Neurological complications of systemic cancer

Review

Neurological complications of systemic cancer Mustafa Khasraw, Jerome B Posner Lancet Neurol 2010; 9: 1214–27 Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, USA (Mustafa Khasraw MD, Jerome B Posner MD) Correspondence to: Dr Mustafa Khasraw, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA [email protected]

Neurological complications of systemic cancer—those arising outside the nervous system—can be distressing, disabling, and sometimes fatal. Diagnosis is often difficult because different neurological disorders may present with similar signs and symptoms. Furthermore, comorbid neurological illnesses, common in elderly patients with cancer, can complicate diagnosis. Early diagnosis and aggressive treatment can improve neurological symptoms and can substantially enhance a patient’s quality of life. We approach the problem of neurological complications of systemic cancer as would a neurologist: first by identifying the anatomical area or areas that are affected (ie, brain, spinal cord, peripheral nerve), then by evaluating the diagnostic approach, considering the symptoms and signs and including appropriate laboratory tests, and finally, by recommending treatment. We focus on disorders that are difficult to diagnose, need neurological consultation, and for which effective treatments exist.

Introduction Neurological complications caused by systemic cancers— those arising outside the nervous system—can cause signs and symptoms that are more distressing and disabling than the cancer itself and, if left untreated, can be fatal. Early diagnosis and aggressive treatment can ameliorate neurological symptoms and substantially improve the patient’s quality of life. However, diagnosis is difficult because many neurological disorders may present with similar symptoms and many cancers affect elderly patients in whom comorbid neurological illnesses can complicate diagnosis. Neurologists usually encounter neurological complications of cancer in one of two ways. Either an oncology patient develops new neurological symptoms or signs, or a patient without known cancer has a neurological disorder caused by an undiagnosed cancer. Previous reviews of neurological complications of cancer have first specified the neurological complication and its causes, and then described its signs and symptoms. But this is not the way a physician would normally encounter a patient in clinical practice; frequently, a patient presents with symptoms and abnormal findings on clinical or laboratory examination, and the physician’s task is to identify the cause of their patient’s symptoms. Accordingly, in this Review, we approach the problem of neurological complications of cancer as a neurologist would do: we consider signs and symptoms first and then the possible causes. A thorough review of all neurological complications of cancer is beyond the scope of this Review, but more extensive reviews are available (recommended references for different complications can be found in table 1).

Brain disorders Neurological complications of cancer can affect the brain, either diffusely (eg, delirium or dementia), focally (eg, hemiplegia or aphasia), or multifocally (eg, left hemiplegia and right visual field defect).

Delirium Delirium, an acute change in cognitive function characterised by confusion, disorientation, reduced 1214

attention span, and misperception, is a common, nonspecific, and sometimes hard to identify symptom in hospitalised patients receiving treatment for cancer, and is a poor prognostic sign. We retrospectively reviewed records of neurological consultations and final diagnoses in patients who received treatment at the medical and surgical units of Memorial Sloan-Kettering Cancer Center (MSKCC) between January, 2009, and December, 2009. Neurological consultation was sought for 1008 patients. In 175 patients (17%), symptoms were new-onset cognitive or behavioural changes or confusion (ie, delirium). These numbers undoubtedly underestimate the occurrence of neurological complications, because neurological consultation was usually not sought when the cause of delirium was obvious (eg, sepsis). Of the 175 patients with delirium, a single cause was identified in 73 patients (42%; figure 1); all other patients had more than one cause of delirium. The causes of delirium recorded at MSKCC in 2009 were strikingly similar to those recorded in a prospective analysis done in our institution in the early 1990s.22 Complications such as dehydration or fever, in the absence of sepsis, were rare causes of delirium but, in both cohorts, worsened symptoms when other causes were present. Patients with toxic or metabolic encephalopathies with more than one underlying cause (eg, anaemia and hyperglycaemia) have a better chance of recovery than do patients whose delirium is caused by structural abnormalities in the brain.23 Delirium occurs in two forms: quiet and withdrawn (hypoactive),24 or hyperactive and agitated. In the hypoactive form, a patient’s confusion is often not noticed or is mistaken for depression; the disorder is usually recognised by nurses or relatives.25 Seizures can be either a symptom or a cause of delirium (both non-convulsive seizures and postictal states after convulsions can cause delirium). A diagnosis of delirium can be established by a brief assessment of mental status that should be done for every patient on presentation and in hospitalised patients at daily rounds. The cause of delirium can be established by careful physical examination and laboratory assessment of potential metabolic causes, assessment of www.thelancet.com/neurology Vol 9 December 2010

Review

Example(s)

Diagnosis

Treatment

Progressive multifocal leukoencephalopathy, bacterial, fungal, viral encephalitis

MRI, LP-PCR

Restore immunity;1 antimicrobials

Non-metastatic complications Infections Side-effects of treatment

Cisplatin neuropathy, steroid myopathy

Clinical, NCS, EMG

Discontinue agents if possible2–4

Metabolic

Hypercalcaemia

Screen serum

Correct imbalances5

Vascular

Cerebral infarct, cerebral haemorrhage

MRI (DWI); CT, MRI (SWI)

Consider thrombolysis, anticoagulants, surgery for haemorrhagic metastases6

Nutritional

Wernicke’s encephalopathy

Measure blood nutrients

Vitamins, nutrients7

Paraneoplastic syndromes

Cerebellar degeneration

Paraneoplastic antibodies

IVIg, rituximab8

Metastatic complications Brain

Parenchymal tumours

MRI

Surgery, WBRT or SRS9–17

Spine

Epidural cord compression

MRI

Surgery, SRS or focal RT18

Leptomeningeal

Focal (brain, spine) or diffuse

MRI, LP

Intrathecal chemotherapy, high-dose methotrexate, or focal RT19

Peripheral nerve and plexus

Neurolymphomatosis, neurotropic melanoma

MRI, PET, nerve biopsy

Focal RT, chemotherapy*20

Muscle

Haematogenous metastases (rare)

MRI, muscle biopsy

Focal RT, chemotherapy21

*Although water-soluble chemotherapeutic agents can enter areas of brain or nerve where tumour has disrupted the blood–brain barrier or blood–nerve barrier, use of drugs that can cross the intact barrier is preferable. LP=lumbar puncture. NCS=nerve conduction studies. EMG=electromyogram. DWI=diffusion-weighted image. SWI=susceptibility-weighted image. IVIg=intravenous immunoglobulin. WBRT=whole-brain radiotherapy. SRS=stereotactic radiosurgery. RT=radiotherapy.

