Long‐term side effects of radiotherapy, with or without chemotherapy, for glioma
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
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).
Background
Description of the condition
Brain and other central nervous system (CNS) tumours are less common than many other cancers, accounting for around 1.9% of new cancer diagnoses annually; however, they are associated with a higher proportion of cancer deaths, approximately 2.3% or 189,382 deaths worldwide in 2012 (GLOBOCAN 2012). Gliomas are brain tumours that arise from glial cells, usually oligodentrocytes and astrocytes. They occur at an annual incidence of four to 11 people per 100,000 and are more frequent in high‐income, industrialised countries (Ohgaki 2009). Gliomas are graded 1 to 4 by the World Health Organization (WHO) according to their aggressive potential in the near term. The 2007 WHO classification system (Louis 2007), used in completed clinical trials since 2007, graded gliomas based on histological characteristics only. However, in the 2016 WHO classification system, to be used in future trials, grading depends on both histological and molecular features, e.g. isocitrate dehydrogenase (IDH) status, chromosome 1p 19q, and other genetic parameters (Louis 2016). Using the 2007 WHO classification, gliomas graded 1 and 2 have low aggressive potential in the near term and are referred to as low‐grade gliomas (LGGs); these include pilocytic astrocytomas (grade 1), diffuse astrocytomas, oligodendrogliomas and mixed oligoastrocytomas (grade 2). High‐grade gliomas (HGGs) include anaplastic astrocytomas, anaplastic oligodendrogliomas (grade 3) and glioblastomas (grade 4). Grades correspond with prognosis. Grade 1 has a good prognosis and can often be cured with surgery alone, whereas grade 4 has a poor prognosis, and can be rapidly fatal (Louis 2007). Thus, tumour grade is a key factor in deciding how to treat gliomas, particularly the need for additional treatment in the form of radiotherapy (RT) or chemotherapy (CT), or both chemo‐radiotherapy (chemoRT) after surgery.
Description of the intervention
Most people with glioma first undergo surgery to resect or biopsy the tumour. The latter is usually performed when resection is not possible, either due to the diffuse, infiltrative nature of the tumour, or its location near important structures. Additional RT, targeting the tumour area (focal RT) is usually given immediately after surgery for HGGs, whereas for grade 2 gliomas it can either be given immediately, or postponed until the development of new symptoms or tumour progression (Sarmiento 2015). Fifty per cent of people with grade 2 and grade 3 gliomas survive at least seven years and four and a half years, respectively, after treatment (Buckner 2016; Cairncross 2013). However, for certain grade 2 and 3 gliomas with particular molecular features, median survival can be extended by a further seven years by the addition of CT to RT (Buckner 2016; Cairncross 2013). Approximately 25% of people with grade 4 gliomas that are treated with chemo‐radiotherapy are alive two years after diagnosis (Stupp 2005).
Radiation exposure of normal brain tissue adversely affects brain plasticity and repair processes (Dhermain 2016), therefore, the treatment of glioma can be complicated by long‐term side effects that present months or years after treatment. These may cause particular problems in people who survive to be followed up in the long term, as the frequency of side effects increases with time. Long‐term side effects include neurocognitive, psychosocial and endocrine (hormonal) side effects, which are particularly common among survivors of childhood brain tumours (Grill 1999; Seaver 1994; Spiegler 2004; Williams 2018). Certain parts of the brain, including the hippocampus, fornix and corpus callosum, are more sensitive to irradiation (Connor 2017; Gondi 2012; Peiffer 2013). Therefore, factors that are important to the risk of long‐term side effects in glioma treatment are the site of the tumour, the volume of brain tissue irradiated, the RT fraction size and the total RT dose. Using chemotherapy with RT might add to the risk. Among adults treated for LGG, studies suggest that the risk of neurocognitive effects is increased when RT is administered to the whole brain (not done nowadays for gliomas) (Gregor 1996; Surma‐aho 2001), but not necessarily when RT is administered to the tumour area only (Brown 2003; Laack 2005; Taphoorn 1994; Vigliani 1996). Endocrine dysfunction affecting adrenal, gonadal and thyroid hormones can also occur due to RT damage to the hypothalamic‐pituitary axis (Taphoorn 1995). Whilst historically this was not thought to be a problem in adults (Taphoorn 1995), recent evidence suggests that it may be (Kyriakakis 2016), and in children it frequently leads to hypothyroidism, growth hormone deficiency and precocious puberty (Terashima 2013). Fatigue, disturbed sleep and depression are also commonly reported side effects of cancer therapy among people with primary brain tumours (Armstrong 2017).
Why it is important to do this review
The focus of clinical practice and of clinical trials of glioma treatment is on increasing survival among people with glioma. However, uncertainty about the possible long‐term side effects of treatment among people with gliomas that have a good prognosis remains a concern for clinicians, affected individuals, and their families. Furthermore, the impact of treatment on long‐term survivors' quality of life remains unclear.
