Long-term effects of radiotherapy for glioma treatment on brain functioning

Background
Gliomas are brain tumours that can be very aggressive and result in death within months; however, people with less aggressive gliomas (low-grade gliomas) can survive for a number of years. Most people are treated with surgery and may also receive radiotherapy with or without chemotherapy. However, radiotherapy can damage healthy brain tissue, and we do not know enough about the possible long-term effects of radiotherapy on brain functioning, such as memory, communication, concentration and speed of thinking (called neurocognition). Progression of the tumour can also cause deterioration in brain functioning. In this review we looked at the possible long-term effects of radiotherapy on the brain in adults with less aggressive gliomas who had survived for at least two years after receiving treatment.

Methods and results
We searched for relevant research studies up to 14 November 2018. We only included studies with a control group (i.e. studies that included groups of people that had or had not received radiotherapy or had received different types or doses of radiotherapy). The review includes nine research studies that collected information on long-term neurocognitive or quality of life outcomes, mostly among people with low-grade gliomas. Altogether 2406 participants were involved in these studies. The studies looked at five different comparisons including radiotherapy versus no radiotherapy, radiotherapy versus chemotherapy, high- versus low-dose radiotherapy, different types of radiotherapy, and radiotherapy versus chemoradiotherapy. Some evidence suggested that radiotherapy might increase the risk of cognitive impairment compared with no radiotherapy after surgery; however, this and evidence for the other comparisons was not convincing. This was partly because many of the people were not followed up, either because they had died or their disease had progressed, and so the resulting evidence was weak.

No studies compared effects of radiotherapy on relevant hormone functioning; we planned to develop a brief economic commentary to summarise information on whether the interventions represented a good use of health services but found no relevant studies.

Conclusions
The risk of long-term deterioration in brain functioning associated with radiotherapy for the treatment of less aggressive gliomas remains uncertain. Further research on glioma treatment options should assess potential long-term cognitive and hormonal side effects, costs and value for money.

Authors' conclusions: 

Radiotherapy for gliomas with a good prognosis may increase the risk of neurocognitive side effects in the long term; however the magnitude of the risk is uncertain. Evidence on long-term neurocognitive side effects associated with chemoradiotherapy is also uncertain. Neurocognitive assessment should be an integral part of long-term follow-up in trials involving radiotherapy for lower-grade gliomas to improve the certainty of evidence regarding long-term neurocognitive effects. Such trials should also assess other potential long-term effects, including endocrine dysfunction, and evaluate costs and cost effectiveness.

Read the full abstract...
Background: 

Gliomas are brain tumours arising from glial cells with an annual incidence of 4 to 11 people per 100,000. In this review we focus on gliomas with low aggressive potential in the short term, i.e. low-grade gliomas. Most people with low-grade gliomas are treated with surgery and may receive radiotherapy thereafter. However, there is concern about the possible long-term effects of radiotherapy, especially on neurocognitive functioning.

Objectives: 

To evaluate the long-term neurocognitive and other side effects of radiotherapy (with or without chemotherapy) compared with no radiotherapy, or different types of radiotherapy, among people with glioma (where 'long-term' is defined as at least two years after diagnosis); and to write a brief economic commentary.

Search strategy: 

We searched the following databases on 16 February 2018 and updated the search on 14 November 2018: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11) in the Cochrane Library; MEDLINE via Ovid; and Embase via Ovid. We also searched clinical trial registries and relevant conference proceedings from 2014 to 2018 to identify ongoing and unpublished studies.

Selection criteria: 

Randomised and non-randomised trials, and controlled before-and-after studies (CBAS). Participants were aged 16 years and older with cerebral glioma other than glioblastoma. We included studies where patients in at least one treatment arm received radiotherapy, with or without chemotherapy, and where neurocognitive outcomes were assessed two or more years after treatment.

Data collection and analysis: 

Two review authors independently extracted data and assessed risk of bias. We assessed the certainty of findings using the GRADE approach.

Main results: 

The review includes nine studies: seven studies were of low-grade glioma and two were of grade 3 glioma. Altogether 2406 participants were involved but there was high sample attrition and outcome data were available for a minority of people at final study assessments. In seven of the nine studies, participants were recruited to randomised controlled trials (RCTs) in which longer-term follow-up was undertaken in a subset of people that had survived without disease progression. There was moderate to high risk of bias in studies due to lack of blinding and high attrition, and in two observational studies there was high risk of selection bias. Paucity of data and risk of bias meant that evidence was of low to very low certainty. We were unable to combine results in meta-analysis due to diversity in interventions and outcomes.

The studies examined the following five comparisons.

Radiotherapy versus no adjuvant treatment
Two observational studies contributed data. At the 12-year follow-up in one study, the risk of cognitive impairment (defined as cognitive disability deficits in at least five of 18 neuropsychological tests) was greater in the radiotherapy group (risk ratio (RR) 1.95, 95% confidence interval (CI) 1.02 to 3.71; n = 65); at five to six years the difference between groups did not reach statistical significance (RR 1.38, 95% CI 0.92 to 2.06; n = 195). In the other study, one subject in the radiotherapy group had cognitive impairment (defined as significant deterioration in eight of 12 neuropsychological tests) at two years compared with none in the control group (very low certainty evidence).

With regard to neurocognitive scores, in one study the radiotherapy group was reported to have had significantly worse mean scores on some tests compared with no radiotherapy; however, the raw data were only given for significant findings. In the second study, there were no clear differences in any of the various cognitive outcomes at two years (n = 31) and four years (n = 15) (very low certainty evidence).

Radiotherapy versus chemotherapy
One RCT contributed data on cognitive impairment at up to three years with no clear difference between arms (RR 1.43, 95% CI 0.36 to 5.70, n = 117) (low-certainty evidence).

High-dose radiotherapy versus low-dose radiotherapy
Only one of two studies reporting this comparison contributed data, and at two and five years there were no clear differences between high- and low-dose radiotherapy arms (very low certainty evidence).

Conventional radiotherapy versus stereotactic conformal radiotherapy
One study involving younger people contributed limited data from the subgroup aged 16 to 25 years. The numbers of participants with neurocognitive impairment at five years after treatment were two out of 12 in the conventional arm versus none out of 11 in the stereotactic conformal radiotherapy arm (RR 4.62, 95% CI 0.25 to 86.72; n = 23; low-certainty evidence).

Chemoradiotherapy versus radiotherapy
Two RCTs tested for cognitive impairment. One defined cognitive impairment as a decline of more than 3 points in MMSE score compared with baseline and reported data from 2-year (110 participants), 3-year (91 participants), and 5-year (57 participants) follow-up with no clear difference between the two arms at any time point. A second study did not report raw data but measured MMSE scores over five years in 126 participants at two years, 110 at three years, 69 at four years and 53 at five years. Authors concluded that there was no difference in MMSE scores between the two study arms (P = 0.4752) (low-certainty evidence).

Two RCTs reported quality of life (QoL) outcomes for this comparison. One reported no differences in Brain-QoL scores between study arms over a 5-year follow-up period (P = 0.2767; no raw data were given and denominators were not stated). The other trial reported that the long-term results of health-related QoL showed no difference between the arms but did not give the raw data for overall HRQoL scores (low-certainty evidence).

We found no comparative data on endocrine dysfunction; we planned to develop a brief economic commentary but found no relevant economic studies for inclusion.

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