published as 10.1136/jnnp.2004.040493 on 14 May 2004. Downloaded from http://jnnp.bmj.om/ on 2 Otober 2018 by guest. Proteted by opyright. www.jnnp.om

Spinal metastases: key points High index of suspiion in aner patients with severe bak pain and neurologial symptoms Early diagnosis and prompt investigations Consider surgery first in appropriate patients Early referral for treatment if the patient walks in they will walk out stereotati radiosurgery to the spine. Perutaneous osteoplasty using CT guidane an be useful in pain from spinal metastases but is not used to treat the symptoms of spinal ord ompression. These tehniques are not freely available in the UK and have not been ompared to standard treatment in RCTs. MENINGEAL DISEASE (LEPTOMENINGEAL, CARCINOMATOSIS MENINGITIS, CSF METASTASES) Meningeal disease ours in 5% of patients with aner. Usually these patients have advaned disease at other sites and 50% have had brain metastases treated previously. It is beoming inreasingly ommon in non-haematologial aners, whih may be as a onsequene of improved diagnosis or with better systemi treatments leading to later relapse in santuary sites. Meningeal disease aused by non-haematologial tumours is assoiated with a median survival time of only three months. Treatment is often ineffetive for a number of reasons; the main diffiulty is delivering hemotherapy agents to the malignant ells in the entral nervous system (CNS), and as meningeal disease presents as a late ompliation of malignant disease the general prognosis is poor. The types of linial features an be divided into three subgroups: (1) erebral (ognitive impairment, headahe, nausea and vomiting, and ataxia); (2) ranial neuropathies; and (3) spinal (bak pain, radiulopathies). These partiular symptoms are produed by the tendeny of malignant ells in the erebrospinal fluid (CSF) to ongregate in speifi sites: base of skull produing ranial neuropathies, obstrution of CSF flow, and raised intraranial pressure (ICP) base of spine produing bak pain, leg weakness, radiulopathies, bowel/bladder disturbane. These areas are the most ommonly identified radiologially and at postmortem examination, and is possibly aused by the effet of gravity and slow flow of CSF. The gold standard for diagnosis is the identifiation of malignant ells in the CSF. Other typial CSF findings of meningeal disease are raised opening pressure, protein, lymphoytes, and redued gluose. These findings are not diagnosti or speifi but a ompletely normal CSF analysis is unommon (, 10%) in diagnosed ases. CSF ytology is a highly speifi but non-sensitive test for the diagnosis of meningeal disease. The sensitivity an be inreased by repeated CSF sampling. In one retrospetive analysis of 49 patients diagnosed with meningeal disease, the first CSF sample was positive in 50% of patients, whih inreased to 90% after three separate samples. 11 Similar findings have been found in other studies and it has been suggested that by inreasing the volume of CSF removed, having immediate analysis, and repeat samples if previously negative, you are able an inrease the sensitivity. Common auses of meningeal metastases Haematologial malignanies Lung aner Breast aner Melanoma CSF an also be analysed for tumour markers suh as a fetoprotein, b HCG, arinoembryoni antigen (CEA), and Ca 15 3, though at present the sensitivity remains low. However, a raised CSF tumour marker in omparison to serum values strongly suggests the presene of meningeal disease. MRI an provide definitive evidene of meningeal disease though its sensitivity and speifiity are yet to be established. Treatment inludes radiotherapy, and intratheal and systemi hemotherapy. Radiotherapy Radiotherapy an be effetive at speifi sites of meningeal disease and provides more rapid relief of symptoms. Radiotherapy should be onsidered in patients with loalisable lesions or those with symptomati identifiable bulk disease on imaging. It is ommonly used to treat speifi problemati areas rather than the whole CNS. Craniospinal radiotherapy is not used in the palliation of meningeal disease as it does not eradiate the disease and has a high inidene of side effets, partiularly myelosuppression. The side effets of loalised radiotherapy depend on the site irradiated. Aute side effets are usually minimal and short lived, and long term side effets are rare beause of the general prognosis of the disease. Intratheal hemotherapy Intratheal hemotherapy has been the standard treatment for meningeal disease. However, it has many limitations: (1) to deliver intratheal hemotherapy the patient has to have either repeated lumbar puntures or the neurosurgial insertion of a reservoir and ventriular atheter. In the palliative setting both forms of delivery an have signifiant patient morbidity and effet quality of life; (2) urrently only a small number of agents an be used whih mainly have an effet against haematologial malignanies rather than solid tumours; (3) when given intratheally it relies on adequate CSF flow to deliver the hemotherapy agent into the subarahnoid spae. However, intratheal radionuleotide sans show that CSF flow is impaired in the majority of patients with meningeal metastases; (4) intratheal hemotherapy does not eradiate bulk disease. Methotrexate is the priniple drug used in the treatment of both non-haematologial malignanies and haematologial malignanies. Intratheal methotrexate an ause leuoenephalopathy with a signifiant inreased risk in those patients reeiving onurrent radiotherapy. Cytarabine and thiotepa an be given intratheally and are used prinipally in haematologial malignanies. Thiotepa has the advantage of being able to be given in onjuntion with radiotherapy and in those patients with methotrexate indued leuoenephalopathy. Cytarabine is less effetive in solid malignanies but is produed in sustained release form with a muh longer half life, thereby reduing the frequeny of injetions. ii41 J Neurol Neurosurg Psyhiatry: first published as 10.1136/jnnp.2004.040493 on 14 May 2004. Downloaded from http://jnnp.bmj.om/ on 2 Otober 2018 by guest. Proteted by opyright. www.jnnp.om