In 2015, this topic was identified among the top 10 priority research questions in neuro‐oncology by the James Lind Alliance and the National Cancer Research Institute (NCRI) (JLA 2015). In view of these factors, and in the context of the current trend towards more aggressive early treatments (e.g. chemo‐radiotherapy) for LGGs, a Cochrane Review evaluating existing evidence on the long‐term effects of RT (with or without chemotherapy) would be helpful to inform individual decisions around glioma treatment options.
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).
Methods
Criteria for considering studies for this review
Types of studies
Randomised and non‐randomised trials, and controlled before‐and‐after studies (CBAS). We will consider non‐randomised trials and CBAS for inclusion if the primary outcome data from randomised trials is inadequate. We will exclude cross‐over designs, case‐control studies, and studies that do not have a control group.
Types of participants
People aged 16 years of age and older with a histopathologically confirmed diagnosis of cerebral glioma who are alive at least two years after diagnosis.
In this review, as we consider late effects to be those that are present at two years or more after diagnosis in people who have a good long‐term prognosis, rather than in those that have a short‐term prognosis, we will exclude studies only involving people with glioblastoma. In studies with mixed HGG participants (grade 3 and grade 4 gliomas) we will attempt to extract data for the participants with grade 3 glioma only.
Types of interventions
Treatment interventions after surgery (biopsy or resection of the tumour) will include the following.
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Radiotherapy (RT) compared with no RT, which includes the following comparison subgroups.
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RT versus no adjuvant treatment (NAT).
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Radiotherapy plus chemotherapy (chemoRT) versus NAT.
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RT versus chemotherapy (CT).
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ChemoRT versus CT.
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Low‐dose RT compared with high‐dose RT.
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ChemoRT versus RT.
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Stereotactic conformal RT (SCRT) compared with conventional RT.
Types of outcome measures
Studies must report the primary outcome in both the intervention and control groups at least two years after receiving the intervention.
Primary outcomes
Cognitive impairment (objective or subjective), as measured by an overall cognitive function score, a change over time score, or as a categorical outcome. We will also evaluate cognitive impairment as individual cognitive function domains, e.g. verbal fluency, processing speed, memory, attention, and executive functioning, using a standardised measurement tool, e.g. Mini Mental State Exam (MMSE), Cognitive Failures Questionnaire (CFQ).
Secondary outcomes
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Functional impairment or disability, as measured by an overall ability score, or as a change of ability over time score, or both, using a standardised measurement tool, e.g. Karnofsky Performance Status Scale, Neurological Functions Score; or as a categorical outcome, as defined by investigators
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Quality of life (QoL), as measured using a standardised questionnaire, e.g. the European Organisation for Research and Treatment of Cancer (EORTC) QLQ‐C30 or QLQ‐BN20 (specific for brain cancer), or the Functional Assessment of Cancer Therapy scale (FACT‐G (general) or FACT‐Br (specific for brain cancer))
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Endocrine dysfunction, as determined by use of hormonal treatment, or as defined by study investigators, or both
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Depression, as measured by a standardised scale, e.g. Hospital Anxiety and Depression Scale (HADS)
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Anxiety, as measured by a standardised scale, e.g. HADS
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Fatigue, according to Common Terminology Criteria for Adverse Events (CTCAE), or as defined by investigators
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Sleep disturbances, as defined by investigators
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Imaging evidence of physical deficit, e.g. general brain atrophy, white matter changes, radionecrosis, stroke
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Social outcomes (e.g. carer strain, relationship status, employment status)
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Second cancers
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Cost of care (as a brief economic commentary)
Search methods for identification of studies
Electronic searches
We will search the following databases.
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Cochrane Central Register of Controlled Trials (CENTRAL; latest issue), part of the Cochrane Library.
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MEDLINE (Ovid 1946 to date of search).
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Embase (Ovid 1980 to date of search).
Please refer to Appendix 1 for draft MEDLINE search strategies.
We will not apply language restrictions to any of the searches.
Searching other resources
We will search the following for ongoing trials.
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ClinicalTrials.gov (clinicaltrials.gov).
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International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch).
If we identify through these searches ongoing trials that have not been published, we will approach the principal investigators to ask for an update on the trial status and relevant data. We will use the related articles feature of PubMed and handsearch the reference lists of included studies to identify newly published articles and additional studies of relevance. We will search conference abstracts of the following journals.
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Journal of Clinical Oncology.
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International Journal of Radiation Oncology, Biology and Physics.
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Neurology.
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Neuro‐oncology.
