Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation

Julia Day; Karolis Zienius; Karin Gehring; David Grosshans; Martin Taphoorn; Robin Grant; Jing Li; Paul D Brown

doi:10.1002/14651858.CD011335.pub2

. 2014 Dec 18;2014(12):CD011335. doi: 10.1002/14651858.CD011335.pub2

Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation

Julia Day ^1,^✉, Karolis Zienius ¹, Karin Gehring ², David Grosshans ³, Martin Taphoorn ⁴, Robin Grant ¹, Jing Li ³, Paul D Brown ⁵

PMCID: PMC6457828 PMID: 25519950

Abstract

Background

Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non‐pharmacological treatment of cognitive deficits in this population is unclear.

Objectives

To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adult patients treated with cranial irradiation.

Search methods

In August 2014. we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and PsycINFO and checked the reference lists of included studies. We also searched for ongoing trials via ClinicalTrials.gov, the Physicians Data Query and the Meta Register of Controlled Trials.

Selection criteria

We included randomised controlled trials (RCTs) that evaluated pharmacological or non‐pharmacological interventions in cranial irradiated adults, with objective cognitive functioning as a primary or secondary outcome measure.

Data collection and analysis

Two review authors (JD, KZ) independently extracted data from selected studies and carried out a 'Risk of bias' assessment. Cognitive function, fatigue and mood outcomes were reported. No data were pooled.

Main results

Sixteen studies were identified for possible inclusion in the review, six of which were included. Three studies investigated prevention and three studies investigated amelioration. Due to differences between studies in the interventions being evaluated, a meta‐analysis was not possible. Two studies investigated a pharmacological intervention for the prevention of cognitive deficits; memantine compared with placebo, and d‐threo‐methylphenidate HCL compared with placebo. In the first study the primary cognitive outcome of memory at six months did not reach significance, but there was significant improvement in overall cognitive function compared to placebo, with similar adverse events across groups. The second study found no statistically significant difference between arms, with few adverse events. The third study investigated a rehabilitation program for the prevention of cognitive deficits but did not carry out a statistical comparison of cognitive performance between groups.

Three studies investigated the use of a pharmacological intervention for the treatment of cognitive deficits; methylphenidate compared with modafinil, two different doses of modafinil, and donepezil compared with placebo. The first study found improvements in cognitive function in both the methylphenidate and modafinil arms; few adverse events were reported. The second study combined treatment arms and found improvements across all cognitive tests, however, a number of adverse events were reported. Both studies were limited by a small sample size. The third study did not find an improvement in the primary cognitive outcome of overall performance, but did find improvement in an individual test of memory, compared to placebo; adverse events were not reported. No non‐pharmacological studies for the amelioration of cognitive deficits were eligible. There were a number of limitations across studies but few without high risks of bias.

Authors' conclusions

There is supportive evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation. There is supportive evidence that donepezil may have a role in treating cognitive deficits in adults with primary or metastatic brain tumours who have been treated with cranial irradiation. Patient withdrawal affected the statistical power of both studies. Further research that tries to minimise the withdrawal of consent, and subsequently reduce the requirement for imputation procedures, may offer a higher quality of evidence.

There is no strong evidence to support any non‐pharmacological interventions (medical or cognitive/behavioural) in the prevention or amelioration of cognitive deficits. Non‐randomised studies appear promising but are as yet to be conclusive via translation into high quality evidence. Further research is required.

Keywords: Adult, Humans, Benzhydryl Compounds, Benzhydryl Compounds/therapeutic use, Cognition Disorders, Cognition Disorders/etiology, Cognition Disorders/prevention & control, Cognition Disorders/therapy, Cranial Irradiation, Cranial Irradiation/adverse effects, Indans, Indans/therapeutic use, Memantine, Memantine/therapeutic use, Methylphenidate, Methylphenidate/therapeutic use, Nootropic Agents, Nootropic Agents/therapeutic use, Piperidines, Piperidines/therapeutic use, Randomized Controlled Trials as Topic

Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation

Background

Problems with mental activities (cognitive deficits) are common in patients who have received radiation to the brain for a primary or secondary (metastatic) brain tumour, or to help prevent a tumour spreading to the brain from elsewhere in the body. This toxic side effect of brain radiation may be acute (during treatment) or early after treatment (one to six months) and may be reversible. However, late toxicities may occur many months or years later and are generally irreversible and are slowly progressive. Late cognitive deficits, such as memory loss, problems planning tasks or behavioural changes, can have a serious impact on quality of life and the ability to carrying out activities normally. Interventions to help prevent or treat these late radiation toxicities may improve a patient's well‐being.

Study Characteristics

In August 2014 we searched four literature databases. Six randomised controlled trials (RCTs), in which patients were randomly assigned to the intervention or a comparison group (control group), were eligible for inclusion. Each trial assessed different interventions, so results were not combined. The largest trial investigated the medical drug memantine in 508 patients with a metastatic brain tumour. Another trial investigated donepezil in 198 patients with a primary or secondary brain tumour. The other trials were smaller and investigated modafinil and methylphenidate. We found one psychological intervention for preventing cognitive deficits during brain radiation. There is one ongoing medical drug trial recruiting participants. There were many non‐randomised and non‐controlled trials that offer promising results for further exploration using an RCT method.

Key findings

Findings into the efficacy of memantine offer supportive evidence for preventing cognitive deficits in patients with a secondary brain tumour receiving brain irradiation. Findings into the efficacy of donepezil offer some support for its use in the amelioration of cognitive deficits in patients with a primary or secondary tumour previously treated with radiation. The remaining studies did not have a sufficient number of participants to provide reliable results. The drugs used had few side effects (adverse events), although these were not reported well. Recruitment and retention of trial participants for these medical drug studies is difficult.

Quality of the evidence

We found limitations in the evidence across studies, most medical drug randomised controlled trials had a low risk of bias, whereas the psychological interventions were at a high risk of bias.

Background

Description of the condition

Cognition refers to the mental abilities that require the high‐level processing of sensory information. Such abilities include memory, executive function, thought, sensory perception, visuo‐spatial processing, concentration, attention, intellectual function, behaviour, personality and mood (Gilroy 2000). Cognitive dysfunction (or deficit) in any of these areas can have a significant impact on a person's ability to function in day‐to‐day life, including work performance, language and communication, social interactions and independent living (Meyers 1998).

Cognitive deficits are common among patients who have received cranial irradiation (Taphoorn 2004) to treat primary or metastatic brain tumours, or as prevention (prophylaxis) of other cancers. Both the brain tumour itself and tumour treatment can cause cognitive deficits (Taphoorn 2004). Over 80% of primary and metastatic brain tumour patients have self‐reported cognitive concerns regarding memory or concentration (Lidstone 2003; Mukand 2001). For example, in a prospective study, cognitive functioning was assessed objectively using neuropsychological testing in patients receiving cranial irradiation for the therapeutic treatment of brain metastases. Results demonstrated cognitive deficits in the domains of learning, delayed recall and recognition six to eight weeks following radiotherapy when compared to baseline scores (Welzel 2008). In another study, patients with lung cancer receiving prophylactic cranial irradiation demonstrated reduced cognitive functioning on subjective and objective measures at six‐ and 12‐month follow‐up assessments when compared to baseline scores (Gondi 2013). A randomised controlled trial (RCT) also documented significant cognitive deficits four months after whole brain radiotherapy (WBRT) compared to patients treated with radiosurgery alone (Chang 2009).

Neurotoxic effects of cranial irradiation

Radiation can be delivered to the brain injury using large focused doses (stereotactic radiation), as part of standard fractionated treatments, or to the whole brain (WBRT). Potential risk factors for cognitive decline following brain radiation include receiving fractionated radiation doses greater than 2 Gy, higher total radiation dose, larger brain volume of irradiation, using a divided‐dose schedule and longer overall treatment time (Lee 2002). Other risk factors may include either combined or subsequent chemotherapy use, age, with those fewer than seven years or greater than 60 years old at higher risk, and comorbid vascular risk factors such as diabetes and hypertension (Crossen 1994; Szerlip 2011). In the identification of treatment‐related neurotoxicity it is important to distinguish symptoms from tumour progression, recurrence or metastases, since continuation of treatment may lead to irreversible central nervous system (CNS) injury (Dietrich 2008).

