Review

Low-grade gliomas: an update on pathology and therapy

Robert Cavaliere, Maria Beatriz S Lopes, David Schiff
Lancet Neurol 2005; 4: 76070 Neuro-oncology Center, University of Virginia, Box 800432, Charlottesville, VA 22908, USA (R Cavaliere MD, M B S Lopes MD, D Schiff MD) Correspondence to: Dr David Schiff ds4jd@virginia.edu

Low-grade gliomas (LGG) are not benign neoplasms. Patients with LGG eventually die as a consequence of this disease. Although the survival of patients with LGG is better than that of patients with higher-grade tumours, many of the treatments can produce or contribute to chronic impairment, particularly radiotherapy. Chemotherapy has emerged as a promising therapy, although denitive ndings are awaited. Breakthroughs in molecular biology have improved our understanding of tumours and have led to the development of novel treatments and better prognoses. Ongoing clinical trials will help to elucidate the optimum management of patients with LGG.

Introduction
Low-grade gliomas (LGG) present a substantial challenge to neuro-oncologists and neurosurgeons. Although more indolent than their high-grade counterparts, they are associated with neurological disability and are fatal. Prognosis is variable; high-risk and low-risk groups have been identied through risk stratication of clinical, tumour, and pathological factors. Optimum treatment is unknown, and the treatment methods routinely used are associated with substantial morbidity. Advances in molecular biology are promising, although more basic and clinical research is needed.

Epidemiology
LGG are a group of tumours with distinct clinical, histological, and molecular characteristics. The WHO classication system classies tumours by predominant cell type and grade.1 Although it is accepted that all grade I and II lesions are low-grade, the clinical diversity of these tumours detracts from a meaningful classication (table 1). A more clinically informative denition of LGG includes only grade II oligodendrogliomas, astocytomas, and oligoastrocytomas, tumours with similar invasive and malignant potential;2 these tumours are the focus of this paper. Although LGG are less common than high-grade gliomas, LGG are not rare (table 2).3 LGG are most common among men and white people and typically affect patients at a younger age than high-grade gliomas (fourth versus sixth decade of life). LGG most commonly involve the cerebral hemispheres, and are typically located in the frontal, parietal, or temporal lobes. Compared with high-grade gliomas, involvement of the insula or supplementary motor area is more
Astrocytic tumours Grade I Pilocytic astrocytoma, subependymal giantcell astrocytoma Diffuse astrocytoma, pleomorphic xanthoastrocytoma Oligodendroglial tumours Mixed tumours Ependymal tumours Subependymoma, myxopapillary ependymoma Ependymoma

common in LGG.4 In adults, LGG rarely involve the cerebellum, brainstem, or spinal cord. Seizure is the presenting symptom in more than 80% of patients.57 Patients also present with focal decits, altered mental state, or headache. Several weak causal associations have been reported in the few epidemiological studies done, including head trauma, mobile-phone use, exposure to power-frequency electromagnetic elds, diet, and occupational exposures including rubber manufacturing, petrochemicals, vinyl chloride, and pesticides.8 The only denite risk factor identied is previous exposure to ionising radiation. Wrensch and colleagues8 review of risk factors is thorough. Hereditary factors do not play a substantial part in development of LGG, although these tumours are more common in patients with neurobromatosis and Li-Fraumeni syndrome.

Neuroimaging
Diagnosis of LGG requires neuroimaging (gure 1). LGG are shown on CT scanning as isointense to hypointense. Evidence of haemorrhage and calcication might be more common in oligodendroglial tumours. On T2-weighted MRI, LGG are hyperintense and either diffuse with indistinct borders or focal with well-circumscribed margins.9 The epicentre of the astrocytoma is typically within the white matter whereas oligodendrogliomas may be more supercial, occasionally expanding the involved gyrus. Lesions extend along white-matter tracts, commonly through the corpus callosum into the contralateral hemisphere. Rarely, large tumours involve three or more cerebral lobes (gliomatosis cerebri). LGG may be multifocal with several non-contiguous regions of involvement (gure 2). LGG are not typically associated with substantial mass effect. 1539% of supratentorial LGG in adults enhance on contrast imaging.1012 Enhancement is typically heterogeneous and faint, and rarely in a ring or nodular pattern. LGG are hypometabolic on PET, a feature that commonly distinguishes them from high-grade gliomas On magnetic resonance spectroscopy, typical spectra include a dominant choline peak (reecting increased membrane synthesis) with low-intensity N-acteylaspartate (reecting decreased neuronal elements) and
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Grade II

Oligodendroglioma

Oligoastrocytoma

Table 1: WHO classication of LGG1

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% of all primary Median age brain tumours at diagnosis Diffuse astrocytoma Oligodendroglioma Oligoastrocytoma
*Per 100 000 person-years.