Data collection and analysis
Selection of studies
The Information Specialist at the Gynaecological, Neuro‐oncology and Orphan Cancer Group (GNOC) will download all titles and abstracts retrieved by electronic searching to Endnote and remove duplicates and those studies that clearly do not meet the inclusion criteria. Two review authors (TL and another) will independently screen the remaining records and exclude studies that clearly do not meet the inclusion criteria. For potentially eligible references, copies of the full texts will be obtained and independently assessed for eligibility by at least two review authors (TL and at least one other). Disagreements will be resolved by discussion between the two review authors concerned and, if necessary, the other review authors will be consulted. We will use Covidence to facilitate this study selection process (Covidence 2018), and document reasons for exclusion.
Data extraction and management
Two review authors (TL and one other) will independently extract data from included studies to a pre designed data extraction form to include:
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author contact details
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country
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setting
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dates of participant accrual
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trial registration number/identification
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funding source
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participant inclusion and exclusion criteria
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study design and methodology
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study population and baseline characteristics
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number of participants enrolled/analysed
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age
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gender
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tumour grade/type
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type of surgery (biopsy or resection)
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other medication, e.g. anti‐epileptics and anti‐depressants (selective serotonin reuptake inhibitors (SSRIs))
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intervention details
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type of intervention
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type of comparator
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duration of follow‐up
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primary outcome/s of the study
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review outcomes
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for dichotomous outcomes, we will extract the number of participants in each treatment arm who experienced the outcome of interest and the number of participants assessed
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for continuous outcomes, we will extract the value and standard deviation of the outcome of interest and the number of participants assessed at the relevant time point in each group. We will also extract change‐from‐baseline score data where reported and note the type of scale used
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we will extract adjusted statistics where reported
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where possible, all data extracted will be those relevant to an intention‐to‐treat analysis, in which participants were analysed in the groups to which they were assigned
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we will resolve differences between reviewers by discussion or by appeal to the other review authors when necessary
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risk of study bias (see below).
Assessment of risk of bias in included studies
For randomised trials, we will assess the risk of bias using Cochrane's tool and the criteria specified in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This includes assessment of:
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random sequence generation;
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allocation concealment;
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blinding of participants and healthcare providers;
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blinding of outcome assessors;
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incomplete outcome data (more than 20% missing data considered high risk);
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selective reporting of outcomes;
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other possible sources of bias, e.g. lack of a power calculation, baseline differences in group characteristics.
For non‐randomised studies (non‐randomised trials and CBASs), we will assess the risk of bias in accordance with four criteria concerning sample selection comparability of treatment groups, namely:
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relevant details of criteria for assignment of people with the condition to treatments;
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representative group of people with the condition who received the experimental intervention;
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representative group of people with the condition who received the comparison intervention;
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baseline differences between groups controlled for, in particular with reference to age, gender, type and grade of glioma and surgical treatment.
Two review authors (TL and at least one other) will assess risk of bias independently and will resolve differences by discussion or by appeal to a third review author. We will summarise judgements in 'Risk of bias' tables along with the characteristics of the included studies. We will interpret results of meta‐analyses in light of the overall 'Risk of bias' assessment. For more details about the assessment of risk of bias, see Appendix 2.
Measures of treatment effect
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For dichotomous outcomes, we will calculate the effect size as a risk ratio (RR) with its 95% confidence interval (CI).
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For continuous outcomes (e.g. QoL scores) in which different measurement scales have been used, we will estimate the standardised mean difference (SMD) and its 95% CI for pooled data. However, if the same measurement scale is used, we will estimate the mean difference (MD) and its 95% CI. If studies do not report total values but, instead, report change‐from‐baseline outcomes, we will attempt to combine these change values with total measurement outcomes by using the (unstandardised) mean difference method in Review Manager (RevMan) (Review Manager 2014). We will use subgroups to distinguish between MDs of change scores and MDs of final values, and pool the subgroups in an overall analysis (Higgins 2011).
Unit of analysis issues
At least two review authors (TL, RG) will review unit of analysis issues according to Higgins 2011 for each included study; we will resolve differences by group discussion. These include reports where there are multiple observations for the same outcome, e.g. repeated measurements with different scales, or outcomes measured at different time points to those stipulated in the review protocol.
Dealing with missing data
We will not impute missing data. In the event of missing data, we will write to study authors to request the data and describe in the 'Characteristics of included studies' tables how we obtained any missing data. Where missing data are substantial, this will be taken into consideration in our grading of the evidence (see Data synthesis).
Assessment of heterogeneity
We will assess heterogeneity between studies in each meta‐analysis by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001), and, where possible, by subgroup analyses. If there is evidence of substantial heterogeneity, we will investigate and report the possible reasons for this.