The neurotoxic effects of brain radiation can be divided into acute, early‐delayed and late‐delayed radiation encephalopathy (Sheline 1980). Acute radiation encephalopathy occurs as a result of disruption to the blood‐brain barrier leading to accumulation of fluid in the tissue (vasogenic oedema). Corticosteroids are used at this stage, and may improve symptoms of somnolence and headache, and prevent further neurologic decline. Early‐delayed radiation encephalopathy may occur at one to six months following completion of treatment, and symptoms of short‐term memory and attentional deficits are seen alongside drowsiness and worsening of pre‐existing neurological deficits. A return to baseline is often found within 12 months (Vigliani 1996). This phase is associated with blood‐brain barrier disruption and with reversible damage to the myelin sheath (Sheline 1980). In contrast to early complications, late‐delayed radiation encephalopathy is viewed as irreversible. This complication occurs months to years following radiation therapy and manifests as white matter lesions (i.e. leukoencephalopathy). In more severe forms it can manifest or lead to a formation of dead brain tissue which, as a result, can lead to a pressure effect and associated neurological dysfunction (Fink 2012).

The precise relationship between initial acute changes and late/chronic radiation damage to the brain is unknown. Clinically, late radiation damage is characterised by progressive mental slowing and impairment in attention and memory, with less commonly gait ataxia, urinary incontinence, apathy, and pyramidal and extrapyramidal signs (Taphoorn 2003). These cognitive deficits increase in incidence and severity over time (Klein 2002). However the exact incidence is hard to distinguish due to the range of neuropsychological tests, the population and the time at which patients are followed up (Taphoorn 2004). For example, up to 90% of adult brain tumour patients who survive for more than six months following WBRT therapy develop (some form of) cognitive impairment (Crossen 1994), and in up to 5% of long‐term survivors the cognitive impairment progresses to dementia necessitating admission to a nursing home (DeAngelis 1989; Vigliani 1996). The incidence of severe cognitive deficits/late delayed radiation encephalopathy is even higher in patients with primary CNS lymphoma, reaching nearly 100% in patients older than 60 years old (Abrey 1998). Due to these adverse effects of cranial irradiation, the benefit of radiotherapy treatment for patients with a more favourable prognosis, such as with a low‐grade glioma (LGG), or as prophylactic cranial irradiation for small cell lung carcinoma, has been the subject of much debate in the past decade (Gondi 2013).

The mechanism of cranial irradiation‐induced cognitive impairment

The mechanisms by which radiation causes cognitive decline, particularly in learning and memory, have been proposed to relate to metabolic changes, white matter changes and radionecrosis, as well as changes in neuronal function, particularly synaptic plasticity, and long‐lasting damage to hippocampal neurogenesis (Greene‐Schloesser 2013). Of those, impaired white matter radiation changes and neurogenesis are the most thoroughly studied.

The primary mechanism of delayed radiation‐induced white matter changes is associated with secondary endothelial damage and microvascular ischaemic insult (Lyubimova 2004), accompanied by a reduction in the proliferative capacity of glial cells (van der Maazen 1993). This leads to a decrease in the volume of cerebral white matter, which is directly associated with cognitive decline (Correa 2004; Mulhern 2004; Reddick 2006). This has been confirmed in a longitudinal study that found medulloblastoma patients receiving a cranial irradiation dose of 36 Gy to show more rapid cerebral white matter volume decrease than those receiving a cranial irradiation dose of 23.4 Gy (Palmer 2002). Rarely, these white matter lesions can increase in size and may progress to frank white matter necrosis characterised by focal cavitations in the white matter within the radiated fields (Anscher 1991). Treatment of radionecrosis involves surgical excision and steroid therapy, and recent studies using bevacizumab, an angiogenesis inhibitor, have also reported high rates of clinical and radiological responses, albeit with small sample sizes (Gonzales 2007; Levin 2011; Torcuator 2009; Wang 2012).

Neurogenesis refers to self‐renewing cells that may produce neurons, glial cells and cells that give rise to restricted cell types (lineage‐restricted precursor cells) throughout life, associated with normal hippocampal functioning (Zhao 2008). This was explored in a post‐mortem study in patients with medulloblastoma that found significantly lower neurogenesis in patients treated with radiotherapy two to 23 years prior to analysis, compared to controls matched for age and sex (Monje 2007). Therefore, radiotherapy strategies that attempt to spare the crucial areas of neurogenesis may produce better cognitive outcomes, compared to WBRT (Dietrich 2008; Peiffer 2011), and are currently being conducted.

Measuring cognitive deficits

Wefel 2011 recommends a core battery of validated neuropsychological tests to assess cognitive function. These include the Hopkins Verbal Learning Test‐Revised (HVLT‐R) (Benedict 1998) to assess learning and memory, Trail Making Test (TMT), (Reitan 1992) to assess processing speed and executive function, and the Controlled Oral Word Association test of the Multilingual Aphasia Examination (COWA), (Benton 1989) to assess verbal fluency. Other tests have also been used, such as digit span and digit symbol (Wechsler 1981) to assess working memory. Cognitive function has also been assessed through the use of brief mental status evaluations, such as the Mini‐Mental State Examination (MMSE), (Folstein 1975). Whilst the MMSE is often shorter than neuropsychological testing, it has been associated with poor sensitivity in detecting cognitive deficits (Meyers 2003). Other studies have used subjective patient reports of cognitive concerns, such as in memory and concentration (Lidstone 2003; Mukand 2001). An additional consistent finding from the research literature is that correlations between subjectively assessed cognitive symptoms and objectively determined cognitive functioning are quite modest, with correlation coefficients generally ranging from 0.20 to 0.30 (Klein 2002).These are suggested to be confounded by some patients' lack of awareness regarding their cognitive impairments, and correlations with fatigue and depression, rather than cognitive test performance (Cull 1996).

Differences in the time points at which cognitive functioning is measured are also present, both in pharmacological and non‐pharmacological intervention studies. One study carried out assessments at baseline, and at four weeks of modafinil or methylphenidate use (Gehring 2012a), whereas another continued to follow up patients at eight, 16, 24 and 52 weeks following initiation of the drug memantine (Brown 2013). In cognitive rehabilitation studies, patients were assessed at baseline and at the end of a two‐week intervention and at three months (Locke 2008). These studies also demonstrate the variations in duration of the intervention.

The variations in tools available, use of both objective and subjective measures, differences in time points at which cognitive functioning is measured and the differences in intervention duration highlight the caution that must be taken when combining and generalising results and conclusions.

Description of the intervention

This review included all interventions that aim to:

prevent, or
ameliorate

any cognitive deficits in patients who have received therapeutic or prophylactic cranial irradiation prior to, or during, participation in the study. These may include pharmacological and non‐pharmacological (medical, psychological or behavioural) interventions for the management of cognitive deficits.

Pharmacological

We defined pharmacological interventions as a drug given by any route at any therapeutic dose with the intention of preventing or ameliorating cognitive deficits in persons who have received cranial irradiation.

Studies investigating the pharmacological prevention of cognitive impairment frequently occur in patients undergoing cranial irradiation during participation. For example, memantine, used in the treatment of Alzheimer's Disease (Robinson 2006), and lithium, used in the treatment of psychiatric disorders (Cipriani 2013) and in patients with cancer (Khasraw 2012), have both been investigated for their neuroprotective role during irradiation.

Studies of pharmacological treatment for cognitive impairment after cranial irradiation have largely focused on psychostimulants, including methylphenidate and modafinil. Objective cognitive functioning and patient‐reported outcomes of fatigue, mood and quality of life have been used to assess the efficacy of methylphenidate and modafinil in brain tumour patients, 83% of whom had received cranial irradiation (Gehring 2012a). Donepezil, used in the treatment of Alzheimer's Disease, has also been investigated for its use in the treatment of cognitive symptoms in brain‐irradiated adults (Shaw 2006).