Age adjusted incidence* 010 037 015

07 27 11

45 41 42

Table 2: Age adjusted incidence of LGG in the USA3

tumours lack the classic features of astrocytic or oligodendroglial differentiation and show much morphological overlap. LGG share some common features. Most tumours are inltrative, with microscopic invasion of normal brain distant from the tumour epicentre. Histological features of anaplasia, including microvascular endothelial proliferation and necrosis, are absent, and mitotic activity is low. Proliferative index, assessed by labelling cells with MIB-1 antibody targeting the Ki-67 antigen expressed only in proliferative stages of the cell cycle, is generally low, typically 24%.1316

no quantiable lipid or lactate (suggesting an absence of necrosis, a feature of high-grade gliomas).9 The choline peak may be associated with cellular density and indices of cellular proliferation, thereby improving selection of targets for biopsy. Magnetic resonance spectroscopy may discriminate radiation necrosis from tumour progression and can be used to monitor treatment progress.9

Astrocytomas
Broadly, low-grade astrocytic tumours include tumours with diffusely inltrating (diffuse astrocytoma) and circumscribed (pleomorphic xanthoastrocytoma, pilocytic astrocytoma, subependymal giant cell astrocytoma) growth patterns (table 1).1 Although these tumours are characterised by slow growth and indolent behaviour, those with more circumscribed growth have specic clinicopathological features that distinguish them from the tumours discussed here. Astroctyomas with diffuse histology (WHO grade II) are characterised by low to moderate cellularity and minimum cellular and nuclear atypia (gure 3). Astrocytomas are subclassied into three variants, representing morphological subtypes of astrocytes in normal and reactive brain: brillary, protoplasmic, and gemistocytic astrocytomas. Most tumours are a mixture of the different subtypes. Fibrillary astrocytomas are composed of cells with multipolar cytoplasmic processes that form a rich brillary glial stroma. Protoplasmic astrocytomas are composed of many stellate-shaped cells with small cytoplasmic processes embedded in a microcystic or loose matrix. Gemistocytic astrocytomas are composed of cells with abundant eosinophilic, round to slightly angulated cytoplasm, and odd nuclei. The brillary matrix,

Neuropathology
Pathological criteria for distinguishing low-grade astrocytoma, oligodendroglioma, and oligoastrocytomas are controversial. Oligodendroglial tumours, either pure or mixed with an astrocytic component, were once thought to be rare. Over the past decade, however, they have been diagnosed at a much greater rate. Concomitantly, the incidence of low-grade astrocytomas has declined. Oligodendroglial tumours are more responsive to treatment than astrocytomas and are associated with a better prognosis. Consequently, diagnostic criteria for oligodendrogliomas and oligoastrocytomas have become less rigid, in part owing to neuropathologists awareness of the need to distinguish oligodendroglial tumours from other gliomas, as well as in response to pressure from clinicians. Neuropathologists are challenged to make a precise diagnosis of an LGG when in fact many of these

Figure 1: Neuroimaging of LGG Left: Non-contrasted head CT of a haemorrhagic and calcied midline, grade II oligodendroglioma. Middle: T2-weighted MRI of a grade II astrocytoma with poorly dened margins and diffuse involvement of the cerebral white matter; involvement of three lobes is consistent with gliomatosis cerebri. Right: T2-weighted MRI of a grade II oligodendroglioma with gyral expansion.

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Figure 2: MRI of a multifocal, grade II oligoastrocytoma Left: Fluid-attenuated-inversion-recovery image. Middle: T1 post-gadolinium image. Right: T1 post-gadolinium image done 3 months after the other images, when the patient presented with an increasing number of seizures and left hemiparesis.

