malaria. But it is still early days for its role in neurocysticer-cosis, Japanese encephalitis and herpes simplex encephalitis.
Future randomized and blinded trials with antimicrobial treatment given to all patients who are then randomized to steroids or placebo will provide clinically relevant results.
Acknowledgements
We wish to thank Vittoria Lutje for conducting the searches and Katharine Jones for assisting in the meta-analysis. We would also like to thank Peter Kennedy, Richard Johnson, Richard Whitely, and Avindra Nath who have given valu-able suggestions.
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160 Part 3: Neurological diseases
Background
Brain tumours are a common consideration in the differen-tial diagnosis of many neurological conditions. Their presence often results in a relentless progression of symptoms and dis-ability, often in a young person. They are the most common solid malignancy of childhood, the fourth most common in the under 45 age group, and the eighth most common in the under 65 age group [1]. Overall, brain tumours are the second most common cause of death from neurological disease, after stroke.
Brain tumours can be either primary or secondary. Primary brain tumours are uncommon, and have an incidence of less than 10 per 100,000/year [1]. Gliomas account for the majority of primary brain tumours. Prognosis is determined by clinical and histological criteria. Histological classification and grading are crucial to the understanding of brain tumours and their management, and most commonly follows the World Health Organisation classification [2]. High-grade gliomas (HGG) account for approximately 80% of gliomas and include most commonly glioblastoma multiforme (GBM), anaplastic astro-cytoma and anaplastic oligodendroastro-cytoma. They have a poor survival of less than 20% at 5 years, with death usually result-ing from expansion of the mass lesion or invasion into vital structures. Low-grade gliomas (LGG) account for approxi-mately 20% of gliomas, and most commonly include astro-cytomas, oligodendrocytomas and oligoastrocytomas. Their natural history is to follow a generally more benign course, with between 50% and 80% of patients alive at 5 years. They infiltrate the brain, and usually transform to a higher grade with death resulting from locally aggressive disease [3].
Pre-therapeutic prognostic factors for gliomas are the most important determinants of survival. For HGG, data from three randomized controlled trials (RCTs) identified age over 50 years, GBM on histology, poor performance status (Table 17.1) or abnormal mental status at diagnosis as poor prog-nostic factors [4]. For LGG two RCTs identified age over 40 years, astrocytoma histology, the presence of clinical neuro-logical deficits, tumour size over 6 cm and tumour crossing the midline (both from computed tomography (CT) scanning) as poor prognostic factors [5]. A subgroup of those patients with LGG who present solely with epilepsy enjoy a much better prognosis [6].
Brain metastases are considerably more common than primary brain tumours. Up to 30% of those with systemic cancer will develop brain metastasis [7]. Brain metastases can present either with a confirmed primary tumour, or as the first presentation of disease. The most common primary sites are the lung (50%) and breast (25%), with other pri-mary sites including kidney and melanoma. Previously up to 50% were thought to be single, but with the advent of mod-ern imaging they are now found to be multiple in around three-quarters of patients [8].
Prognostic factors for brain metastasis include age, perform-ance score, the number of brain metastasis, the site of the pri-mary tumour and the activity of any extracranial disease.
These variables can be used to stratify patients into prognostic groups, with the best group having a median survival of 13.5 months, and the worst only 2.3 months [9,10].
Patients are usually referred to general physicians or neurologists first. The most common symptom at hospital refer-ral is headache (46.5%) [11]. Further symptoms were present in 86%, and include a mixture of focal signs (hemiparesis, hemisensory symptoms, dysphasia or diplopia) and non-focal symptoms (confusion/memory problems, personality change, visual changes or unsteadiness). Overall, seizures were present in 26.5% of patients, but are much more common in LGG (between 60% and 80% prevalence), where they may also be the sole complaint.
C H A P T E R 1 7
Brain tumours
Michael G. Hart, Robin Grant
17
161 Table 17.1 KPS score (adapted from Karnofsky D, et al. Cancer 1948;
1: 634–56).