Non‐pharmacological

We defined non‐pharmacological interventions as any non‐drug intervention given with the intention of ameliorating or preventing cognitive deficits during or following cranial irradiation. These can include, but are not limited to, medical, psychological and behavioural interventions, as well as alternative interventions such as the use of dietary supplements.

Medical interventions include any biomedical intervention given to a person in which the intervention is not primarily investigating cancer treatment or control. For example, one study explored the use of hyperbaric oxygen therapy in cranial irradiated brain tumour patients using 31 neuropsychological tests (Hulshof 2002).

Psychological interventions may include (but are not limited to) retraining, education and compensation strategies. A randomised clinical trial investigating the use of cognitive rehabilitation in glioma patients, 61% of whom had received cranial irradiation, investigated computer‐based retraining and compensatory strategies. Objective and subjective cognitive functioning, as well as perceived burden and mental fatigue, were assessed (Gehring 2009).

Behavioural interventions can include exercise, as well as behavioural modification interventions.

Dietary supplements such as Ginkgo biloba have also been investigated in irradiated brain tumour patients (Attia 2012).

How the intervention might work

Clinical trials have explored the prevention and treatment of cognitive deficits by targeting pharmacological, psychological or behavioural pathways, as well as other biological pathways.

Pharmacological

Pharmacological interventions may prevent cognitive deficits via their neuroprotective role during WBRT such as memantine, an N‐Methyl‐D‐aspartate receptor antagonist (Brown 2013), and lithium, found to reduce oxidative distress via the glutathione system (Machado‐Vieira 2007).

Pharmacological interventions may ameliorate cognitive deficits via their involvement in critical neurotransmitter pathways. Methylphenidate is a CNS stimulant found to have a positive effect on attention due to its action on the brain centre for attention control, the fronto‐striatal network, by increasing dopamine and noradrenaline concentrations (Volkow 2002). Another centrally acting drug is donepezil, a reversible cholinesterase inhibitor involved in inhibiting the breakdown of the neurotransmitter acetylcholine. This may have a cognitive enhancing effect by prolonging and improving cholinergic function, associated with learning and memory (Steinberg 2011).

Non‐pharmacological

Medical interventions have also been considered to help prevent or treat cognitive deficits. Hyperbaric oxygen therapy has been used to improve damage to the nervous system by stimulating angiogenesis, the process through which new blood vessels are formed from pre‐existing blood vessels (Gill 2004).

Psychological interventions may help prevent and improve cognitive deficits by retraining cognitive capacities such as attention and memory, or via compensation strategies such as memory aids. These interventions target the plasticity of the brain, via restoration or reorganisation of function (Miotto 2013; Mora 2013). For example, Cicerone 2011 reviewed 370 cognitive rehabilitation interventions and found supportive evidence for its role in patients with traumatic brain injury and stroke.

Behavioural interventions, such as exercise, may also help ameliorate or prevent cognitive deficits. Exercise has been associated with increases in cerebral blood flow, increased hippocampal neurogenesis, changes in neurotransmitter release and arousal levels and brain structure, and particularly through the involvement of Brain Derived Neurotrophic Factor (Gligoroska 2012).

Other non‐pharmacological interventions, such as those involving diet modifications, may also play a role in improving cognitive functioning. The dietary supplement Ginkgo biloba has been associated with regulating signalling pathways, cellular metabolism and gene transcription (Smith 2003).

Why it is important to do this review

As anti‐cancer treatments become more effective and readily available across treatment centres, patients live longer disease‐free but with long‐term sequelae of the disease and the neurotoxic side effects of treatment (Cochran 2012).Greater emphasis is now being placed on quality of life and with the establishment of neurocognitive function as a predictor of survival (Meyers 2000) and quality of life (Mitchell 2010), cognitive functioning is an essential outcome measure. There is currently no standard policy to direct treatment, and there are no systematic reviews of preventive measures or interventions for cognitive problems specifically associated with cranial irradiation in adult cancer survivors. With even mild cognitive impairment leading to negative functional and psychiatric consequences, especially if persistent and untreated, it is important to identify ways to reduce the long‐term impact of cranial irradiation on neuropsychological function.

Objectives

To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adult patients treated with cranial irradiation.

Methods

Criteria for considering studies for this review

Types of studies

Prevention

For studies investigating the prevention of cognitive deficits, we searched for any studies fulfilling the following criteria:

randomised controlled trial (RCT) or non‐randomised controlled trial (non‐RCT), including cluster and cross‐over controlled trials;
they have included a control group or comparison group receiving no intervention for cognitive function, standard care, or are compared with a normative data control group;
they involve an intervention aimed at the prevention of cognitive deficit in adults who are all receiving cranial irradiation during participation;
they include cognitive performance, as assessed by neuropsychological tests (and not self‐report), as the primary outcome, or include cognitive performance as the secondary outcome to an alternative primary quality of life measure (e.g. fatigue, mood).

We included studies in which cognitive functioning was measured at baseline and following intervention at any time point.

Whilst we included studies that investigated the preventative role of an intervention during cranial irradiation, we did not include those where the intervention being investigated was cranial irradiation itself, associated with treating the tumour or improving tumour control. Such excluded studies included those on:

hippocampal sparing techniques;
techniques limiting radiation dosage to healthy tissue (e.g. intensity‐modulating radiation therapy);
the addition of chemotherapy agents (e.g. motexafin gadolinium).

Although these techniques can be associated with reduced or limited cognitive side effects, these techniques would best fit a separate Cochrane systematic review investigating the effect of dose of radiotherapy in causing cognitive problems.

Amelioration

For studies investigating the amelioration of cognitive deficits, we included any studies fulfilling the following criteria:

randomised controlled trial (RCT) or non‐randomised controlled trial (non‐RCT), including cluster and cross‐over controlled trials;
they have included a control group or comparison group receiving no intervention for cognitive function, standard care, or are compared with a normative data control group;
they involve an intervention for ameliorating cognitive function in adults to which the majority (> 80%) have received cranial irradiation prior to participation;
they include cognitive performance, as assessed by neuropsychological tests, as the primary outcome, or include cognitive performance as the secondary outcome to an alternative primary quality of life measure (e.g. fatigue, mood);
cognitive functioning has been measured at baseline and following intervention initiation at any time point.

To improve the relevance of the review, we included non‐RCTs in our search. These studies are described in the excluded studies section. They were not included in the main body of evidence but offer preliminary findings for the justification of further research.

Types of participants

Prevention

For studies investigating the prevention of cognitive deficits, we included studies that involved adult patients (aged 18 years and over), who had undergone cranial irradiation (whole brain or partial brain radiation) during participation in the study, for the treatment of primary or secondary brain cancer, or prophylactic treatment for other cancers.

Since these studies refer to interventions for preventing cognitive deficits, the presence of cognitive deficits at baseline was not an inclusion criterion. However, we only included studies where cognitive functioning was assessed via neuropsychological testing both prior to and following the start of the intervention.

Amelioration

For studies investigating the amelioration of cognitive deficits, we included studies that involved adult patients (aged 18 years and over) with impairment in at least one cognitive domain, who had previously undergone cranial irradiation (whole brain or partial brain radiation) prior to participation in the study for the treatment of primary or secondary brain cancer, or prophylactic treatment for other cancers. Participants could have received cranial irradiation during childhood, but had to be an adult (aged 18 years and over) during participation in the study. Cognitive impairment was determined prior to participation via neuropsychological testing.

We also included studies that involved only a subset of patients who had undergone cranial irradiation in the review, if this group formed a large majority (> 80%) of the study population or had been explored via subgroup analyses.

Types of interventions

Studies that were included could have utilised pharmacological (e.g. stimulants, or neuro‐protective agents) or medical (e.g. hyperbaric oxygen therapy) approaches, or psychological (e.g. cognitive rehabilitation) or behavioural (e.g. exercise) interventions, targeted to prevent or ameliorate radiation‐related cognitive deficits.