common in brillary tumours, is less conspicuous. As a pure histological variant, gemistocytic astrocytomas are rare.17 The presence of substantial gemistocytes suggests a much shorter time to progression than with other grade II astrocytomas (gure 3).18 Astrocytomas are recognised for immunoreactivity for glial brillary acidic protein (GFAP), vimentin, and S-100 protein. The proportion of positive tumour cells varies among diffuse astrocytomas; tumours with more prominent brillary and gemistocytic components show stronger GFAP immunoreactivity than protoplasmic variants. Genetic abnormalities that might be involved in tumour formation and progression have been well

characterised in astrocytic tumours. In low-grade astrocytomas, the most common chromosomal abnormality is loss of heterozygosity on 17p and mutations of TP53 tumour suppressor gene. p53, a transcription factor present in low concentrations in normal cells, regulates cell-cycle arrest, DNA repair, and apoptosis in response to cell stress. Mutation of the TP53 gene is present in 60% of low-grade astrocytomas and 80% of gemistocytic astrocytomas.19 In the absence of a mutation, p53 function may be disrupted by other mechanisms, such as promoter hypermethylation and the resulting inhibition of the tumour suppressor gene p14ARF. This gene encodes a protein that regulates p53.20 Platelet-derived-growth-factor receptor and ligand are commonly overexpressed in low-grade astrocytomas, resulting in autocrine activation of downstream pathways to which they are linked. For example, ras is an intracellular signal transduction network that is commonly overactivated in low-grade astrocytoma. These pathways result in uncontrolled cell growth. Platelet-derived-growth-factor ligands and receptors are expressed about equally in all grades of astrocytomas, suggesting that this pathway is important in the initial steps of astrocytoma pathogenesis. Other chromosomal abnormalities present in low-grade astrocytomas include gains of chromosome 7 and losses of 22q, 13q, 10p, chromosome 6, and sex chromosomes.19,21

Oligodendrogliomas
Oligodendrogliomas (WHO grade II) are soft, gelatinous masses that extend from white to grey matter, obliterating the greywhite junction. Areas of cystic degeneration and calcication are common. The typical oligodendroglioma has a distinct histology: a uniform population of cells with round nuclei and a delicate chromatin pattern and scant cytoplasm (gure 3).22 Artefactual clearing of the cytoplasm gives the cell a characteristic fried-egg appearance. The tumour cells are dispersed in a loose brillary matrix traversed by delicate, branching vessels that occasionally subdivide the tumour into pseudolobules. This distinctive vascular pattern is referred to as a chicken-wire pattern. Oligodendrogliomas diffusely inltrate the cerebral cortex, forming characteristic secondary structures such as perineuronal satellitosis, perivascular accumulations, and subpial inltration. Neoplastic oligodendrocytes commonly have a small rim of eosinophilic cytoplasm and eccentric nuclei, socalled mini-gemistocytes. Immunocytochemical markers that reliably distinguish neoplastic oligodendrocytes do not exist. Most markers expressed by developing and mature oligodendrocytes are inconstantly expressed by neoplastic oligodendrocytes. Therefore, the diagnosis of oligodendrogliomas is primarily made from observations on haematoxylin and eosin stained sections and the absence of reactivity for markers
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Figure 3: Histopathological features of low-grade gliomas Haematoxylin and eosin staining showing diffuse astrocytoma (A); diffuse astrocytoma with gemistocytic component (B); oligodendroglioma (C); and mixed oligoastrocytoma (D). Magnication 100 (A,C,D) and 200 (B).

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associated with astroglial differentiation. Most oligodendrogliomas do not express GFAP and vimentin although mini-gemistocytes commonly show intense GFAP immunoreactivity.23,24 In the past 5 years, identication of a new class of oligodendrocyte-specic genes, the basic helix-loop-helix transcription factors Olig1 and Olig2, has given hope for new markers specic to oligodendroglial tumour identication. Olig1 and Olig2 are involved in the specication of oligodendrocyte precursors, but are also expressed by oligodendrocytes in the mature CNS.25,26 Although initial reports conrmed that neoplastic oligodendroglial cells overexpress Olig1 and Olig2,2729 recent studies have shown that these markers are present in high concentrations in inltrating astrocytomas (low and high grade) and pilocytic astrocytomas.30,31 Mixed oligoastrocytomas (WHO grade II) are gliomas with areas that resemble both oligodendroglioma and astrocytoma (gure 3). The distinction between oligodendrogliomas and oligoastrocytomas can be problematic. There are no denitive histological criteria for conrming the mixed oligoastrocytoma diagnosis. The two glial elements may be distributed in distinct areas (biphasic pattern) or in an intermingled pattern, the latter being more common. The main cell component is commonly oligodendroglial. Some researchers have dened mixed glioma as a tumour in which a second minor glial component is present in at least one eld magnied at 100-times magnication.32 Other researchers avoid diagnosing mixed gliomas or oligoastroctyomas, choosing to classify the tumour according to predominant glial morphology.33 At present, the combination of light microscopy, immunohistochemical studies, and cytogenetic or molecular analysis seems to be the best method for identifying these ambiguous gliomas.33 Oligodendroglial tumours have a more distinct genetic prole than astrocytomas. Somatic deletions of chromosomes 1p and 19q are the most important events in tumorigenesis of oligodendrogliomas, occurring in about 4070% of tumours (gure 4).34 The presence of 1p and 19q deletions is highly associated with the oligodendroglial phenotype.35 Point mutations of TP53 in oligodendrogliomas rarely occur and are less common than in astrocytic tumours.36 p53 protein overexpression, as measured by immunohistochemistry, is not uncommon, suggesting mechanisms of p53 pathway disruption other than gene mutation.37 Oligoastrocytomas are genetically heterogeneous. 3070% of oligoastrocytomas have allelic losses on chromosomes 1p and 19q, thus resembling oligodendrogliomas. Another 30% have genetic aberrations commonly found in diffuse astrocytomas, including mutations of TP53 and loss of heterozygosity
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on chromosome 17p.38 Identical genetic changes have been identied in both astrocytic and oligodendroglial elements in a given tumour, indicating a clonal origin of mixed gliomas.39 The presence of TP53 mutations or 17p loss and 1p and 19q deletions seems to be exclusive in the individual groups.4042

