Elsevier

The Lancet

Volume 360, Issue 9343, 2 November 2002, Pages 1361-1368
The Lancet

Articles
Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study

https://doi.org/10.1016/S0140-6736(02)11398-5Get rights and content

Summary

Background

Because survival benefits of treatment with radiotherapy are questionable and such treatment can cause substantial damage to the brain over time, the optimum management strategy for low-grade gliomas remains controversial. We aimed to identify the specific effects of radiotherapy on objective and self-reported cognitive function, and on cognitive deterioration over time, in patients with low-grade gliomas treated with early radiotherapy.

Methods

195 patients with low-grade glioma (of whom 104 had received radiotherapy 1–22 years previously) were compared with 100 low-grade haematological patients and 195 healthy controls. Our analyses aimed to differentiate between the effects of the tumour (eg, disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, antiepileptic drugs) on cognitive function and on relative risk of cognitive disability.

Findings

Low-grade glioma patients had lower ability in all cognitive domains than did low-grade haematological patients, and did even less well by comparison with healthy controls. Use of radiotherapy was associated with poorer cognitive function; however, cognitive disability in the memory domain was found only in radiotherapy patients who received fraction doses exceeding 2 Gy. Antiepileptic drug use was strongly associated with disability in attentional and executive function.

Interpretation

Our findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used. Additionally, the effects of other medical factors, especially antiepileptic drug use, on cognitive function in glioma patients deserve attention.

Introduction

Among adult cancer patients, patients with gliomas (ie, primary brain tumours arising from glial tissue) form a minority. Compared with lung and breast cancer, which have rates of about 60 per 100 000 in the Netherlands, the rate of gliomas is tenfold lower, with about 1000 new patients every year.1 Nevertheless, these cancers have a serious effect on the health-care system in general, and especially on patients and their families. Not only do glioma patients have to cope with the diagnosis of incurable disease, they and their families are usually also confronted with the patient's decrease in cognitive and emotional function as a result of cerebral disease.

Although the median survival of adult glioma patients with low-grade tumours is much longer than that of those with high-grade tumours, nearly all will die of their disease. In these patients, early treatment does not prolong survival,2 and no randomised prospective studies have been done to assess the effects of neurosurgery. Moreover, retrospective data on the role of neurosurgery in extended survival (as opposed to a policy of observation) are controversial.3

What is the role of early radiotherapy in these patients? Low-grade gliomas can be moderately responsive to radiotherapy,4 but the survival benefits of adjuvant radiotherapy after neurosurgery are debatable. Results of some retrospective studies suggest that early radiotherapy improves survival;5 other investigators have reported that it does not,6 or have shown that older patients might benefit most.5 Findings of several studies by the European Organisation for the Research and Treatment of Cancer (EORTC) clearly do not recommend early treatment with radiotherapy of patients with low-grade gliomas.7, 8

Apart from potential favourable survival effects, radiotherapy itself could negatively affect the patient's health-related quality of life through irreversible late-delayed brain damage induced by irradiation, ultimately resulting in cognitive deficits and dementia.9, 10 In long-term survivors of brain metastases from systemic cancer, and in patients with primary lymphoma of the central nervous system, treatment with whole-brain radiotherapy can lead to radiation-induced encephalopathy.11, 12 Partly because of these side-effects, standard treatment of glioma patients is based on focal radiotherapy rather than on whole-brain radiotherapy. Apart from a large radiotherapy treatment volume, high radiotherapy total and fraction dose, concomitant chemotherapy, and old age have been identified as potential risk factors for cognitive deterioration in glioma patients.9 The incidence of late-delayed encephalopathy in these patients is steadily increasing, not only because of increased survival but also because of improved detection (neuroimaging and extensive cognitive function testing) and raised awareness among physicians and patients.9

With 5-year and 10-year progression-free rates of 50% and 12%, respectively, for supratentorial low-grade astrocytomas, low-grade oligodendrogliomas, and mixed gliomas,13 and a median better survival of 16–7 years for the latter two groups,14 patients with low-grade gliomas can survive in a stable state for several years after diagnosis. The long-term cognitive and psychosocial sequelae of the disease and its treatment in these longterm survivors are especially salient. In 1994, we showed serious cognitive deficits in low-grade glioma patients, which, surprisingly, could not be attributed to focal radiotherapy.15. Here, we present results from a nationwide study with a larger group of such patients and with the use of a more extensive cognitive test battery than in our previous report.

We aimed to delineate changes in cognitive function and cognitive disability as defined by the WHO International Classification of Functioning, Disability and Health (ICIDH-2).16 ICIDH-2 components of function and disability can be expressed in two ways. They can be used to indicate non-problematic aspects of health and health-related states, summarised under the umbrella term functioning; or they can indicate problems (eg, impairment, activity limitation, or participation restriction), summarised under the umbrella term disability.

In line with our previous research, we aimed to establish the effect of the tumour (ie, duration of disease, tumour lateralisation) and of treatment (ie, neurosurgery, radiotherapy, antiepileptic drugs) on the mid-to-long-term cognitive function of patients with low-grade glioma. Since we postulated that reductions in cognitive function caused by radiation therapy increase over time, the long-term effect of radiotherapy received special attention. Furthermore, we aimed to find out whether, because the central nervous system is implicated, braintumour patients have more extensive cognitive deficits than patients with cancer outside the brain. Cognitive function in patients with non-brain tumours is thought to be compromised by the psychological effect of cancer. Additionally, we tested the hypothesis that especially in brain-tumour patients, there is a dissociation between subjective cognitive complaints and observed cognitive functioning.

With the ICIDH-2 classification in mind, we first defined the extent of restrictions in cognitive function in glioma patients by comparison with patient controls and with healthy controls, and by identification of tumour and treatment characteristics related to cognitive functioning. Subsequently, we investigated which tumour-related and treatment-related characteristics were associated with increased risk of cognitive disability.

Section snippets

Patients and methods

In this multicentre study, we recruited low-grade glioma patients and patients with low-grade haematological cancers who had (a) no clinical signs of tumour recurrence for at least 1 year after the histological diagnosis and primary treatment, and (b) no radiological signs of recurrence within 3 months before testing. Patients were recruited from neurosurgical centres throughout the Netherlands (listed in the acknowledgments section). Between these centres, therapeutic policies differed as to

Results

195 adult patients with supratentorial low-grade gliomas were recruited between February, 1997, and January, 2000, of whom 104 (53%) had received radiotherapy 1–22 years previously. Focal radiotherapy, with a margin of 2 cm around the lesion seen by CT or MRI, was mostly used. In several centres, a boost radiation dose, limited to the tumour volume, was given alongside focal radiotherapy. About 10% of patients had whole-brain radiotherapy, with or without boost. The main reason for whole-brain

Discussion

We have shown that both irradiated and non-irradiated low-grade glioma patients have significantly poorer cognitive functioning than do NHL/CLL patients and, moreover, that these deficiencies are not restricted to a single cognitive domain. Disturbances of cognitive function in glioma patients are even more pronounced when compared with matched healthy controls.

These results are in accord with our previous work, which showed that the tumour itself, rather than irradiation, adversely affects

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