Table 1: Common neurological complications in patients with systemic cancer

a patient’s treatment history (with both prescribed and over-the-counter drugs), and diagnostic imaging. If an initial examination suggests dementia, the examining physician should forewarn all caregivers, because preexisting dementia is the most common risk factor for delirium in patients who are in hospital. Treatment with methylphenidate can be beneficial for patients with hypoactive delirium when no cause is identified and, thus, no specific treatment is available.26 By contrast with hypoactive delerium, hyperactive delirium is easily recognised and requires prompt pharmacological treatment (usually with haloperidol);5 restraints are sometimes necessary to prevent injury. Seizures, either focal or generalised, can cause hyperactive delirium or worsen causes of delirium. Seizures are especially common in patients with brain metastases. In a study of 470 patients with brain metastases, seizures occurred either at presentation or during the course of the illness in 113 patients (24%).27 The likelihood of seizures was highest in patients with melanoma (67%; n=12), but patients with lung cancer (29%; n=41), gastrointestinal tumours (21%; n=13), and breast cancer (16%; n=17) also had a high frequency of seizures compared with patients with cancer but without primary or metastatic brain tumours (4%; n=273). When patients have seizures, anticonvulsants should be prescribed; care should be taken when choosing anticonvulsant drugs because they have side-effects and many can interact with chemotherapeutic and other drugs. We recommend beginning treatment with levetiracetam because it does not interact with chemotherapeutic drugs; if seizures are not well controlled, we recommend adding valproate.28 Prophylactic anticonvulsants do not always prevent seizures from developing, even if the drugs are within www.thelancet.com/neurology Vol 9 December 2010

therapeutic range.29 Because some prophylactic anticonvulsants are ineffective for prophylaxis and have the potential to produce cognitive dysfunction and other serious side-effects (eg, Stevens-Johnson syndrome30), they should not be prescribed for seizure prophylaxis. Non-convulsive status epilepticus28 should be considered in any stuporous or comatose patient.31 In a study of patients at a general hospital,32 researchers suggested that 8% (n=19) of comatose patients with no clinical signs of seizure activity had non-convulsive status epilepticus. Data from MSKCC indicate about the same frequency of non-convulsive status epilepticus in patients with cancer. Observation of some patients indicates mild seizure activity affecting the eyes, face, or hands, but movements can be subtle; mild myoclonic jerks might be present.33 However, many patients do not have any signs of seizure activity; they are only stuporous or comatose. The absence of seizure activity does not prove the absence of seizures; an electroencephalogram usually helps to establish the diagnosis; however, a definitive diagnosis is established only if the patient awakens after treatment with anticonvulsants. Chemotherapeutic agents34 and antibiotics35 can cause non-convulsive status epilepticus. Delirium usually has a multifactorial cause. However, when a single cause is identified, metabolic abnormalities (especially as a result of drug intoxication) and previously unrecognised brain metastases are the most frequent causes (figure 1). Even when there is more than one cause, treatment of a single abnormality usually reverses delirium. Thus, when there is an obvious cause (eg, brain metastases) other additional abnormalities (eg, sedative drugs or metabolic disturbances) should be considered. Whenever possible, sedatives and other drugs that can cause delirium should be withdrawn. 1215

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Other 2

Infection 4

Psychiatric 3

Metabolic 28 Side-effects 15

Metastases 21

Figure 1: Causes of delirium in patients with systemic cancer A retrospective review of all patients who were referred for neurological consultation at Memorial Sloan-Kettering Cancer Center from January, 2009, until December, 2009. Data are number of patients.

Infections Septic encephalopathy is a frequent sole cause of delirium and a very common cofactor in patients with multifactorial delirium.1,5 Delirium can precede fever or complicate afebrile sepsis. An important factor might be blood–brain barrier derangement, which allows otherwise excluded neurotoxic substances to enter the brain;36 other factors include brain inflammation, apoptosis, and endothelial activation.37 Antibiotic treatment usually resolves the problem. Rare infectious causes of delirium in patients with cancer, especially those who are immunosuppressed, include herpes simplex encephalitis and fungal (eg, Cryptococcus spp or Aspergillus spp) or bacterial (eg, Nocardia spp or Listeria spp) meningitis or meningoencephalitis.5 Lumbar puncture and cerebrospinal fluid (CSF) analysis with PCR usually establishes the diagnosis.

Metastases Some patients with brain or leptomeningeal metastases, especially those with multiple small metastases or diffuse cortical involvement,38 present with delirium without focal signs. Our review of data from patients who received treatment at MSKCC shows that metastases were a sole cause of delirium in 21 of 73 patients who had a single cause of delirium and a contributory cause in 32 of 175 who had more than one cause of delirium. A brain MRI with gadolinium identifies metastases as small as 1 mm. Brain metastases cause symptoms by at least two mechanisms: they can directly damage nerve tissue, provoking focal symptoms such as hemiparesis, aphasia, or ataxia, or they can raise intracranial pressure, which causes diffuse symptoms. Because most patients with brain metastases have focal signs, the treatment of 1216

such metastases will be discussed with that of focal encephalopathy. Increased intracranial pressure can result from mass lesions and surrounding oedema (eg, metastases or brain haemorrhage); lesions that obstruct spinal fluid pathways, causing hydrocephalus (eg, leptomeningeal metastases); or diffuse brain oedema that complicates metabolic disorders (eg, hyponatraemia). Headache, nausea, and vomiting suggest increased intracranial pressure. Papilloedema, in our experience, is rare. Metabolic disorders, vascular disorders, and infections can permanently damage the brain or reveal a pre-existing, previously unrecognised, mild dementia. The choice of treatment of increased intracranial pressure depends on the cause. Mass lesions can be treated surgically. Brain oedema usually responds to corticosteroids. In rare cases in which oedema or a mass lesion causes herniation, emergency treatment with hyperosmolar agents might be needed until definitive surgical treatment can be started.39 The treatment of the obstruction of spinal fluid pathways usually requires shunting. High intracranial pressure can complicate treatment of leptomeningeal tumours without causing much ventricular dilatation; patients with high intracranial pressure usually respond to shunting.