Assessment of reporting biases
If there are 10 or more studies in meta‐analyses we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
Data synthesis
We will conduct meta‐analyses if we judge participants, comparisons and outcomes to be sufficiently similar to ensure an answer that is clinically meaningful. We will use the random‐effects model with inverse variance weighting for all meta‐analyses. If any trials contributing to a meta‐analysis have multiple intervention groups, we will divide the 'shared' comparison group into the number of treatment groups and comparisons between each treatment group and treat the split comparison group as independent comparisons. We will perform a meta‐analysis of the results assuming that we find at least two included studies that are sufficiently similar for the findings to be clinically meaningful. When a meta‐analysis is not possible, e.g. due to the availability of single studies only, or due to studies reporting findings in different ways, where possible we will enter available data into RevMan without totals (Review Manager 2014), and report the unpooled findings narratively.
'Summary of findings' table and results reporting
Based on the methods described in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we will prepare a 'Summary of findings' table to present the results of the following outcomes (Table 1).
| Radiotherapy compared with no radiotherapy for glioma: long‐term side effects | ||||||
| Patient or population: people with glioma surviving at last two years Settings: tertiary care Intervention: radiotherapy Comparison: no radiotherapy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No radiotherapy | Radiotherapy | |||||
| Cognitive impairment at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| QoL score at ≥ 2 years | The mean [outcome] ranged across control groups from | The mean [outcome] in the intervention groups was | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | ||
| Functional impairment at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| Endocrine dysfunction at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| Depression at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| Fatigue at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
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Cognitive impairment at ≥ 2 years.
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Functional impairment at ≥ 2 years.
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Quality of life (QoL) score at ≥ 2 years.
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Endocrine dysfunction at ≥ 2 years.
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Depression at ≥ 2 years.
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Fatigue at ≥ 2 years.
We will also include evidence for these outcomes measured at later annual time points in the 'Summary of findings' table if available.
We will use the GRADE system to rank the quality of the evidence (Schünemann 2011). Two review authors will independently grade the evidence. Differences will be resolved by discussion and, if necessary, by involving a third review author. Where the evidence is based on single studies, or where there is no evidence on a specific outcome, we will include the outcome in the 'Summary of findings' tables and grade or explain accordingly. We will consider downgrading evidence limited to a single small study, irrespective of the estimate of effect. In addition, we will provide a rationale for each judgement of assumed risk in the table footnotes. We will also grade narrative summaries of outcomes for which meta‐analysis is not possible, due to the different ways that investigators have reported or measured outcomes, using a GRADE working group approach (Murad 2017). We will interpret the results of the graded evidence based on Cochrane Effective Practice and Organisation of Care guidance (EPOC 2017).
Brief economic commentary
We will develop a brief economic commentary (BEC) based on current methods guidelines (Shemlit 2011a; Shemlit 2011b), to summarise the availability and principal findings of trial‐based and model‐based economic evaluations (cost analyses, cost‐effectiveness analyses, cost‐utility analyses, and cost‐benefit analyses) that compare the use of different treatments for gliomas. We will identify relevant studies for this BEC during searches conducted for the intervention review and during supplementary searches performed in accordance with search strategies developed by the Economics Methods Group (Shemlit 2017). This commentary will focus on the extent to which principal findings of eligible economic evaluations indicate that an intervention might be judged favourably (or unfavourably) from an economic perspective, when implemented in different settings.
Subgroup analysis and investigation of heterogeneity
For the comparison 'RT versus no RT', we will perform a subgroup analysis according to the type of control group. We will use formal tests for subgroup differences to determine whether the effect of interventions differ according to these subgroups. Depending on these findings, we will consider whether an overall summary is meaningful. We will consider factors such as age, gender, treatment regimen, and risk of bias in interpretation of any heterogeneity. If we identify substantial heterogeneity, we will investigate it in sensitivity analyses.
Sensitivity analysis
We will perform a sensitivity analysis to investigate substantial heterogeneity identified in meta‐analyses of the primary outcome, and also to estimate the effect after excluding studies at high risk of bias, to investigate how trial quality affects the certainty of the findings.
| Radiotherapy compared with no radiotherapy for glioma: long‐term side effects | ||||||
| Patient or population: people with glioma surviving at last two years Settings: tertiary care Intervention: radiotherapy Comparison: no radiotherapy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No radiotherapy | Radiotherapy | |||||
| Cognitive impairment at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| QoL score at ≥ 2 years | The mean [outcome] ranged across control groups from | The mean [outcome] in the intervention groups was | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | ||
| Functional impairment at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| Endocrine dysfunction at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| Depression at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| Fatigue at ≥ 2 years | [value] per 1000 | [value] per 1000 | RR [value] ([value] to [value]) | [value] | [Delete as ⊕⊝⊝⊝ ⊕⊕⊝⊝ ⊕⊕⊕⊝ ⊕⊕⊕⊕ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