ii42 Systemi hemotherapy Systemi hemotherapy has the theoretial advantage of treating both CNS and systemi disease. It also spares the patient either repeat lumbar puntures or the insertion of a ventriular reservoir. However, patients may have developed meningeal disease despite systemi hemotherapy, presumably due to the lak of hemotherapy penetrane into the CSF. Certain hemotherapy agents are lipid soluble suh as thiotepa and therefore an ross the blood brain barrier more effiiently. Another strategy is to give high doses of agents to attain good CSF onentrations. High dose methotrexate has been used and an give CSF onentrations similar to intratheal methotrexate, but requires prolonged hospital admission for intravenous biarbonate, hydration, and folini aid resue. Other agents suh as ytarabine an ahieve CSF penetration at high doses but inrease the risk of signifiant toxiity. Unfortunately, thiotepa, ytarabine, and methotrexate are not partiularly effetive in the treatment for solid, nonhaematologial malignanies, and therefore their role is limited. Meningeal metastases disrupt the blood brain barrier allowing intravenous hemotherapy agents to penetrate more effetively into the CSF. Theoretially, this would suggest that standard hemotherapy agents used in the treatment of metastati disease would have an effet on meningeal deposits. In reality the effetive penetration of systemi hemotherapy to meningeal deposits remains poor. At present the role of systemi hemotherapy in treating meningeal disease alone has not been evaluated, though is widely used where there is o-existent meningeal and other sites of metastati disease. Surgery The role of surgery is very limited in meningeal disease. It is prinipally used for the insertion of ventriular atheters/ reservoirs and ventriuloperitoneal shunts for the treatment of symptomati hydroephalus. In pratie, ombinations of radiotherapy, and intratheal and intravenous hemotherapy are used in the symptomati management of leptomeningeal disease. Combination treatments in non-haematologial malignanies do not appear to inrease the response rates or overall survival but have a higher inidene of treatment related ompliations. Aute ompliations are related to insertion of the drain, injetion of the intratheal hemotherapy, and CNS infetions. However, the risk of delayed leuoenephalopathy is inreased when radiotherapy and intratheal hemotherapy are ombined. Therefore evaluation of a patient s age, performane status, non-cns systemi disease, and prognosis is required before deiding on therapeuti options. All the treatments an impat on quality of life and have signifiant ompliations, partiularly intratheal hemotherapy. In haematologial malignanies omplete remission an be ahieved by ombinations of radiotherapy and intratheal and intravenous hemotherapy. Symptomati bulk disease should be treated by foused radiotherapy. In non-haematologial malignanies the aim of treatment is improvement in overall survival and palliation. More aggressive treatments should be onsidered in patients with good performane status, well ontrolled non-cns disease, and breast aner. CONCLUSION Brain, spinal, and meningeal metastases are a ommon ompliation of aner. Early diagnosis is important, espeially in spinal ord ompression, to obtain the best outome from treatment. Treatment an often involve a ombination of therapeuti modalities and therefore multidisiplinary assessment is required. Careful onsideration of the patient s performane status, prognosis, and wishes are neessary before embarking on treatment. Although some treatments an be urative the majority are palliative and therefore the patient s quality of life is of key importane.... Authors affiliations G Gerrard, K N Franks, Cookridge Hospital, Leeds Teahing Hospitals NHS Trust, Leeds, UK REFERENCES 1 Veht CJ, Hovestadt A, Verbiest HB, et al. Dose-effet relationship of dexamethasone on Karnofsky performane in metastati brain tumors: a randomized study of doses of 4, 8, and 16 mg per day. Neurology 1994;44:675. 2 Forsyth PA, Weaver S, Fulton D, et al. Prophylati antionvulsants in patients with brain tumour. Can J Neurol Si 2003;30:106 12. 3 Gaspar L, Sott C, Rotman M, et al. Reursive partitioning analysis (RPA) of prognosti fators in three radiation therapy onology group (RTOG) brain metastases trials. Int J Radiat Onol Biol Phys 1997;37:745 51. 4 Hoskin PJ, Brada M. Seond workshop on palliative radiotherapy and symptom ontrol. Radiotherapy for brain metastases. Clin Onol (R Coll Radiol) 2001;13:91 4. 5 Pathell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494 500. 6 Veht CJ, Haaxma-Reihe H, Noordijk EM, et al. Treatment of single brain metastasis: radiotherapy alone or ombined with neurosurgery? Ann Neurol 1993;33:583 90. 7 Mintz AH, Kestle J, Rathbone MP, et al. A randomized trial to assess the effiay of surgery in addition to radiotherapy in patients with a single erebral metastasis. Caner 1996;78:1470 6. 8 Levak P, Graham J, Collie D, et al. Don t wait for a sensory level listen to the symptoms: a prospetive audit of the delays in diagnosis of malignant ord ompression. Clin Onol 2002;14:472 80. 9 Sorensen S, Helweg-Larsen S, Mouridsen H, et al. Effet of high-dose dexamethasone in arinomatous metastati spinal ord ompression treated with radiotherapy: a randomised trial. Eur J Caner 1994;30A:22 7. 10 Regine WF, Tibbs PA, Young A, et al. Metastati spinal ord ompression: a randomized trial of diret deompressive surgial resetion plus radiotherapy vs. radiotherapy alone. Int J Radiat Onol Biol Phys 2003;57(2 suppl):s125. 11 Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumours. Experiene with 90 patients. Caner 1982;49:759 72. J Neurol Neurosurg Psyhiatry: first published as 10.1136/jnnp.2004.040493 on 14 May 2004. Downloaded from http://jnnp.bmj.om/ on 2 Otober 2018 by guest. Proteted by opyright. www.jnnp.om