Side-effects of treatment Because cancer surgery is often long and arduous, and requires many hours of anaesthesia, which can increase the risk of metabolic and other derangements, postoperative delirium is not rare and can be one of the most florid and frightening complications a physician can face.40 The disorder usually begins within 48 h of surgery, after a postoperative lucid period. The clinical picture varies from mild cognitive impairment, which is often unrecognised, to acute hyperactive delirium that may cause physical damage. For severely agitated patients, several drugs are recommended.5 Haloperidol is the treatment of choice.5 A long-term alcohol misuser who stops drinking just before cancer surgery can develop delirium tremens after surgery;41 benzodiazepines such as lorazepam ameliorate symptoms in these patients.42 With the exception of ifosfamide, substantial delirium from chemotherapy is rare (table 2). Ifosfamide causes encephalopathy in about 12% of patients;44 chloroacetaldehyde is believed to be the toxic metabolite of ifosfamide. Methylthioninium chloride (methylene blue) has been used to prevent and treat established encephalopathy.44,45 Intravenous treatment with thiamine might also be effective.46 Even without treatment, delirium usually resolves within a few days. High-dose methotrexate occasionally causes delirium, often with focal motor signs that fluctuate and alternate from side to side of a patient’s body. The encephalopathy begins several days after the infusion, lasts for a few days, and then remits spontaneously.47 Patients who are susceptible to adverse events after treatment with high-dose methotrexate might carry polymorphisms in www.thelancet.com/neurology Vol 9 December 2010

Review

Onset

Additional symptoms

Mechanism(s)

Usual outcome

Chemotherapy-induced cognitive dysfunction Acute post IT chemotherapy

Hours

Meningitic symptoms, seizure, paraparesis, paraplegia Aseptic meningitis; spinal cord toxicity Spontaneous recovery is likely

Transient acute encephalopathy with IV drugs—eg, MTX, ifosfamide etc

Days to weeks

Confusion, disorientation

Persistent leukoencephalopathy Chemobrain

Multiple

Recovery

Months to years Cognitive impairment, dementia; MRI shows diffuse white matter changes

Possibly neuronal loss; mineralising microangiopathy

Permanent

Weeks to years

Mild memory loss, executive function

Unknown

Recovery is likely

Somnolence, increased focal signs, worsening MRI

Demyelination; cerebral oedema

Recovery

Radiation-induced cognitive dysfunction Early encephalopathy

4–16 weeks

Late- delayed encephalopathy

Months to years Focal signs, MRI enhancement

Brain necrosis, vasculopathy

Corticosteroids; surgical removal

Leukoencephalopathy

Years

Amnesia, dementia, incontinence, gait ataxia; MRI shows ventriculomegaly, leukoencephalopathy

Cellular loss, demyelination with or without hydrocephalus

Slight response to shunting in some cases

Haemorrhage

Years

Focal signs, abnormalities on CT or MRI

Telangiectasias, vasculopathy

Partial recovery

Infarction

Years

Focal signs, abnormalities on MRI

Cerebral or carotid vasculopathy

Variable

Endocrinopathy (neck radiation)

Months to years Confusion, disorientation

Hypothyroidism

Recovery with treatment

Neoplasm

Years

RT-induced neoplasm

Poor

Focal signs

Data from reference 43. IT=intrathecal. IV=intravenous. MTX=methotrexate. RT=radiotherapy.

Table 2: Therapy-induced cognitive dysfunction

genes that encode methionine synthase48 or methyltetrahydrofolate reductase.49 Posterior reversible encephalopathy syndrome can complicate the treatment of cancer with some drugs, such as methotrexate, bevacizumab, and sunitinib.50 In addition to delirium, many patients with this syndrome are cortically blind (visual loss with intact pupillary responses), but unaware of their blindness. Symptoms result from oedema of white matter in the posterior hemispheres of the brain. In many patients, the disorder is associated with hypertension. An MRI showing the characteristic T2 hyperintensity in the posterior portions of both hemispheres, and sometimes the cerebellum, establishes diagnosis. Symptoms usually resolve spontaneously, but hypertension, if present, should be controlled. Other drugs that are rare causes of delirium include interferons, ciclosporin, high-dose cytarabine (usually with cerebellar signs), 5-fluorouracil, paclitaxel, tacrolimus, and cephalosporins.2 Radiation treatment with fractions of 300 cGy or more to a large brain portal can cause acute encephalopathy and can contribute to delirium. Patients with large tumours and raised intracranial pressure who receive high dose per fraction radiation might develop acute encephalopathy and brain herniation after their first few treatments.51 Corticosteroids usually prevent or treat symptoms.

Vascular disease Intravascular lymphomatosis, hyperviscosity, and disseminated intravascular coagulation can cause acute delirium without focal signs or evidence of systemic disease.52 Symptoms usually fluctuate and transiently affect one area of the nervous system, resolve, and then affect a different area of the nervous system. www.thelancet.com/neurology Vol 9 December 2010

Hyperviscosity can be directly measured and, in many patients, can be identified by haemorrhages and dilated vessels in the retina;53 measurement of coagulation factors in the blood identifies intravascular coagulation.54 These disorders are usually associated with previously diagnosed haematological tumours. Intravascular lymphomatosis occurs in the absence of involvement of lymph nodes or bone marrow. Thus, a patient is not known to have cancer until biopsy shows the intravascular lesions. The disorder usually presents with neurological symptoms such as altered mental status or focal neurological abnormalities, which are suggestive of brain or spinal cord lesions. Biopsy is needed to establish diagnosis but can be negative because of sampling error.52 Chemotherapy regimens that include rituximab can prolong survival.55 Limbic encephalopathy that manifests as acute and persistent memory loss with behavioural changes can be the problem with which patients with cancer present, especially patients with small-cell lung cancer.56 Because it is not very common, if a patient presents with acute, persistent memory loss, limbic encephalopathy—either paraneoplastic or non-paraneoplastic (autoimmune)— should be considered; transient memory loss, as in transient global amnesia, is a more common problem, but not a specific complication of cancer. Imaging changes in the medial temporal lobes due to limbic encephalopathy can easily be mistaken as being due to herpes simplex virus infection. In any patient with acute memory loss, even when an MRI does not reveal the characteristic medial temporal lobe lesions, a physician should consider lab testing for paraneoplastic antibodies. If no paraneoplastic antibodies are found, and PCR rules out herpes simplex encephalitis, a physician should consider a cancer diagnosis, by use of PET imaging.57 1217