Animal models of LGG

Animal models of glioma have contributed to the understanding of glioma pathogenesis. They also enable preclinical testing of developmental therapies. Tumours can be induced in animals through activation of growth-factor-induced signal transduction pathways or targeting of specic genes that are commonly altered in human gliomas.43 An international consortium recently reviewed the histology of gliomas in genetically engineered mice and provided guidelines for histological classication.44 Most animal models have generated high-grade gliomas. A GFAP/v-src mouse45 and a transgenic mouse with a GFAP/H-ras construction,46 however, have resulted in low-grade astrocytomas. Mice infected with retroviruses expressing platelet-derived-growth-factor B develop either oligodendrogliomas or oligoastrocytomas depending upon the initial expression of plateletderived-growth-factor B in either neural progenitor cells or astrocytes.47 Transfer of polyoma middle T antigen into a Gtv-a mouse induces oligoastrocytomas.48 Deletions of 1p and 19q, commonly seen in human oligodendrogliomas, are not present in animal oligodendroglial tumours induced by platelet-derived growth factor.

Prognostic factors
Although LGG seem more indolent than high-grade gliomas, they are not benign and eventually prove fatal. Extraneural metastases of LGG are rare. Neoplastic cells, however, can inltrate surrounding brain. Tumour cells acquire genetic defects which result in anaplastic transformation to a high-grade lesion, and 5070% of lesions are high grade at the time of tumour progression.5,12,49 The clinical effects of LGG are

Figure 4: Fluorescence in-situ hybridisation for chromosomes 1 and 19 in an oligodendroglioma showing codeletion of chromosomes 1p and 19q Formalin-xed, parafn-embedded tissues were analysed with four human DNA probes localising 1p, 1q, 19p, and 19q. Left: Analysis of chromosome 1 shows one signal for 1p (rhodamine red), compared with 1q (FITC green). Right: Analysis of chromosome 19 shows one signal for 19q (rhodamine red), compared with 19p (FITC green).

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variable, with survival ranging from less than 2 years to more than 10 years. Clinical, tumour, and treatmentrelated factors each contribute to the variability.

Clinical factors
Age over 40 years is a predictor of poor outcome. In multivariate analysis of two large, prospective trials, age over 40 years had a hazard ratio for death of 143 (95% CI 117174); this increased risk is unlikely to result from age-related treatment disparity.7 Age-associated physiological and pathological changes and comorbidities may predispose to adverse outcomes. Bahary and colleagues50 noted that tumour volumes in patients older than 35 years were larger than those in younger patients. Alternatively, tumour biology may differ in old patients. Age at diagnosis of low-grade astrocytoma is inversely correlated with time to progression,51 and proliferative index may be higher among those older than 40 years.52,53 Ageing-related impairment of DNA repair and the resulting acquisition of mutations may promote rapid progression after transformation occurs.51,54 Clinical presentation is a strong prognostic factor, whether expressed as the presence of seizures, absence of neurological decits, or good performance status.7,11,55 These factors are inter-relatedeg, neurologically intact patients who present with isolated seizures have a better performance status and prognosis.7,11,55,56 The presence of seizures may select otherwise intact patients for earlier diagnosis than in those without seizures.57 Patients who present with seizures tend to be younger and have smaller tumours than those without seizures.5759 LGG associated with epilepsy might differ biologically from LGG in patients presenting with neurological decits.6,60 Tumours in patients presenting with epilepsy may represent histological variants of other, more benign, low-grade tumours, such as dysembryoplastic neuroepithelial tumours.60 Corticallybased tumours associated with seizures may be derived from a different astrocytic lineage than tumours in white matter.61 Occasional association with cortical dysplasia suggests derivation of these tumours from a developmental abnormality.60,62