Score Description
100 Normal: no complaints; no evidence of disease 90 Able to carry on normal activity; minor symptoms 80 Normal activity with effort; some symptoms 70 Cares for self; unable to carry on normal activities 60 Requires occasional assistance; cares for most needs 50 Requires considerable assistance and frequent care 40 Disabled: requires special care and assistance
30 Severely disabled: hospitalized but death not imminent 20 Very sick: active supportive care needed
10 Moribund: fatal processes are progressing rapidly
0 Dead
Following the presumptive diagnosis of a brain tumour, management decisions follow an orderly pattern, including the use of:
• Steroids: to reduce peri-tumoural oedema and improve symptoms.
• Surgery: The first decision is whether surgery should be performed or not, and if the decision is to operate, the second decision is whether diagnostic biopsy or resection should be performed.
• Radiotherapy: either as an adjunct to resection or as primary therapy after biopsy.
• Chemotherapy: either during primary therapy, either con-comitantly or adjuvantly or for recurrence.
The majority of tumours are not curable, and management is geared towards symptomatic relief and increasing survival.
With a multitude of treatment options available and almost universally poor results, careful attention to evidence-based practice will result in an optimum balance of symptom relief while avoiding side effects and intensive treatment regimes that may impinge on a vastly shortened life.
An evidence-based medicine approach to management of brain tumours is aided by clear guidelines for grading and interpreting evidence [12]. Phase II studies should simply be considered a step on the way to a well-conducted RCT.
With regard to brain tumours, specific questions include whether prognostic stratification was used during random-ization: poor prognosis patients do badly regardless of treat-ment, while it should be no surprise that well-selected good prognosis patients do substantially better, often regardless of treatment. Attention should be paid to the degree of miss-ing data and drop-outs. Outcome measures should pay atten-tion to quality of life outcomes as well as survival. For interpretation to clinical practice, care should be taken in considering how highly selected were the participants, and to what degree they reflect normal clinical practice. Finally, the practicality of the therapeutic approach is also import-ant. Attention to these methodological principles should allow proper interpretation of trials and useful therapeutic appli-cation of results.
Formulation of clinical questions
In the management of brain tumours, the application of evidence-based practice required the formulation of specific questions ideally where there is an area of controversy in the management. Literature searching was done using a wide variety of search headings and Boolean operator characteris-tics. Specific questions were formulated to include the patient, intervention, comparison and outcome:
1 In patients with a clinically suspected brain tumour, what is the best method for diagnosis? [Diagnostic test] Specific outcomes include will sensitivity, specificity, false positives and negatives, predictive value. Trials will be prospective series only.
2 For patients with presumed HGG, should surgery be either biopsy or resection? [Therapy] Lesions will not have been confirmed histologically prior to intervention. Any form of resection or biopsy will be valid. Specific outcomes include survival, symptom relief, quality of life and procedure-related complications. Trials considered will be meta-analyses, RCTs or prospective cohort studies only.
3 In patients with primary or secondary brain tumours, what is the evidence that corticosteroids are more effect than placebo?
[Therapy] All lesions must be histologically proven. Inter-ventions are any corticosteroid via any route of administration.
Outcomes include survival, quality of life, symptoms and side effects. Trials again will include meta-analyses or RCTs only.
4 For patients with HGG, is radiotherapy an effective treat-ment, and what should be given? [Therapy] Patients have histologically proven disease. Interventions include radio-therapy of any kind including stereotactic radiosurgery (SRS) and focal techniques. Outcomes include survival, quality of life, symptoms and side effects. Trials again will include meta-analyses or RCTs only.
5 For those with HGG, is chemotherapy an effective treat-ment? [Therapy] Patients are histologically proven HGG.
Interventions include chemotherapy of any nature, includ-ing focal techniques. Outcomes include survival, quality of life, symptoms and side effects. Trials again will include meta-analyses or RCTs only.
6 For patients with brain metastasis, what is the optimum regime of therapy, when considering surgery, focal radiother-apy or whose brain radiotherradiother-apy (WBRT)? [Therradiother-apy] Patients include those with histologically proven or clinically sus-pected metastasis. Intervention: surgery or radiotherapy (either focal of any kind or WBRT). Outcomes include sur-vival, quality of life, symptoms and side effects. Trials again will include meta-analyses or RCTs only.