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When florid delirium suggestive of acute psychosis develops in young women, a paraneoplastic syndrome associated with ovarian teratoma caused by an N-methylD-aspartate receptor antibody should be suspected. Making this diagnosis is important because the illness, if diagnosed correctly, is treatable, but if not, can be fatal.58

Dementia, chronic encephalopathy, and cognitive impairment Most disorders that cause acute encephalopathy can become chronic. Paraneoplastic limbic encephalopathy can cause permanent memory loss even after successful tumour treatment. Metabolic disorders, vascular disorders, and infections can permanently damage the brain. Chronic and often permanent changes in cognitive function that are not preceded by delirium can be caused by radiotherapy, especially whole-brain radiotherapy, and can sometimes be worsened by chemotherapy, especially with methotrexate (table 2). This is especially evident in long-term survivors of radiosensitive malignant diseases such as CNS lymphomas and in some patients with small-cell lung cancer. Methotrexate, whether given intravenously or intrathecally, is one of the few chemotherapeutic agents that can cause substantial cognitive dysfunction. When such dysfunction occurs, MRI can reveal hyperintensity of the white matter on T2 and fluid-attenuated inversionrecovery sequences (methotrexate leukoencephalopathy). Children and elderly people are especially susceptible to cognitive dysfunction caused by methotraxate. Cognitive abnormalities, often referred to as “chemobrain”, have been studied in women with breast cancer. Results from such studies seem to show a (sometimes transient) decline in cognitive function, particularly in executive function and short-term memory after chemotherapy or haemopoietic stem cell transplantation.59,60 However, even before chemotherapy, some patients with breast cancer did less well in cognitive function tests than did those who had already received chemotherapy, suggesting that pre-treatment cognitive changes are paraneoplastic. Little association exists between a patient’s perception of their cognitive function and the results of their neuropsychological assessment.61 Stress caused by cancer and its treatment might lead patients to overestimate or underestimate their cognitive impairment, irrespective of the presence of a demonstrable neuropsychological abnormality.62 Functional neuroimaging has shown abnormal activity in the frontal cortex, cerebellum, and basal ganglia in patients who have survived breast cancer, for as long as 5–10 years after chemotherapy.63 Neuropsychological training and treatment with modafinil might improve cognitive function in patients with chemobrain.64,65 Depression and fatigue are common in patients with cancer and can cause impairment of cognitive function, which can be mistaken for dementia (pseudodementia of depression). About 50% of patients with advanced 1218

cancer are depressed.66 Although, in many patients, depression and fatigue occur together and can have the same cause, attempts should be made to distinguish between specific causes, because their treatment can differ. However, sometimes treatment of depression can improve fatigue and treatment of fatigue can alleviate depression. Depression should also be differentiated from the apathy (abulia) that accompanies frontal lobe metastases, because antidepressants can worsen abulia. Pharmacological treatment with tricyclic antidepressants, selective serotonin reuptake inhibitors,66 or a combination of both, is the mainstay of depression treatment. Selective serotonin reuptake inhibitors have fewer side-effects, especially anticholinergic symptoms (dry mouth and somnolence), than do tricyclics, but do not have the analgesic effectiveness of tricyclics. Psychostimulants such as methylphenidate67 or modafinil65 sometimes improve depression, fatigue, and cognitive dysfunction. Fatigue is the most widely reported symptom in patients with cancer; roughly 40% of patients have fatigue at diagnosis and up to 90% of patients with advanced cancer have fatigue.68 It is a symptom in patients with brain tumours, both before and after radiotherapy.69 Although no studies have compared fatigue in patients with cancer and brain metastases with that in those with cancer alone, the high frequency of fatigue in patients with structural disease of the brain, including brain tumours and multiple sclerosis,43 suggests that fatigue can be a symptom of a brain metastasis. Irrespective of whether a patient with a brain metastasis is fatigued before treatment, if they are to receive whole-brain radiotherapy a patient should be warned that fatigue will occur during the course of radiation. Although most patients regain their pre-radiotherapy energy levels, fatigue can persist even when brain metastases are effectively treated. Several pharmacological70 and non-pharmacological71 interventions have been proposed to treat cancer-related fatigue. Methylphenidate and modafinil are safe and effective. Corticosteroids also improve a patient’s sense of wellbeing but side-effects prohibit long-term use. Nonpharmacological interventions include exercise and improved nutrition. Focal encephalopathy applies to specific neurological findings, such as paralysis, sensory changes, and language disturbances, with or without diffuse changes in cognitive function. Metastatic disease in a patient’s brain or cerebral leptomeninges is the most common cause of focal or multifocal encephalopathy in patients with cancer. Less common causes include strokes, both haemorrhagic and ischaemic, and infections (especially progressive multifocal leukoencephalopathy). Although usually a late manifestation of cancer, brain or leptomeningeal metastases can be the problem with which a patient presents. Many patients with lung cancer present with neurological symptoms due to metastatic and non-metastatic neurological complications.72 www.thelancet.com/neurology Vol 9 December 2010

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Brain metastases Breast cancer and lung cancer (the cancers that most often metastasise to the brain) are discussed here, but space limitations preclude discussing nuances of the management of other tumour types. Intracranial metastases affect up to 25% of patients with metastatic cancer,73 two-thirds of whom are symptomatic. Brain metastases are more common than are primary brain tumours. The frequency of brain metastases seems to be increasing74 because patients with cancer are surviving for longer than before and are therefore more likely to develop complications and recurring cancers; moreover, the advent of MRI has enabled detection of small asymptomatic metastases, which would have been otherwise missed. The blood– brain barrier creates a sanctuary for cancer cells, so that successful chemotherapy of systemic cancer might not eradicate small CNS metastases until they become large enough to disrupt the blood–brain barrier.75,76 Malignant diseases differ in their propensity to metastasise to the brain. Breast cancers that are hormonereceptor negative or that overexpress human epidermal growth factor receptor-2 (HER-2) are more likely to develop a brain metastasis.9,77,78 Triple negative (HER-2, oestrogen, and progesterone negative) breast cancers have a tendency to metastasise to the brain, leading to shortened life expectancy.79,80 Small-cell lung cancer is more likely to metastasise to the brain than is non-smallcell lung cancer and is more likely to cause multiple rather than a single metastases. In patients with nonsmall-cell lung cancer, adenocarcinomas metastasise more frequently than do squamous carcinomas. MRI usually establishes diagnosis; however, not every contrast-enhancing lesion in a patient with cancer is a metastasis. In a study10 of 54 patients with cancer and a suspected single metastasis, the diagnosis was incorrect in six patients. If doubts about the diagnosis exist, a physician should consider brain biopsy. In those patients in whom the site of the cancer is unknown, immunohistochemistry of the brain lesion might identify the primary site.81 Results from two randomised trials have shown that surgical removal of a single metastasis is better than whole-brain radiotherapy for improving a patient’s quality of life and chances of survival.10,11 Results from another randomised trial65 did not show a difference in outcome between these techniques, although patients in this trial had more severe systemic disease than did those in the other two, and many who received radiotherapy alone had surgery at relapse. A patient with controlled systemic disease and a single brain metastasis should be given focal treatment—ie, either surgery or stereotactic radiosurgery. Although no controlled trials have been done, matched-pair analysis suggests that surgery and stereotactic radiosurgery are equivalent.13 Whether or not to give whole-brain radiotherapy after focal treatment is controversial. Results from one randomised study14 showed a decrease in both local www.thelancet.com/neurology Vol 9 December 2010