Pharmacological interventions

We investigated the effectiveness of any drug given by any route for any duration, and at any therapeutic dose, with the objective of preventing or treating cognitive deficits in patients who had received, or were receiving, cranial irradiation. Such drugs are likely to include psychostimulants (e.g. methylphenidate, modafinil), and might include drugs to treat cognitive deficits in other neurological conditions (e.g. donepezil, memantine). For ethical reasons, studies involving drugs may not automatically include a placebo arm. To increase the relevance of the review we included studies without a placebo arm if the study involved a group of participants who have been randomised to a control group of some kind (e.g. treatment as usual, another active drug or allocation to a waiting list), or that have been compared to normative control data with correction of practice effects caused by repeated neuropsychological testing.

Non‐pharmacological interventions

For medical interventions, we investigated any medical intervention, such as hyperbaric oxygen therapy, which aimed to prevent or improve cognitive deficits in patients who had received, or were receiving, cranial irradiation.

For psychological and behavioural interventions, we reviewed any cognitive and/or behavioural treatment given with the intention or preventing or treating cognitive deficits in patients who had received, or were receiving, cranial irradiation; these could include, but were not limited to, retraining, education or teaching of compensation strategies, physical exercise interventions or dietary supplements.

Types of outcome measures

Primary outcomes

The primary outcome was cognitive performance; this could be a general or composite cognitive score or individual cognitive test scores using validated neuropsychological tests (e.g. HVLT‐R, COWA). In studies involving preventative interventions, we determined efficacy as a statistically significant improvement in cognitive functioning, or no change/decline from baseline. In studies involving treatment interventions, we determined efficacy as a statistically significant improvement, or no change, in cognitive functioning from baseline. To increase the relevance of the review, we did not restrict eligible reviews with respect to the time point at which cognitive functioning was measured at baseline or at follow‐up. We noted and discussed the time points at which cognitive functioning was measured.

Secondary outcomes

Self‐reported cognitive functioning via interviews or questionnaires.
General functioning including mood/psychiatric symptoms (e.g. Hospital Anxiety and Depression Scale), self reported fatigue (e.g. Brief Fatigue Inventory) and quality of life measurements (e.g. FACT‐Br).
Adverse events (e.g. nausea, skin reactions, headache).

We noted and reviewed the secondary outcomes if recorded, but these were not eligibility criteria for this review.

Search methods for identification of studies

Electronic searches

We searched the following electronic databases for published studies and conference abstracts:

the Cochrane Register of Controlled Trials (CENTRAL, 2014, Issue 8);
MEDLINE (1950 to August 2014);
EMBASE (1980 to August 2014);
PsycINFO (1974 to August 2014).

The search strategies are listed in Appendix 1 (MEDLINE), Appendix 2 (EMBASE), Appendix 3 (PsycINFO) and Appendix 4 (CENTRAL). The search strategies were not restricted by year of publication, language or publication type.

Searching other resources

We searched the reference lists of included studies.
We searched for ongoing trials using ClinicalTrials.gov (www.clinicaltrials.gov), the Physicians Data Query (www.cancer.gov/clinicaltrials) and the metaRegister of Controlled Trials (www.controlled‐trials.com/mrct).

Data collection and analysis

Selection of studies

We used the reference management database EndNote to download all titles and abstracts retrieved by electronic searching. We removed duplicates and two review authors (JD, KZ) independently examined the remaining references. The review authors were not blinded to the authors or affiliations of the studies. We excluded studies clearly not meeting the inclusion criteria and obtained full‐text copies of potentially relevant references. Two review authors (JD, KZ) independently assessed the eligibility of retrieved papers, with disagreements resolved by discussion with a third author (KG). We documented reasons for exclusion of studies.

Data extraction and management

Data extraction

We used the recommendations from the Cochrane Handbook for Systematic Reviews of Interventions to abstract data from included trials using a data extraction form specifically designed for this review (Higgins 2011). Two review authors (JD, KZ) completed data abstraction independently. Differences between review authors were resolved by discussion.

Data abstracted included the following:

article details (author, year of publication, journal, country and language);
methodology (study design, participant recruitment method, inclusion and exclusion criteria, informed consent, ethical approval, statistical analyses);
population demographics (geographical location, setting, age, gender, ethnicity, total number included in trial and analyses);
details of participants health status (including disease status, tumour pathology, tumour treatment details, antiepileptic medication, corticosteroid use);
intervention (characteristics such as drug dose, preparation and route of administration, frequency and duration, detail of providers);
outcomes (primary and secondary outcomes assessed, method and timing of assessments);
results of cognitive functioning measure (neuropsychological test performance);
results of other outcome measures (including self reported cognitive questionnaires, quality of life, depression, fatigue and adverse events);
risk of bias.

Where possible, all data extracted were those relevant to an intention‐to‐treat (ITT) analysis, in which participants are analysed in the groups to which they are assigned.

Data management

We used Review Manager 5.3 to collate data (RevMan 2014). For continuous outcomes (e.g. cognitive performance and quality of life measures), we extracted the final value and standard deviation, and the number of patients assessed at endpoint for each treatment arm to estimate the mean difference between treatment arms and its standard error. We noted and reviewed the time points for outcome assessment. Where participant and study details were missing; we noted these as a potential limitation of the study.

Assessment of risk of bias in included studies

We used the Cochrane Handbook for Systematic Reviews of Interventions 'Risk of bias' tool to assess the risk of bias in included studies (Higgins 2011), including the assessment of:

selection bias: random sequence generation and allocation concealment;
performance bias: blinding of participants, personnel (patients and treatment providers) and outcome assessors;
attrition bias: incomplete outcome data;
reporting bias: selective reporting of outcomes;
other possible sources of bias.

A full 'Risk of bias' item list with specific criteria for each item can be found in Appendix 5.

We interpreted and reported all bias criteria as having a low, high or unclear risk of bias. We reported an unclear risk of bias when insufficient information was provided, or when uncertainty over the potential for bias was present. Two review authors (JD, KZ) applied the 'Risk of bias' tool independently and resolved differences by discussion. We summarised results in a 'Risk of bias' graph and 'Risk of bias' summary and interpreted the results with respect to risk of bias.

Measures of treatment effect

For continuous outcomes, we used the mean difference (MD) with 95% confidence interval (CI). We planned to use the standardised mean difference with 95% CIs to combine trials that measured the same outcome, but used different methods.

For dichotomous outcomes we used the risk ratio (RR) with 95% CI.

Dealing with missing data

We did not impute missing outcome data for any outcomes.

Assessment of heterogeneity

We aimed to asses heterogeneity between studies by a formal statistical test to indicate the significance of the heterogeneity (Deeks 2001). We planned to Investigate and report heterogeneity according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and via visual inspection of forest plots.

Assessment of reporting biases

Two review authors (JD, KZ) reviewed and recorded reporting bias. We aimed to exam funnel plots, if a meta‐analysis that included more than 10 trials was possible, to assess potential small study effects, such as publication bias.

Data synthesis

If sufficient clinically similar trials had been available, we intended to combine data for meta‐analysis using the Cochrane Review Manager software 5.3 (RevMan 2014), as follows:

for continuous outcomes, we planned to pool MDs between treatment arms at the end of follow‐up if trials measured the outcome on the same scale and at the same primary study endpoint, otherwise we planned to pool SMDs;
we intended to use random‐effects models for all meta‐analyses, with 95% CIs (DerSimonian 1986);
for dichotomous data, we planned to pool RRs (RevMan 2014).

Subgroup analysis and investigation of heterogeneity

If sufficient data had been available, we would have reviewed studies separately using the following categories:

drug dose;
World Health Organization (WHO) tumour grade (low‐grade/high‐grade).

Sensitivity analysis

If sufficient data had been available, we would have considered the following factors:

differing study quality (high or low risk of bias);
different classes of agents, doses or scheduling differences.

We anticipated that additional types of sensitivity analyses would have been identified during the conduct of the review.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies

Results of the search

Details can be found in Figure 1.