with a worse outcome in some11,65 but not all studies.5,10 One explanation is sampling errorie, the reviewed sample may not reect the pathology in the enhancing portion of the tumour. The proportion of LGG with contrast enhancement has not declined substantially in the modern surgical era when enhancing regions can accurately be targeted for biopsy. Thus, one cannot exclude an underlying biological effect to account for this relation.

Treatment
Surgery
Surgery has long been important in the diagnosis and treatment of LGG. Although the presence of a nonenhancing mass lesion on imaging suggests LGG, about 30% of such lesions are higher grade than predicted by imaging, particularly those in old patients.66,67 At a minimum, stereotactic biopsy is required to establish diagnosis, although timing is debatable. A neurosurgeon using image guidance can precisely target a radiographic abnormality via a burr hole to sample a lesion without exposing the patient to unnecessary risk. Compared with craniotomy, stereotactic biopsy is less invasive and requires a shorter period of hospitalisation. However, biopsy provides only a sample of a potentially heterogeneous lesion. Biopsy tissue might be insufcient for additional molecular and genetic testing that could facilitate diagnosis, provide prognostic information, and affect subsequent treatment. Alternatively, cytoreductive surgery allows for rapid decompression of larger lesions associated with mass effect. Debulking may palliate symptoms, improve quality of life, and allow for rapid tapering of corticosteroids. Nonetheless, the anatomic constraints of the CNS may limit the extent to which a lesion is surgically accessible. Furthermore, the inltrative growth pattern of these tumours means that an attempt to resect the tumour places the patient at risk of neurological injury.68 The effect of surgery on overall and progression free survival is uncertain. The inltrative nature of LGG is such that that they are not surgically curable. To date, a prospective randomised surgical trial has not been done. The available data are derived from retrospective series that have substantial limitations. Until recently, the extent of resection was based on the surgeons intraoperative assessment. Currently, postoperative neuroimaging allows for more accurate assessment of extent of resection. The method by which extent of resection was dened and presented has varied between studies.69 For example, some studies compared biopsy with resection, whereas others compared gross total resection with less extensive surgery. Sample size can be insufcient for multivariate analysis. Thus, the benet of surgery may be gained or lost in analysis based on other clinical or treatment variables. Although
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Tumour factors
The median survival for oligodendrogliomas is 10 years, a better prognosis than for astrocytomas, which have a median survival of 7 years. Gemistocytic astrocytomas, a subtype of grade II astrocytomas, are more aggressive than predicted by grade. Large tumours, non-lobar gliomas, and tumours that cross midline are associated with a short survival (and time to progression) and a high rate of malignant dedifferentiation.7,10,11,63 Such tumours can be less amenable to surgical resection. Proliferative index has occasionally been inversely related with outcome.16,64 Contrast enhancement of LGG has been associated
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some studies found a survival advantage with more extensive surgery,5,50,70 others did not.10,65,71 In some series, the extent of resection lost signicance in favour of other related variables, such as preoperative7,10 or postoperative tumour volume,72 or the location or distribution of the lesion.7,63,73 Nonetheless, evidence that more extensive surgery may have a positive effect on outcome is growing.69 The timing of surgery is controversial. A large proportion of patients with LGG are young and present with isolated seizures that may be medically well controlled. Potential surgical morbidity may compromise their otherwise intact functional status. Some have advocated deferring surgery in lieu of radiographic surveillance in select populations.74 The risk of deferring surgery includes managing a larger tumour that may have undergone anaplastic transformation in an older patient. Tumour progression may also result in increased symptom burden. Based on limited retrospective data, however, the timing of surgery does not seem to affect overall or progression-free survival, the time to malignant progression or the rate of malignant progression.12,74