recurrence and new brain lesions after such treatment. In two different studies, whole-brain radiotherapy plus stereotactic radiosurgery compared with stereotactic radiosurgery alone did not improve survival for patients with one to four metastases, but relapse occurred more frequently in those who did not receive radiotherapy.82,83 In a retrospective study,84 adjuvant whole-brain radiotherapy substantially reduced local and distant recurrences when compared with patients who did not receive such radiotherapy. Local recurrence was frequent in patients whose resected metastases were larger than 3 cm or in those who had active systemic disease, but survival of patients in the two groups did not differ. Physicians should also consider potential cognitive sideeffects of whole-brain radiotherapy, especially in patients with a good prognosis for long survival. A randomised study85 comparing radiosurgery before whole-brain radiotherapy with radiosurgery alone for treatment of one to three brain metastases was stopped early when whole-brain radiotherapy was shown to cause neurocognitive dysfunction. The role of radiation sensitisers to improve whole-brain radiotherapy is controversial.86 Most are ineffective, but evidence from a randomised trial87 suggests that motexafin gadolinium improves time to neurological and neurocognitive progression in patients with lung cancer. Efaproxiral can also be efficacious, but the evidence is less compelling.86 Prophylactic whole-brain radiotherapy is indicated for patients with limited-stage small-cell lung cancer.88 It is also recommended for patients with specific haematological malignant diseases and has shown promise in randomised trials of patients with extensivedisease small-cell lung cancer and extensive-disease non-small-cell lung cancer.89,90 Small-molecule targeted treatments, such as erlotinib in non-small-cell lung cancer and lapatinib in breast cancer, have not been shown prospectively to be effective in the treatment of brain metastases. In a study of 223 women with breast cancer and brain metastases, who received whole-brain radiotherapy and reported increased survival, improved control of extracranial disease seemed to be an important factor.91 Figure 2 outlines our general approach to the management of brain metastases. This algorithm is based on high-quality evidence when available and on our clinical experience when evidence is inconclusive or absent. Because no two patients are identical, treatment should be individualised and, when designing individualised treatment regimens, four main considerations should be taken into account. The first consideration is the number and size of metastases. Single and sometimes two or three lesions are amenable to focal treatment (eg, surgery or stereotactic radiosurgery), whereas multiple metastases are usually treated with whole-brain radiotherapy. Radiosurgery is not indicated for metastases larger than 3 cm. A single, large metastasis 1219

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may require surgery to improve symptoms, even when the patient has other smaller metastases. The second consideration is a patient’s age and performance status, and the extent of their disease.15 Patients who are younger than 65 years and have a good performance status and those with controlled or no extracranial lesions respond best to treatment; patients with a poor performance status respond worst. A recursive partitioning analysis has been devised with pretreatment prognostic characteristics and treatmentrelated variables to decide appropriateness of treatment based on a patient’s likelihood of survival.15 Results from one study15 suggest that, for patients with the best prognosis (recursive partitioning analysis class I), the average survival is 7 months after initiation of wholebrain radiotherapy, and, for those with the worst prognosis (recursive partitioning analysis class III), average survival is 2 months. Nevertheless, most patients initially respond to treatment and a few patients (less than 2%) survive for up to 5 years.16 The third consideration is the histology of the primary tumour—ie, its radiosensitivity and chemosensitivity. Even when in the same organ, tumours with different histologies differ in their likelihood to metastasise to the brain. For example, small-cell lung cancer has a propensity for early spread to the brain and causes multiple metastases that are usually responsive to chemotherapy; therefore, surgical resection, even of a

single brain metastasis, is rarely considered, whereas a single brain metastasis that occurs synchronously with non-small-cell lung cancer is usually treated surgically. The fourth consideration is the site of metastasis; basal ganglia metastases are not amenable to surgical removal but do respond to radiosurgery. Surgical removal of cerebellar metastases can lead to the development of subsequent leptomeningeal tumours.92

Leptomeningeal metastases Spread of cancer to the leptomeninges, either focally or diffusely, and with or without brain metastases, is seen in 8% of cancer patients in autopsy studies and seems to be increasing as patients with cancer live longer.81,82 Haematological malignant diseases, breast cancer, and melanoma are common causes of such spread. A tumour usually elicits an inflammatory response, even without malignant cells in the spinal fluid, which is sometimes called carcinomatous meningitis.93 Symptoms, such as diffuse or focal encephalopathy, cranial nerve palsies, spinal root dysfunction, and meningismus, are caused by tumours that invade structures that are in contact with CSF. Headache, nausea, vomiting, and obtundation are caused by obstruction of spinal fluid pathways that leads to increased intracranial pressure with or without hydrocephalus. An identifying feature of leptomeningeal metastases is simultaneous involvement of more than one area of the neuraxis.94,95

No systemic disease

Surgery with or without SRS

Systemic disease

Surgery with or without SRS or WBRT

Single metastasis

Radiosensitive >3 cm

Radioresistant

WBRT No systemic disease

Surgery

Systemic disease

Surgery or WBRT

Radiosensitive

WBRT or SRS

2–3 metastases

≤3 cm Brain metastases

No systemic disease

SRS or surgery

Systemic disease

SRS

Radioresistant Symptomatic

WBRT

>3 metastases Asymptomatic

Chemotherapy or WBRT

No systemic disease

Follow-up or WBRT

Systemic disease

WBRT

Postoperative or post-SRS recurrence

Figure 2: Treatment of brain metastases High-quality evidence is not available to support many clinical decisions; therefore, some decisions are based on clinical experience. SRS=stereotactic radiosurgery. WBRT=whole-brain radiotherapy.