We found 2762 citations using the initial search strategy following de duplication of the results. Upon screening of titles, this narrowed the results to 16 articles. Six studies were included in this review. Four published trials met our inclusion criteria for analysis; two trials investigating the prevention of cognitive deficits and two trials investigating the amelioration of cognitive deficits. In addition, we identified one study when searching clinical trial databases for ongoing trials. Three conference abstracts were also identified, data were available for one study (Kaleita 2006) and, following correspondence, data were obtained for another study (Rapp 2013); the third study is awaiting classification (Shaw 2013).

Included studies

For detailed information on included studies see the 'Characteristics of included studies' table.

Prevention

Two included studies investigated a pharmacological intervention for the prevention of cognitive deficits during cranial irradiation (Brown 2013; Butler 2007). One included study investigated a cognitive rehabilitation and problem‐solving program for the prevention of cognitive deficits in primary brain tumour patients receiving radiotherapy (Locke 2008).

Pharmacological Studies

One study recruited 554 eligible patients with brain metastases primarily from lung cancer, with breast, colon and other cancers also included; 46 patients did not meet the inclusion criteria, therefore 508 participants were allocated to intervention or placebo (Brown 2013). This was greater than the calculated 221 participants required in each arm to reach 80% statistical power. One study recruited 68 of the 81 projected patients, calculated for a 90% statistical power. Patients had a primary (N = 33) or metastatic brain tumour (Butler 2007); further details concerning the brain tumour ere not reported. Both studies recruited participants in the United States, and both studies were multi‐centre studies involving four centres (Butler 2007), and 143 centres, including Canada (Brown 2013). Both studies reported obtaining ethical approval and informed consent from participants and recorded adverse events. Cranial irradiation schedule requirements varied between studies with patients receiving 37.5 Gy of WBRT via 15 fractions of 2.5 Gy (Brown 2013), or receiving partial or WBRT of at least 25 Gy in at least 10 fractions of 1.8 to 3.0 Gy/fraction (Butler 2007). Both studies reported using a randomisation method, which was confirmed via correspondence as random number generation using a computer program. Both studies reported the use of a double‐blinding and allocation concealment technique, which was also confirmed via correspondence through the use of a pharmaceutical company providing matched drug containers.

Interventions included d‐threo‐methylphenidate (d,l‐MPH; Butler 2007) and memantine (Brown 2013). Both studies compared the interventions with a matched placebo. Both studies included dose escalation techniques, continued for eight (Butler 2007) or 24 (Brown 2013) weeks. Dose reduction and withdrawal techniques were included if patients experienced severe adverse events (Butler 2007) or when the patient's creatine clearance declined (Brown 2013).

Both studies assessed cognitive functioning using the MMSE. One study included a neuropsychological test battery that assessed memory, processing speed, executive function and verbal fluency (Brown 2013). One study also included self‐report measures of fatigue, depression and quality of life (Butler 2007). Timing of outcome assessment varied between studies, with patients assessed at baseline and then at eight, 16, 24 weeks of drug use (Brown 2013), or at the end of radiation therapy and at eight weeks of drug use (Butler 2007). Both studies carried out a final follow‐up assessment after the drug was stopped, at 12 (Brown 2013) and 52 (Butler 2007) weeks.

Non‐Pharmacological Studies

Locke 2008 recruited 19 participants receiving cranial irradiation for the treatment of a primary brain tumour (17 glioma, two meningioma). Recruitment was carried out at a single radiation oncology clinic. Ethical approval was obtained and informed consent sought. Patients were required to have a caregiver available to accompany them to each follow‐up to complete a quality of life questionnaire. Radiation schedule requirements were not reported. The use of a randomisation method was reported, however this was abandoned due to low accrual and the final three participants were enrolled into the intervention arm. Due to the nature of the study, participants were not blinded. Blinding of personnel was not reported.

The intervention included six 50‐minute sessions of cognitive rehabilitation and six 50‐minute sessions of problem‐solving therapy over two weeks, compared with standard medical care. The cognitive rehabilitation intervention was particularly aimed at memory. This involved the education and use of a calendar to compensate for cognitive problems. The problem‐solving intervention involved the education and training of a positive problem‐solving model via constructive thinking, using feelings as cues and reversed advocacy role play.

The primary aim of the study was to assess the tolerability and feasibility of the program. This was assessed through the use of the Mayo‐Portland Adaptability Inventory (Malec 2003), primarily used in the evaluation of rehabilitation programs designed for patients with acquired brain injury, and via patient feedback questionnaires. Cognitive functioning was assessed using the cognitive test battery Repeatable Battery for the Assessment of Neuropsychological Status (R‐BANS; Randolph 1998). Self‐reported quality of life, mood and fatigue were also assessed. Assessments were taken at baseline, following the two‐week intervention, and at three months.

Amelioration

Three pharmacological studies were included that investigated the treatment of cognitive deficits (Gehring 2012a; Kaleita 2006; Rapp 2013). No non‐pharmacological studies were eligible.

Pharmacological Studies

The first study recruited 30 of 30 expected patients with a primary brain tumour, 87% of whom had received radiotherapy (Kaleita 2006); the distribution of tumour grade was almost equal between grade II, III and IV tumours, with two patients with a grade I tumour. The second study recruited 34 of the 75 planned patients with a primary brain tumour, calculated to have 90% statistical power; 24 patients were included in the analysis (21 glioma, one medulloblastoma, one primary CNS lymphoma, one hemangiopericytoma); 83% of whom had received cranial irradiation (Gehring 2012a). The third study recruited 198 of the required 200 patients, required to reach 90% statistical power, from 26 sites; 66% had a primary brain tumour, 27% a metastatic brain tumour and 8% had received prophylactic cranial irradiation (Rapp 2013). Two studies reported their results as a conference abstract (Kaleita 2006; Rapp 2013). All three studies were conducted in the United States. Ethical approval and informed consent was reported for two studies (Gehring 2012a; Rapp 2013) and all reported adverse events. Two studies did not restrict patients to those receiving cranial irradiation (Gehring 2012a; Kaleita 2006). In one study, patients were eligible to participate following partial or whole brain irradiation of 30 Gy or greater (Rapp 2013). The use of a randomisation method was reported by all studies, and correspondence confirmed this and was through the use of a computer program in two studies (Gehring 2012a; Rapp 2013). Two studies used double‐blinding (Kaleita 2006; Rapp 2013) and one study also reported an allocation concealment method via a pharmaceutical company (Rapp 2013). One study used an open‐label design, although all treatment arms were experimental (Gehring 2012a).

Intervention arms varied between studies. Gehring 2012a included three intervention arms using two forms of methylphenidate (immediate release; sustained release), compared to a modafinil arm. Rapp 2013 included one intervention arm of donepezil, with an increasing dosage from 5 mg/day for six weeks and 10 mg/day for 18weeks if tolerated, compared with placebo. Kaleita 2006 compared two dosages of modafinil followed by an extended treatment phase using a titrated dose between 50 and 600 mg/day for eight weeks.

All studies assessed cognitive functioning using neuropsychological testing, and one also calculated a cognitive composite score (Rapp 2013). All studies included self‐reported measures of mood and fatigue, and one also included a measure of quality of life (Gehring 2012a). Assessments were taken at baseline and at four weeks of drug use (Gehring 2012a), at baseline, 12 and 24 weeks of drug use (Rapp 2013) or at baseline and at one, three, four, eight and 12 weeks of drug use (Kaleita 2006). Assessments were not carried out following withdrawal of the drug, but were recorded in one study during a washout period prior to the extension phase (Kaleita 2006).

Non‐Pharmacological Studies

No studies were eligible.

Excluded studies

For detailed information on excluded studies see the 'Characteristics of excluded studies' table.

An initial screening of the search results was carried out, and reasons for excluding publications were the following:

studies were not intervention studies, such as reviews, comments or correspondence;
studies were conducted in a paediatric population;
studies were evaluating different cranial irradiation schedules, such as hippocampal sparing techniques (see Types of interventions);
studies did not assess cognitive functioning as the primary outcome, or as the secondary outcome to another quality of life measure (e.g. fatigue, mood);
cognitive functioning was assessed via a self‐reported measure only, and not via neuropsychological testing.