Radiotherapy
Although radiotherapy has played an important part in the management of LGG, the efcacy and timing of this treatment has been debated. Until recently, data were derived from retrospective case series that yielded conicting resultsie, some studies found a survival advantage with radiotherapy,75 whereas others failed to do so.70 Non-uniformity of inclusion criteria and the therapeutic regimens used may account for the differences.76 Also, clinical or radiographic factors of prognostic importance are used in treatment selection.5,50 Although it has become practice in some institutions to defer therapy until progression, most patients eventually receive treatment. Several retrospective case series reported similar survival among patients treated postoperatively or at progression.5,50,65,77,78 The European Organisation for Research and Treatment of Cancer randomly assigned patients with LGG to postoperative radiotherapy or observation.79 Patients given radiotherapy had a substantially longer time to progression (48 years) than those who were observed (34 years). 66% of those who were initially observed received radiotherapy at progression. Survival was identical between groups, suggesting that radiotherapy is as effective if given at progression as at initial diagnosis. The results must be interpreted with caution because median follow-up was only 60 months and only 32% of patients died. Radiation treatment elds and doses have varied with time and treatment facility. The inltrative nature of LGG is such that tumour cells may be identied at sites distant from radiographic abnormalities. Early practice was to treat patients with whole brain radiotherapy with
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or without a boost to the lesion. Recurrences, however, generally occurred in the vicinity of the original lesion. Common practice now is to use partial elds directed at the tumour with a small surrounding margin; although this has not compromised outcome it has reduced treatment toxicity.80 The optimum radiation dose was also debatable because early studies reported conicting data for dose response. Two prospective clinical trials in Europe and the USA assigned patients to low-dose and high-dose regimens (table 3).10,63,79 Neither study found a difference in overall or progression-free survival, and there was more toxicity in high-dose groups.10,81 Radiographic response rate was similar in high-dose and low-dose groups with at least a 50% reduction in tumour size occurring in 32% of patients.10 The adverse effect of radiation on cognition and quality of life is an important part of the debate about radiotherapy and LGG. Of greatest concern to oncologists and patients with LGG is radiation encephalopathy, a neurobehavioural syndrome with some similarities to normal pressure hydrocephalus. Onset is delayed, commonly beginning months to years after the completion of radiotherapy. Patients typically have personality changes, impaired gait and balance, urinary incontinence, and declines in attention, memory, and executive functioning.82 As a result, patients are commonly unable to maintain employment and overall quality of life is diminished. The syndrome is progressive and may culminate in death despite tumour control.82 Although the mechanism of injury has not been elucidated, demyelination and a small-vessel vasculopathy are suspected.82,83 No treatments are available; stimulants and acetylcholinesterase inhibitors are being investigated.8486 Clinical improvement with CSF diversion has been reported87 although the improvement may not be sustained.82 Risk factors for radiation encephalopathy include treatment and patient-related parameters. The larger the volume of brain irradiated, the greater the risk of toxicity. Patients treated with whole-brain radiotherapy have a high incidence of radiation encephalopathy.80,88 Risk of radiation encephalopathy is also associated with high total-radiation dose10,89 and large fraction size.88 Current practice of targeting the tumour with a small
Reference 10 63 79 Treatment (dose/fractions) 504/28 648/36 45/25 594/33 54/30 Number of patients 101 102 171 172 140 150 % 5 year PFS 55 52 47 50 37* 44 % 5 year OS 72 65 58 59 66 63 Median follow-up (months) 768 74 60

PFS=progression-free survival; OS=overall survival. *p 005.

Table 3: Prospective randomised studies of radiation treatment of LGG

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surrounding margin reduces treatment volumes and minimises the exposure of normal brain to radiation. Unfortunately, the inltrative nature of LGG at times necessitates large treatment elds even when focal strategies are used. Modern regimens that incorporate total doses of less than 60 Gy and fraction sizes of less than 2 Gy have minimised but not eliminated this complication. Children irradiated within the rst decade of life have a higher rate of learning disabilities than those irradiated at an older age. People older than 60 years develop radiographic evidence of injury sooner and more severely than younger patients.88,89 Comorbidities (eg, hypertension, stroke, diabetes, and degenerative brain) and concomitant chemotherapy may predispose patients to radiation encephalopathy.90 The effect of radiotherapy on cognitive status and quality of life in patients with LGG is uncertain because the available data have several limitations. Studies commonly included tumours other than gliomas,80,91 and gliomas of higher or lower grade.89,92,93 Most studies were small and occasionally included paediatric patients and patients treated with chemotherapy. Methods of neuropsychological assessment and grading of imaging abnormalities varied. Few studies included an untreated LGG control group.94,95 Treatment regimens were heterogeneous both within and between studies, with some series including patients treated with whole brain radiotherapy.80,88,92,94,96 Quality-of-life assessment was rarely done. Information about the outcomes of patients with LGG who are treated with radiotherapy continues to grow. Patients with LGG have worse cognition than healthy controls and patients with systemic cancers regardless of treatment.94,95 Most studies failed to identify a statistically signicant, detrimental effect of radiotherapy on outcome. Surma-aho and colleagues92 noted that 28 patients receiving postoperative radiotherapy (19 of whom received whole-brain elds and 9 of whom received focal therapy) did worse on several cognitive tests than those who deferred treatment. Vigliani and colleagues93 noted that patients treated with focal radiotherapy have slower reaction times and a lower rate of employment during the year after treatment than those who deferred treatment. In addition, mean scores in ten of 12 additional test batteries were lower among those treated with radiotherapy postoperatively. By 1 year, the groups were similar. Up to 4 years posttreatment, no additional differences were present. Selective decline in visual memory, beginning at 5 years post-treatment, was noted by Armstrong and colleagues.91 No other differences between pre-treatment and post-treatment cognitive status were found. Other studies failed to show an adverse effect of radiotherapy on cognition. In fact, radiotherapy was associated with improved cognition in some studies.91,93,94,97 Radiotherapy had no effect on quality of life.81