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Hydrocephalus, which is caused by obstruction of spinal fluid pathways without other changes detected by MRI, is a common complication of leptomeningeal metastases. Leptomeningeal enhancement might only be evident on MRI of the cauda equina. Therefore, ventriculomegaly suggestive of hydrocephalus requires an MRI of the lumbar spine to detect nerve root enhancement of these metastases. Even in patients whose symptoms suggest brain or cranial nerve disease, imaging of the cauda equina can show enhancement along nerve roots. Hyperintensity of the subarachnoid spaces on fluid-attenuated inversion-recovery images, with or without contrast enhancement, suggests leptomeningeal metastases. However, other lesions, such as those caused by bacterial or fungal meningitis, can show a similar picture.96,97 Imaging should precede lumbar puncture because pachymeningeal enhancement, caused by the removal of spinal fluid, can complicate diagnosis. An MRI characteristic of leptomeningeal metastases usually needs no further assessment, unless a patient has symptoms of raised intracranial pressure (eg, headache, nausea, and vomiting). If there are such symptoms or if the MRI does not unequivocally establish diagnosis, the CSF should be assessed by lumbar puncture. Opening pressure should be measured because a raised CSF pressure, even in the absence of hydrocephalus, indicates obstruction of spinal fluid pathways and suggests the need for a ventriculoperitoneal shunt to relieve symptoms.98 The presence of malignant cells in CSF unequivocally establishes diagnosis.19 In patients who have tumour markers in their serum, measurement of the markers in their CSF can be helpful. A concentration of tumour markers in CSF higher than that in serum can only be explained by intrathecal production of the marker by metastatic cells in the nervous system. A lymphocytic pleocytosis of 20–100 cells is common; a raised protein concentration (>2·0 g/L) or a low glucose concentration (<2·2 mmol/L) can suggest a diagnosis of leptomeningeal metastases even in the absence of malignant cells. Immunocytochemistry of cells detected in the CSF with disease-specific monoclonal antibodies can also aid diagnosis.99 Conventional treatment consists of radiotherapy to bulky or symptomatic disease sites and intrathecal or systemic chemotherapy. The use of parenteral chemotherapy might benefit patients with bulky disease, whereas intrathecal chemotherapy is used in patients with subtle or linear enhancement on MRI without parenchymal involvement. To allow treatment (ie, focal radiation) to areas that impede normal CSF flow, CSF flow dynamics should be measured before intrathecal drugs are given. Intrathecal chemotherapeutic agents include methotrexate and conventional or liposomal cytosine arabinoside. Novel intrathecal agents such as rituximab and trastuzumab are increasingly used in the treatment of leptomeningeal www.thelancet.com/neurology Vol 9 December 2010

metastases.100,101 Intralumbar drug delivery can be used, but an intraventricular route through an Ommaya reservoir is effective and can obviate the need for frequent lumbar punctures.102 Leptomeningeal leukaemia or lymphoma usually responds to treatment, which is often curative. By contrast, patients with solid tumours do not generally benefit from intrathecal chemotherapy, with the possible exception of those with breast cancer. Initial performance status and tumour type (solid vs haemopoietic) are important prognostic indictors.103 Median survival for most patients with solid tumours and leptomeningeal metastases is 2–3 months. However, up to 15% of patients with breast cancer survive for more than a year after treatment.94

Vascular disorders Cerebrovascular complications of cancer can be arterial or venous, ischaemic or haemorrhagic, and thrombotic or embolic.104–107 Thrombotic material, in addition to the usual fibrin and platelet clots, can consist of tumour emboli, mucin, or infectious tissue.108 Cerebral infarction is occasionally the first manifestation of cancer;109,110 more often, cerebral infarcts or haemorrhages occur in patients with established cancer. Most strokes in patient with cancer are caused by the same factors as in patients who do not have cancer,6,107 but a few are cancer-specific. For example, cancer-associated hypercoagulability can cause nonbacterial thrombotic endocarditis with embolic infarction; some chemotherapeutic agents (eg, asparaginase) induce venous thrombosis. In a retrospective review111 of 70 patients with cancer and acute cerebral infarcts, researchers identified 60% of infarcts as embolic, which is a substantially higher proportion than in individuals who do not have cancer. Heparin is more effective and has a safer profile than warfarin for prophylaxis against cancer-related strokes caused by hypercoagulability.112 Cerebral haemorrhages are usually the result of bleeding into a metastasis.104,113 Thrombocytopenia is a less common cause of cerebral haemorrhages. By contrast with primary intracerebral haemorrhage, corticosteroids can be beneficial in intratumoural haemorrhage,114 and surgical evacuation of bleeding into a metastasis is helpful. Radiation-induced vascular malformations are an occasional cause of cerebral haemorrhage.115 A sudden onset of focal neurological symptoms, even in a patient with known brain metastases, requires urgent imaging. A CT scan without contrast will identify haemorrhage and sometimes infarction; however, MRI is more sensitive and specific. Susceptibility-weighted images to identify haemorrhage and diffusion-weighted images to identify infarction can aid diagnosis. Patients with cancer should receive the same treatment as patients without cancer for haemorrhage or infarction that is not related to a metastasis. 1221

Review

Life-threatening intracranial haemorrhage was once thought to be a complication of treatment with bevacizumab. However, several studies have shown a very low rate of intracranial bleeding, even in the presence of CNS metastases.116,117 A retrospective analysis118 of 4191 patients who were treated with bevacizumab at MSKCC identified 13 patients (0·3%) who had intracranial haemorrhage. Of these 13, ten had pre-existing brain metastases; four were also receiving low-molecular-weight heparin. During the same period, 129 patients with brain metastases were treated with bevacizumab and did not have a haemorrhage; 58 patients with brain metastases who had not received the drug developed intracranial haemorrhages.118

Infections Progressive multifocal leukoencephalopathy—a serious and usually fatal CNS infection that occurs in immunosuppressed individuals—is caused by the JC polyomavirus. Rituximab, which is widely used in lymphoproliferative, paraneoplastic, and other autoimmune disorders, leads to extended B-lymphocyte depletion. Rituximab can, rarely, cause progressive multifocal leukoencephalopathy, which is usually lethal unless immunity can be restored.119

Paraneoplastic syndromes Limbic encephalopathy (acute memory loss with behavioural changes) can be the disorder with which a patient with small-cell lung cancer and some other cancers initially presents.56 The disorder can also occur in patients with known cancer and can be mistaken for treatment effects, an opportunistic infection, or any other cause of delirium.