After this initial screening, the full‐text articles were retrieved of the remaining 16 potential studies. From these full‐text articles a further seven studies were excluded:

three prevention studies investigating methylphenidate (Meyers 1998), donepezil (Shaw 2006) and Ginkgo biloba (Attia 2012) did not include a comparison group e.g. control group or comparison with normative data;
two prevention studies investigating hyperbaric oxygen therapy (Schellart 2011) and Vitamin E (Chan 2003) did not randomise participants to treatment arms;
two amelioration studies investigating modafinil (Boele 2013) and a cognitive rehabilitation program (Gehring 2009) did not include a majority (> 80%) of participants who had received cranial irradiation or did not analyse these patients separately.

Following discussion, a further three RCTs were removed. A brief description of each study is provided below.

Levin 2011 was excluded as the primary aim was improvement of radionecrosis via magnetic resonance imaging (MRI) imaging. Whilst cognitive impairment is one symptom of radionecrosis, other neurological symptoms may be present, as well as, or instead of, cognitive impairment. This study did not require patients to have a cognitive deficit prior to participation. Nineteen patients with a primary brain tumour (grade II‐III) with neurological signs or symptoms of radiation necrosis were randomly assigned to receive bevacizumab or a matched placebo. All 11 patients who received bevacizumab showed an improvement in neurological symptoms after six weeks, including memory, compared to no symptom improvements in the seven control patients.

Jatoi 2005 was excluded due to only one of the nine recruited participants completing the study, with only two participants receiving the intervention and four participants placebo at the first assessment following intervention initiation. Patients were also removed from the intervention group, and the study, following worsening of cognition or depression, as this indicated failure of the intervention. This study investigated the prevention of cognitive deficits using combined donepezil and Vitamin E in nine of the 104 projected small cell lung cancer patients receiving prophylactic cranial irradiation. Cognitive functioning was assessed using the MMSE, and self‐report measures of functional capacity, depression and quality of life were also included. Descriptive results were reported for one month, three months and six months of drug use. Stable cognitive function was reported in all but one patient, and stable depression and quality of life in all but one patient. Three participants withdrew after the baseline measure, three after one month and two after three months. The study was closed early, resulting in a smaller sample size than expected. Additional reasons for poor accrual were attributed to the strict inclusion criteria resulting in few eligible patients, lack of tolerability immediately following high intensity cancer treatment and the focus on prevention of cognitive deficits in all patients rather than treatment for those already cognitively impaired.

Hulshof 2002 was excluded following correspondence with an author as, contrary to what the study reported, randomisation had not been carried out. This study investigated the amelioration of cognitive deficits in seven patients following cranial irradiation; the reason for cranial irradiation not reported. Cognitive functioning was assessed using neuropsychological testing, and no statistically significant improvements were found.

Studies Awaiting Classifications

One study, for which data could not be obtained, was published in conference proceedings and was identified in the initial search (Shaw 2013). The study investigated the use of armodafinil in improving cognitive functioning in patients who had received cranial irradiation, compared with a placebo drug. The study is described in more detail in the 'Characteristics of studies awaiting classification' table.

Ongoing Studies

The search for ongoing studies found one RCT. Umphrey 2013 is investigating the use of armodafinil in patients with high grade glioma following surgery and radiotherapy. This ongoing study is described in more detail in the 'Characteristics of ongoing studies' table. There are several ongoing studies for the treatment of cognitive deficits in patients with a primary brain tumour, however cranial irradiation is not an inclusion criteria. Thus we cannot pre‐determine if these studies will be eligible for inclusion following completion.

Risk of bias in included studies

We assessed studies using the Cochrane 'Risk of bias' tool (Higgins 2011). Between the two review authors (JD, KZ) there was agreement in the 'Risk of bias' scores following discussion. Attempts to contact authors were carried out where there was an risk of unclear bias. A summary of the risk of bias is presented in Figure 2 and Figure 3.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Three of the four pharmacological studies were at a low risk of bias and used a stratification randomisation method and a pharmaceutical company to create identical drug containers (Brown 2013; Butler 2007; Rapp 2013). One study was at an unclear risk of bias reported the use of a randomisation method, however the method used could not be identified (Kaleita 2006). Two studies were at a high risk of bias: one study used an open‐label design (Gehring 2012a); one non‐pharmacological study reported the use of a randomisation method, but this was abandoned due to low accrual (Locke 2008).

Blinding

Four of the five pharmacological studies were at a low risk of bias and blinded participants and personnel to the intervention group (Brown 2013; Butler 2007; Kaleita 2006; Rapp 2013); one study was at a high risk of bias and used an open‐label design (Gehring 2012a). The non‐pharmacological study was at a high risk of bias; blinding of participants to the intervention was not possible due to the nature of the intervention, however blinding of assessors was also not carried out (Locke 2008).

Incomplete outcome data

The majority of studies included reasons for participant drop‐out, which were unlikely to be related to the outcomes and all studies were judged at a low risk of bias. Three studies performed intention‐to‐treat analysis (Brown 2013; Butler 2007; Rapp 2013). One study was terminated early (Butler 2007). Two studies recruited the projected number of participants (Brown 2013; Kaleita 2006). However, no study was able to include the number of participants required to reach the desired statistical power due to withdrawal from participation as a result of patient death, tumour progression or withdrawal of consent. One study reported the use of a multiple imputation procedure via the Markov chain Monte Carlo method for patients still alive at the time of assessments; this included the imputation of scores for 47% of recruited participants at 24 weeks (Brown 2013). One study reported the use of an imputation method in all participants who provided at least baseline data (Rapp 2013). Two studies carried out statistical comparisons between patients who withdrew consent, and those who remained in the study (Brown 2013; Butler 2007). Butler 2007 reported that patients who dropped out were significantly older and with worse performance status, but not in any of the outcome measures. Brown 2013 reported that patients who could not complete cognitive assessments were more likely to have worse neurological function and a shorter survival time and had not undergone surgery or radiosurgery.

Selective reporting

All outcomes were reported by all included studies and therefore were all judged at a low risk of bias. It was noted that some studies did not report assessments carried out following withdrawal of the drug (Brown 2013; Butler 2007) or report interim assessments (Kaleita 2006; Rapp 2013).

Other potential sources of bias

An unclear risk of bias was reported for two studies. Due to a small sample size, two studies combined intervention groups of participants receiving different forms of the drug methylphenidate (Gehring 2012a) and different doses of modafinil (Kaleita 2006) when analysing results.

Effects of interventions

Study interventions and comparisons were heterogenous, and were not sufficiently clinically similar to pool data. Six studies were identified for inclusion in the review; due to differences in interventions and aim of interventions (prevention versus amelioration) investigated, including the use of drugs with different modes of actions and dosage schedules, and one study's use of a non‐pharmacological intervention, the results are reviewed separately in this review.

Prevention

Pharmacological Studies

The large differences in the mode of action of the drugs investigated, and the unavailability of mean changes in scores, standard deviations or P values, meant pooling of the data was inappropriate. Therefore, results of the studies are reviewed separately and the data are reviewed as reported in the study.

Brown 2013 compared memantine, which acts on the glutamatergic system as an N‐Methyl‐D‐aspartate receptor antagonist, with placebo intervention. Of the 508 eligible patients, 55 patients withdrew consent and 271 patients died prior to completion of the study. Percentages of patients who missed assessments escalated from 41% to 57% from eight‐ to 52‐week assessments. Overall, 31% and 33% of participants completed 24 weeks of drug use as per the study protocol in the memantine and control groups respectively. Imputation was carried out for participants still alive at the time of missed assessment. Therefore, mean cognitive decline was reported for 280 participants with brain metastases at eight, 16 and 24 weeks assessments. Wilcoxon rank‐sum test, Gray’s Test, Cox proportional hazards regression model, stratified log‐rank test statistical analyses were performed. The primary endpoint was HVLT‐R, which did not reach significance (P value = 0.59); this was attributed to attrition. Median change and interquartile ranges were also reported for individual neuropsychological tests at 24 weeks, which are summarised in Table 6. There was significantly less decline in the memantine arm for processing speed (Median difference = .29, P value = .01) and delayed recognition (Median difference = .72, P value = .01). A cognitive functioning composite score was also calculated and the median change was ‐0.41 (interquartile range (IQR) ‐1.30 to 0.12) in the control group and ‐0.03 (IQR ‐0.90 to 0.72) in the intervention group at 24 weeks, which was reported to be significantly different (P value = 0.02). This indicated a stability of cognitive function in the intervention group and a decline in the control group. The most common adverse events were fatigue, alopecia, nausea and headache; there was no difference in the adverse events reported between groups (RR 1.00; 95% CI 0.76 to 1.32). It was noted that more participants in the memantine group were receiving steroids at entry into the study than the control group (P value = .05), which may have played a role in the expression of cognitive deficits, although this difference in steroid use did not continue over time.