The adverse effects of radiotherapy can also be assessed radiographically. Chronically, radiotherapy is associated with diffuse cerebral atrophy and lesions within the white matter. Hypolucencies on CT and T2 hyperintensities on MRI, typically within the treatment elds, suggest white-matter lesions.89,91 Abnormalities are more common in patients treated with whole-brain radiotherapy. A relation between radiographic abnormalities and cognition was present in studies that included a large proportion of patients treated with whole-brain radiotherapy.88,92 On the contrary, this correlation was not present in studies composed predominantly of patients treated with focal regimens.89,91 Although early radiotherapy does not affect the overall survival of all patients with LGG, some subgroups of patients may benet from early treatment. Several studies noted that patients over age 40 years beneted from radiotherapy more than younger patients.98101 Also, patients with a large volume of residual tumour may benet from postoperative radiotherapy relative to those treated with a gross total resection.98,102 Tumours with a high proliferative index, substantial enhancement, or aggressive histological subtypes, such as the grade II gemistocytic astrocytoma, may benet from early treatment. Prospective study of these factors has not been reported.

Chemotherapy
Until recently, chemotherapy was thought to be of only small benet in the treatment of patients with gliomas. In the late 1980s, anaplastic oligodendrogliomas, with or without an astrocytic component, were recognised to be chemosensitive.103 Identication of genetic markers that predicted a better response to chemotherapy further increased interest in this type of treatment.104 Several phase II trials of procarbazine, lomustine, and vincristine (PCV) or temozolomide in the treatment of new, progressive, or recurrent LGG have been done (table 4).105112 Follow-up was short and radiographic response was the primary endpoint. Comparison between studies was difcult because inclusion criteria varied. Patients with enhancing lesions, possibly reecting high-grade pathology, were more responsive to chemotherapy than those without.105,111 A similar response rate was noted for astrocytomas and oligodendroglial tumours.106,111,112 Resolution of focal neurological decits and improvement in seizure frequency and quality of life were reported in responders and those with stable disease.105,109,111114 Chemotherapy was effective in previously treated and untreated patients.107,108,112 Although LGG with deletion of chromosome 1p and 19q may be more sensitive to treatment,109,115 tumours without these deletions were also responsive to chemotherapy.114 The most extensively studied drugs are PCV and singleagent temozolomide. Lomustine is associated with
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Study 105 106 107 108 109 110 111 112

Pathology Oligodendroglioma, oligoastrocytoma Astrocytoma, oligodendroglioma, oligoastrocytoma Oligodendroglioma, oligoastrocytoma Oligodendroglioma, oligoastrocytoma Oligodendroglioma, oligoastrocytoma Oligodendroglioma, oligoastrocytoma Astrocytoma, Oligodendroglioma, oligoastrocytoma Astrocytoma, Oligodendroglioma, oligoastrocytoma

Chemotherapy PCV Temozolomide Temozolomide Temozolomide Temozolomide PCV; radiotherapy Temozolomide Temozolomide

% previous radiotherapy 42 15 100 100 0 0 0 70

% previous CT 0 22 0 100 0 0 0 37

% contrast enhancement 73 70 100 100 11 43 0 61

1-year PFS 80* 76 40 11 73 91 92* 39

% radiographic response 62 61 53 22 17 29 10 47

PFS=progression-free survival. *Estimated; regression.