Myelopathy Spinal cord dysfunction (myelopathy) usually results from epidural spinal cord compression that in turn is caused by bony vertebral metastases;120 prostate, breast, and lung cancer each cause 15–20% of cases.18,121 In most patients, myelopathy is a late manifestation of metastatic cancer, but in up to 20% of patients, especially patients with lymphoma, myeloma, and lung cancer, epidural spinal cord compression is the initial symptom.122 Other less common causes of myelopathy include intramedullary metastases, epidural abscesses (some result from epidural catheters placed for pain, others after surgery), vascular disorders, radiation damage, and paraneoplastic syndromes. An MRI will establish many of these diagnoses and rule out others. In most patients with epidural spinal cord compression, focal and radicular pain precedes development of myelopathy by several weeks.123 Thus, a physician should routinely enquire about neck or back pain in patients being treated for cancer. For those who report such pain, an MRI of the entire spine should be done because there are often multiple sites of epidural spinal cord compression. Prompt treatment prevents development of paralysis. In patients with neurological signs, imaging is urgent and treatment should be started immediately. If the patient cannot lie flat, a bolus of corticosteroids can relieve pain and allow imaging. Figure 3 outlines our approach to treatment of epidural spinal cord compression. As for brain metastasis, treatment should be individualised. All patients with myelopathy should receive corticosteroids. Results from a small controlled trial indicated that a bolus of 10 mg dexamethasone, followed by 16 mg in

Radioresistant

Surgical resection or SRS

Radiosensitive

RT

Radioresistant

Surgery followed by SRS

Radiosensitive

Surgery followed by RT

Radioresistant

Surgery followed by SRS

Radiosensitive

Surgery followed by RT

Radioresistant

Low-dose CS, surgery followed by SRS

Radiosensitive

Low-dose CS, surgery if possible or RT

Radioresistant

High-dose CS, surgery followed by SRS

Radiosensitive

High-dose CS, RT

Lesion >1 mm from spinal cord Spine stable Lesion abuts spinal cord Epidural mass, no myelopathy

Spine unstable Malignant spinal cord involvement Pain ESCC

Spine stable Myelopathy

Figure 3: Treatment of epidural spinal cord compression High-quality evidence is not available to guide some clinical circumstances; therefore, many decisions are based on clinical experience. SRS=stereotactic radiosurgery. RT=radiotherapy. ESCC=epidural spinal cord compression. CS=corticosteroids.

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divided doses, was sufficient to treat a myelopathy.124 However, we recommend higher doses, starting with 100 mg intravenous infusion of dexamethasone.125 Results from a randomised trial that compared a placebo with high-dose corticosteroids (a bolus of 96 mg dexamethasone followed by the same dose orally for 3 days, halving the dose every 3 days), showed that patients in the treatment group had a better outcome than did those in the placebo group.126 In a randomised study,127 decompressive surgery plus postoperative radiotherapy was superior to treatment with radiotherapy alone. However, even gross total resection of the tumour does not prevent recurrence and all patients need postoperative radiotherapy. Most patients with a myelopathy from epidural spinal cord compression have widely metastatic disease and are not candidates for treatment other than external beam radiotherapy. Results from a study128 of 231 patients that compared short-course and long-course radiotherapy (five doses of 4 Gy in 1 week vs ten doses of 3 Gy in 2 weeks) showed similar functional outcome and survival, but the longer course resulted in improved progressionfree survival and local control. Irrespective of the type of treatment, early diagnosis is essential. Patients who can walk at the time of treatment almost always maintain that ability, whereas only a few who cannot walk regain the ability to do so.18,128 Other causes of myelopathy include intrathecal chemotherapy with methotrexate or cytarabine, both of which occasionally cause a subacute myelopathy. Paraneoplastic syndromes can cause myelopathy, but are usually part of more widespread encephalomyelitis.8

Cranial and peripheral nerves and muscles Cancer-associated complications in cranial and peripheral nerves and muscles have been reviewed elsewhere8,20,129 and are therefore discussed only briefly in this section (table 3). Peripheral neuropathy is the most common non-metastatic cancer complication, and is mostly caused by chemotherapeutic agents. Muscle disorders are less common than such neuropathy. Diagnosis is usually easily established by history and physical examination (distal sensory change and weakness for neuropathy, and proximal weakness for myopathy) and confirmed by electrodiagnostic studies that distinguish between neuropathy and myopathy.8,129

Metastases The peripheral nervous system and the muscles can be affected by metastatic disease, usually by compression or invasion from contiguous structures (Pancoast tumour), occasionally by direct invasion, and sometimes in the absence of other metastatic diseases (neurolymphomatosis).20 Because the blood–nerve barrier protects peripheral nerves against water-soluble chemotherapeutic agents, treatment should use agents that cross the blood–nerve barrier. Direct haematogenous metastases to muscle are quite rare, but muscle can be invaded by tumours that involve contiguous tissues. Pain and weakness can be mistaken for peripheral neuropathy.