Table 1.

Summary of findings: Memantine versus placebo

Cognitive functioning measure (standardised scores)	Memantine		Placebo		P
Cognitive functioning measure (standardised scores)	N	Median change after 24 weeks (IQR)	N	Median change after 24 weeks (IQR)	P
Short‐term verbal memory	77	‐0.23 (‐1.16 to 0.70)	90	‐0.415 (‐1.86 to 0.46)	0.21
Long‐term verbal memory (recall)	76	0 (‐1.67 to 0.59)	90	‐0.90 (‐2.22 to 0.55)	0.06
Long‐term verbal memory (recognition)	76	0 (‐1.12 to 1.43)	90	‐0.72 (‐2.73 to 0.71)	0.01*
Verbal Fluency	78	‐0.10 (‐0.62 to 0.53)	90	‐0.16 (‐0.83 to 0.61)	0.31
Trail making test A	76	0.08 (‐1.01 to 1.82)	92	‐0.37 (‐2.08 to 0.50)	0.02*
Trail making test B	74	‐0.45 (‐2.37 to 1.04)	90	‐0.49 (‐2.60 to 0.62)	0.30
Cognitive composite score	73	‐0.03 (‐0.90 to 0.72)	90	‐0.41 (‐1.30 to 0.12)	0.02*

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cognitive functioning composite score			Other data	No numeric data
2 Cognitive functioning sub‐tests			Other data	No numeric data
2.1 Short‐term verbal memory			Other data	No numeric data
2.2 Long‐term verbal memory (recall)			Other data	No numeric data
2.3 Long‐term verbal memory (recognition)			Other data	No numeric data
2.4 Trail making test A			Other data	No numeric data
2.5 Trail making test B			Other data	No numeric data
2.6 Verbal fluency			Other data	No numeric data
3 Adverse events	1	509	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.76, 1.32]

Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5	Heading 6	Heading 7
Short‐term verbal memory
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Long‐term verbal memory (recall)
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Long‐term verbal memory (recognition)
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Trail making test A
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Trail making test B
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Verbal fluency
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013
Brown 2013

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 General cognitive functioning			Other data	No numeric data
2 Depression			Other data	No numeric data
3 Fatigue	1	28	Mean Difference (IV, Fixed, 95% CI)	3.30 [‐10.37, 16.97]
4 Quality of life			Other data	No numeric data
4.1 FACT			Other data	No numeric data
4.2 Brain subscale			Other data	No numeric data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cognitive functioning			Other data	No numeric data
2 Cognitive functioning sub‐test			Other data	No numeric data
2.1 Attention			Other data	No numeric data
2.2 Short‐term verbal memory			Other data	No numeric data
2.3 Short‐term visual memory			Other data	No numeric data
2.4 Long‐term verbal/visual memory			Other data	No numeric data
2.5 Language			Other data	No numeric data
3 Mood			Other data	No numeric data
4 Fatigue			Other data	No numeric data
5 Functional capacity	1	13	Mean Difference (IV, Fixed, 95% CI)	‐8.55 [‐22.57, 5.47]
6 Quality of life	1	13	Mean Difference (IV, Fixed, 95% CI)	6.0 [‐21.55, 33.55]

Study	Heading 1	Heading 2	Heading 3	Heading 4	Heading 5
Attention
Locke 2008
Short‐term verbal memory
Locke 2008
Short‐term visual memory
Locke 2008
Long‐term verbal/visual memory
Locke 2008
Language
Locke 2008

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cognitive functioning (calculated score)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 Attention (Digit Span)	1	24	Mean Difference (IV, Fixed, 95% CI)	0.38 [0.03, 0.73]
1.2 Speed of processing (Digit symbol)	1	24	Mean Difference (IV, Fixed, 95% CI)	0.37 [‐0.30, 1.04]
2 Cognitive functioning (timed tasks)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 Speed of processing (TMTA)	1	23	Mean Difference (IV, Fixed, 95% CI)	‐2.48 [‐4.82, ‐0.14]
2.2 Executive function	1	22	Mean Difference (IV, Fixed, 95% CI)	0.69 [‐0.50, 1.88]
2.3 Psychomotor functioning (dominant hand)	1	24	Mean Difference (IV, Fixed, 95% CI)	0.61 [‐1.36, 2.58]
2.4 Psychomotor functioning (non‐dominant hand)	1	22	Mean Difference (IV, Fixed, 95% CI)	‐5.38 [‐51.16, 40.40]
3 Cognitive functioning (total score)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.1 Verbal fluency	1	23	Mean Difference (IV, Fixed, 95% CI)	0.33 [‐0.16, 0.82]
3.2 Short‐term verbal memory	1	23	Mean Difference (IV, Fixed, 95% CI)	0.42 [‐0.35, 1.19]
3.3 Long‐term verbal memory (recall)	1	23	Mean Difference (IV, Fixed, 95% CI)	‐0.38 [0.00, 1.24]
3.4 Long‐term verbal memory (recognition)	1	23	Mean Difference (IV, Fixed, 95% CI)	1.62 [‐0.56, 3.80]
4 Self‐reported confusion	1	24	Mean Difference (IV, Fixed, 95% CI)	‐1.04 [‐4.76, 2.68]
5 Anxiety	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
5.1 STAI State anxiety	1	23	Mean Difference (IV, Fixed, 95% CI)	‐1.35 [‐11.66, 8.96]
5.2 STAI Trait anxiety	1	24	Mean Difference (IV, Fixed, 95% CI)	‐0.83 [‐22.21, 20.55]
5.3 POMS anxiety	1	24	Mean Difference (IV, Fixed, 95% CI)	3.56 [‐0.37, 7.49]
6 Depression	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
6.1 BDI‐II	1	24	Mean Difference (IV, Fixed, 95% CI)	0.44 [‐1.93, 2.81]
6.2 POMS depression‐dejection	1	24	Mean Difference (IV, Fixed, 95% CI)	0.37 [‐0.48, 1.22]
7 Anger	1	24	Mean Difference (IV, Fixed, 95% CI)	‐0.5 [‐5.99, 4.99]
8 Fatigue	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
8.1 Brief Fatigue Inventory	1	24	Mean Difference (IV, Fixed, 95% CI)	‐5.2 [‐12.56, 2.16]
8.2 POMS‐Fat	1	24	Mean Difference (IV, Fixed, 95% CI)	0.23 [‐1.30, 1.76]
9 Sleep	1	24	Mean Difference (IV, Fixed, 95% CI)	‐2.39 [‐6.27, 1.49]
10 Activity	1	24	Mean Difference (IV, Fixed, 95% CI)	1.94 [‐1.79, 5.67]
11 Quality of life	1	24	Mean Difference (IV, Fixed, 95% CI)	2.71 [‐14.46, 19.88]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cognitive composite score	1	144	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.05, 0.11]
2 Cognitive functioning (timed tasks)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 Speed of processing	1	145	Mean Difference (IV, Fixed, 95% CI)	‐1.82 [‐11.49, 7.85]
2.2 Executive function	1	143	Mean Difference (IV, Fixed, 95% CI)	1.61 [‐15.98, 19.20]
2.3 Psychomotor functioning (dominant hand)	1	141	Mean Difference (IV, Fixed, 95% CI)	‐11.93 [‐21.51, ‐2.35]
2.4 Psychomotor functioning (non‐dominant hand)	1	142	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐5.21, 5.19]
3 Cognitive functioning (total score)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.1 Attention (Digit span (total))	1	145	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐1.12, 0.80]
3.2 Attention (Digit span (backward))	1	145	Mean Difference (IV, Fixed, 95% CI)	‐0.4 [‐1.01, 0.21]
3.3 Attention (Digit Span (forward))	1	145	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.57, 0.69]
3.4 Verbal fluency	1	145	Mean Difference (IV, Fixed, 95% CI)	‐0.92 [‐3.19, 1.35]
3.5 Short‐term verbal memory	1	145	Mean Difference (IV, Fixed, 95% CI)	0.32 [‐0.93, 1.57]
3.6 Long‐term verbal memory (recall)	1	145	Mean Difference (IV, Fixed, 95% CI)	0.35 [‐0.36, 1.06]
3.7 Long‐term verbal memory (retention)	1	145	Mean Difference (IV, Fixed, 95% CI)	3.96 [‐4.40, 12.32]
3.8 Long‐term verbal memory (recognition)	1	145	Mean Difference (IV, Fixed, 95% CI)	0.57 [0.07, 1.07]
3.9 Long‐term verbal memory (discrimination)	1	145	Mean Difference (IV, Fixed, 95% CI)	0.94 [0.27, 1.61]
3.10 Short‐term visual memory (copy)	1	144	Mean Difference (IV, Fixed, 95% CI)	‐0.69 [‐1.63, 0.25]
3.11 Short‐term visual memory (recall)	1	144	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐1.51, 0.51]
3.12 Long‐term visual memory (retention)	1	143	Mean Difference (IV, Fixed, 95% CI)	‐0.39 [‐1.48, 0.70]