Table 4: Phase II studies of chemotherapy in LGG

substantial cumulative myelotoxicty and uncommonly irreversible pulmonary injury. Procarbazine produces putative weak monoamine-oxidase-inhibitor activity, and patients taking this drug should be given dietary restrictions. Vincristine, an intravenous chemotherapy, may result in neuropathy and ileus. Patients are commonly unable to complete scheduled treatment despite tumour stability.110,114 Temozolomide, an oral alkylating drug with good bioavailability and CNS penetration, is generally well tolerated.116 Substantial toxicity occurs in less than 10% of patients and cumulative toxicity has not been reported. A standard regimen, adopted from use in high-grade gliomas, is dosing on days 15 of a 28 day cycle. Alternatively, a protracted course of low-dose temozolomide, given on days 121 of a 28 day cycle, has been used. This regimen provides 158 times greater drug exposure over 4 weeks than the standard regimen, and it depletes the DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase, thereby theoretically decreasing drug resistance.117 A protracted course of low-dose temozolomide may also interfere with tumour angiogenesis.118 The favourable side-effect prole and ease of use of temozolomide have made it the drug of choice. Although comparative studies have not been reported, the efcacy of the regimens seems similar.

The future
Many issues are unresolved in the management of LGG. Chemotherapy is emerging as an alternative to radiotherapy as a neoadjuvant treatment. Whether chemotherapy is more effective than up-front radiotherapy is unknown, as is optimum timing of intervention. Ideally, risk stratication from clinical, radiographic, and tumour factors would identify patients who would benet from early treatment. Although this approach is used in practice, it has yet to be proven. Molecular markers may allow oncologists to tailor treatment to a particular patient. For example, promotor hypermethylation of O6-methylguanine-DNA methyltransferase, a gene that encodes a DNA repair enzyme, has been associated with better response to temozolomide in high-grade gliomas.119 Whether it confers the same benet in LGG is to be determined. Other markers of tumour behaviour and responsiveness, such as 1p/19q status, need to be investigated further. Therapies that specically target molecular and genetic abnormalities within neoplastic cells are emerging. The advantage of non-cytotoxic strategies is that they specically target tumour cells while minimising toxicity. Currently, such strategies are being explored in high-grade gliomas. Alternative modes of chemotherapy delivery, such as delivery of drugs via catheters surgically placed in the vicinity of
Stratication End points 3 year overall survival; PFS; toxicity PFS

Inclusion RTOG Phase II trial of previously untreated high-risk* patients with grade II inltrating gliomas Phase III trial of adults with untreated progressive or recurrent grade II gliomas Proposed phase III trial of adults with symptomatic (with exception of wellcontrolled seizures) or progressive grade II gliomas

Treatment Radiation (5400 cGy in 30 fractions) with concomitant daily temozolomide (75 mg/m2) followed by 12 cycles standard temozolomide Patients randomised to radiation (5040 cGy in 28 fractions) or temozolomide (75 mg/m2) on days 1 through 21 of 28 day cycle Patients randomised to radiation (5040 cGy in 28 fractions) with or without concomitant temozolomide (75 mg/m2 during radiotherapy) followed by standard temozolomide

EORTC

1p status; age ( 40 years or 40 years); contrast enhancement; performance status 1p/19q status; age ( 40 years or 40 years); postoperative tumour size ( or 5 cm); performance status

ECOG/ NCCTG

PFS; survival; quality of life

RTOG=radiation therapy oncology group; EORTC=European Organisation for Research and Treatment of Cancer; ECOG/NCCTG=Eastern Cooperative Oncology Group/North Central Cancer Treatment Group; PFS=progression-free survival. *High risk=three of these features: age 40; tumour 6 cm or crossing midline; astrocytoma or astrocytic predominant mixed glioma; zubrod 02; preoperative NFS 1.

Table 5: Ongoing and proposed large phase II and III trials of LGG

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Search strategy and selection criteria We identied references by searching MEDLINE (1966 to 2005) in March 2005 for low-grade glioma, radiotherapy, chemotherapy, surgery, and molecular genetics. Although all studies that included patients treated after the introduction of CT were considered, preference was given to studies published after 1995 and to prospective studies. Only studies published in English and focusing on LGG were considered. References were also identied from relevant articles and through searches of our les.

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the tumour, and the targeting of tumour cells via a viral vector are also being explored in high-grade gliomas. Whether these approaches may benet patients with LGG is unknown. Several clinical trials designed to explore some of these issues are ongoing (table 5).
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