Non-metastatic neuropathy and myopathy Side-effects of chemotherapeutic agents are the most common causes of peripheral neuropathy. Most chemotherapy-induced neuropathy is predominantly

Direct effect from tumour

Paraneoplastic syndrome

Toxicity

Other cases

Cranial nerves

Leptomeningeal metastases, skull base metastases, perineural infiltration

Brainstem encephalitis

RT, chemotherapy, or surgery

Herpes zoster

Sensory ganglia

Metastases

Sensory neuronopathy

Chemotherapy

Herpes zoster

Nerve roots

Leptomeningeal metastases, compression from bony metastases

RT (rare)

Herpes zoster

Nerve plexuses Cervical

Head and neck tumours

Brachial

Breast or lung cancer

Inflammatory plexopathy

RT

RT Acute brachial neuritis

Lumbosacral

Gynaecological and prostate cancer

Inflammatory plexopathy

RT

Acute lumbosacral neuritis

RT

Femoral nerve, iliopsoas haemorrhage, peroneal nerve palsy after weight loss

Paraneoplastic neuropathy, vasculitis

Chemotherapy

Cachexia, metabolic

Neuromyotonia with VGKC-Ab and thymoma

Transient neuromyotonia with chemotherapy and focal neuromyotonia with RT

Peripheral nerves Mononeuropathy

Metastases, compression, or invasion

Polyneuropathy

Neurolymphomatosis

Neuromyotonia

Lower motor neuron

Paraneoplastic ALS

RT

Neuromuscular junction

LEMS in SCLC

Myasthenia (interferon)

Aminoglycoside

Dermato/polymyositis

Chemotherapy-induced myositis

Steroid myopathy

Muscle

Haematogenous or direct invasion

RT=radiotherapy. VGKC-Ab=voltage-gated-potassium-channel antibodies. ALS=amyotrophic lateral sclerosis. LEMS=Lambert-Eaton myasthenic syndrome. SCLC=small-cell lung cancer.

Table 3: Common peripheral nervous system and muscular complications in patients with systemic cancer

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sensory. Some patients improve after chemotherapy—for example, with a taxane—is withdrawn. In other patients the disease might not improve and even progresses after chemotherapy—for example, with cisplatin—has been completed. Oxaliplatin causes a unique acute toxicity that includes cold-sensitive paraesthesias and pharyngeal spasm, leading to dysphagia. Acute symptoms resolve spontaneously but a chronic sensory neuropathy might persist. Other than stopping chemotherapy, there is no established prophylaxis or treatment,3 except perhaps for complications of treatment with oxaliplatin. Acute and chronic oxaliplatin toxicity can be ameliorated by treatment with calcium and magnesium, which modify voltage-gated sodium ion channels,130 although there is concern that the treatment might diminish the effectiveness of oxaliplatin. Vascular, infectious, and metabolic disorders are rare causes of peripheral neuropathy. Nutritional disorders such as thiamine7 and vitamin B12131 deficiencies are also rare causes. Paraneoplastic syndromes can affect peripheral nerves, the neuromuscular junction, or muscle. As in all paraneoplastic syndromes, the first goal is to treat the cancer; effective treatment can stabilise or reverse neurological complications. Immunosuppressive treatments including intravenous gammaglobulin (IVIg), rituximab, and cytotoxic agents such cyclophosphamide might help. Both myasthenia gravis (a thymoma) and Lambert-Eaton myasthenic syndrome (a small-cell lung cancer) can cause the initial symptoms with which a patient with an underlying cancer presents. Diagnosis is established by electrodiagnostic studies and measurement of paraneoplastic antibodies.8 Dermatomyositis and polymyositis can also be paraneoplastic syndromes, but only 10% of patients with those neuromuscular disorders have cancer. Immunosuppressive treatment is usually effective.8

Conclusions Neurological complications of cancer are a substantial challenge in both diagnosis and treatment. Accurate diagnosis and appropriate treatment are especially important because many patients with systemic cancers respond well to treatment and have a good chance of long survival. Diagnostic techniques, especially advances in imaging (MRI and PET) and discovery of new paraneoplastic antibodies, have allowed for earlier diagnosis. Advances in treatment, particularly radiosurgery for metastases, and better immunosuppressive agents for paraneoplastic syndromes have improved prognosis. Nevertheless, the prognosis of many complications is poor. New classes of anticancer treatments introduced into practice lead to rare but serious side-effects that reinforce the need for phase 4 studies with these agents. Factors that hamper clinical research include methodological difficulties in study design and identification of patients for trials of some of the less common complications. Different biological subtypes such as triple negative breast cancer or pulmonary adenocarcinoma tend 1224

Search strategy and selection criteria References for this Review were identified through searches of PubMed (from 2004 until November, 2009), The Cochrane Library (from 2004 until November, 2009), and Scopus (from 2004 until November, 2009). Medline MeSH subject headings used were “Paraneoplastic Syndromes, Nervous System”, “Neoplasms”, “Antineoplastic Agents/adverse effects”, “Peripheral Nervous System Diseases/chemically induced”, “Cognition Disorders/chemically induced”, combined with various keywords limiting the search to cancer and neurological complications. The last search was done on Nov 23, 2009. Searches in PubMed were limited to clinical trials, meta-analyses, practice guidelines, randomised control trials, guidelines, systematic reviews, and reviews (published in English). Scopus search terms were “cancer”, “neoplasm”, “sarcoma”, “carcinoma”, “neuropathy”, “neurologic”, “paraneoplastic”, “nervous”, “brain”, “cereb*”, “therapy”, and “treatment”. References lists of retrieved articles were then searched to identify other relevant publications. The “Related articles” feature of PubMed was also used to identify other relevant publications. Review articles in the bibliography provided additional citations in the literature. References from the author’s book (reference 43) have been cited if literature from the search period supplied no new data on specific topics.

to have a high tendency to metastasise to the brain. Whether targeting these distinct biological subgroups with tailored systemic treatments will alter the outcome is unknown, but clinical trials are being developed to address this issue. Controversies about the use of stereotactic radiosurgery or whole-brain radiotherapy exist, and treatment will need to be individualised until strong evidence for either treatment emerges. New technologies in neuroimaging, surgery, and radiotherapy are being implemented in this specialty. Nevertheless, basic clinical principles for the management of patients are indispensable. Contributors Both authors contributed equally. Conflicts of interest JBP has received royalties from Oxford University Press. MK declares that he has no conflicts of interest. Acknowledgments The authors would like to thank Alexandra Sarkozy from the MSKCC library for her assistance with the literature search and Judy Lampron for her editorial assistance. References 1 Pruitt AA. Central nervous system infections in cancer patients. Semin Neurol 2004; 24: 435–52. 2 Schiff D, Wen PY, van den Bent MJ. Neurological adverse effects caused by cytotoxic and targeted therapies. Nat Rev Clin Oncol 2009; 6: 596–603. 3 Kaley TJ, Deangelis LM. Therapy of chemotherapy-induced peripheral neuropathy. Br J Haematol 2009; 145: 3–14. 4 Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D, Delattre JY. CNS complications of radiotherapy and chemotherapy. Lancet 2009; 374: 1639–51. 5 Bush SH, Bruera E. The assessment and management of delirium in cancer patients. Oncologist 2009; 14: 1039–49.

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