Methods	Randomised controlled trial, parallel arm, double‐blind, stratification by recursive partitioning analysis class and prior surgical therapy.
Participants	Inclusion criteria: Adult patients; pathologically proven diagnosis of solid malignancy within 5 years of registration; brain metastases visible on contrast‐enhanced MRI (or a contrast‐enhanced CT for patients unable to have an MRI) with stable systemic disease 3 months prior to study entry; receiving 37.5 Gy of WBRT via 15 fractions of 2.5 Gy; KPS ≥ 70; serum creatinine ≤ 3 mg/dL, creatinine clearance ≥ 30 mL/min, total bilirubin ≤ 2.5 mg/dL, blood urea nitrogen (BUN) 20 mg/dL; MMSE score > 18; negative serum pregnancy test. Exclusion criteria: Memantine allergy, current alcohol or drug abuse, chronic use of benzodiazepines, severe active comorbidity. No. randomised: Memantine: 278; placebo: 276. Follow‐up: 8, 16, 24 and 52 weeks. Setting: 143 centres in the United States and Canada
Interventions	Treatment arm schedule: Week 1: 5 mg oral memantine taken in the morning Week 2: 10 mg oral memantine taken in divided dosage (5 mg morning, 5 mg night) Week 3: 15 mg oral memantine taken in divided dosage (10 mg morning, 5 mg night) Week 4‐24: 20 mg oral memantine taken in divided dosage (10 mg morning, 10 mg night) Control Arm: Matched placebo The dosage was lowered to 10 mg twice daily, as week 2, if creatinine clearance decreased to 30 mL/min, and was continued at this dosage if creatine clearance fell below 5 mL/min following a weekly recheck.
Outcomes	Cognitive function (HVLT‐R, COWA, TMT)
Notes	Efficacy reported via median change and interquartile ranges.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“The Zelen treatment allocation scheme was used to stratify patients according to according to recursive partitioning analysis (RPA) class and prior surgical therapy.Within each stratum, patients were randomised in a 1:1 ratio to placebo or memantine.” "A computer at RTOG headquarters randomly generated the sequences for the randomization" (obtained via correspondence).
Allocation concealment (selection bias)	Low risk	"The placebo was actually provided by the company (Forest Pharma) and it was impossible to tell which was placebo and which was active drug." (obtained via correspondence).
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding carried out.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding carried out.
Incomplete outcome data (attrition bias) All outcomes	Low risk	"All eligible patients randomised to the study were included (intent‐to‐treat analysis)...The multiple imputation procedure employing the Markov chain Monte Carlo method was also used to determine values for all remaining living patients missing assessments."
Selective reporting (reporting bias)	Low risk	All outcomes reported.
Other bias	Low risk	None.

Methods	Randomised controlled trial, three arms, open‐label, stratification by tumour location.
Participants	Inclusion criteria: age > 18; KPS > 70; primary brain tumour; subjective complaint of cognitive decline or fatigue; being considered for stimulant therapy by their neuro‐oncologist; the ability to speak and understand English or Spanish. Exclusion criteria: current use of psychostimulants, monoamine oxidase inhibitors, anticoagulants, drugs similar to erythropoietin, or illicit drugs; history of hypersensitivity reaction to methylphenidate or modafinil; history of uncontrolled seizures, cardiac or pulmonary disease, or hypertension (systolic > 140 mm Hg, diastolic > 90 mm Hg, or not on a stable dose of anti‐hypertensive medication for the past month; severe headaches; current glaucoma, narcolepsy, Tourette’s syndrome, major psychiatric diagnosis, alcohol or drug abuse; current use of herbals/supplements for fatigue relief, e.g. Ginkgo biloba, ginseng, St John's Wort, dehydroepiandrosterone; unstable dose of antidepressants; comorbidities or medications that in the treating physician’s opinion could potentially interfere with safe administration of MPH or MOD. No. randomised: methylphenidate: 24; modafinil: 10. Follow‐up: 4 weeks. Setting: one cancer centre in the United States.
Interventions	Arm I: 10 mg of oral methylphenidate (immediate release) taken in divided doses for 4 weeks Arm II: 18 mg or oral methylphenidate (sustained release) taken in the morning for 4 weeks Arm III: 200 mg of oral modafinil taken in the morning for 4 weeks.
Outcomes	Cognitive function (WAIS‐III Digit span and Digit symbol, TMT, HVLT‐R, grooved pegboard, MAE COWA). Fatigue (BFI, POMS‐Fat, POMS‐Vig sub‐scales) Sleep disturbance (BSDS) Mood (POMS, BDI‐II, STAI) QoL (FACT general and brain modules, FIM)
Notes	Arm I and II combined for statistical analysis. Second drug used as control arm, rather than placebo. Groups also compared with normative data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were stratified by tumour location (i.e., right verses left hemisphere) and randomly assigned to one of three conditions." "a computer performed the randomization" (obtained via correspondence).
Allocation concealment (selection bias)	High risk	An open‐label design was used.
Blinding of participants and personnel (performance bias) All outcomes	High risk	An open‐label design was used.
Blinding of outcome assessment (detection bias) All outcomes	High risk	An open‐label design was used.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing outcome data were balanced in numbers across treatment groups, and reasons for missing outcome data similar between treatment groups and unlikely to be related to outcomes measured.
Selective reporting (reporting bias)	Low risk	All outcomes reported.
Other bias	Unclear risk	Possible recruitment bias: "PBT patients were considered eligible for participation if… being considered for stimulant therapy by their neuro‐oncologist."

Study	Reason for exclusion
Attia 2012	Not a controlled trial.
Boele 2013	Study included > 20% non‐irradiation patients and did not analyse cranial irradiation patients separately.
Chan 2003	Patients not randomised.
Gehring 2009	Study included > 20% non‐irradiation patients and did not analyse cranial irradiation patients separately.
Hulshof 2002	Patients not randomised.
Jatoi 2005	1 participant completed the study.
Levin 2011	The primary outcome not cognitive functioning or other quality of life measure.
Meyers 1998	Not a controlled trial.
Schellart 2011	Patients not randomised.
Shaw 2006	Not a controlled trial.

Methods	Phase II double‐blind placebo‐controlled RCT. Patients were randomly assigned to receive armodafinil or a placebo during cranial irradiation and for four weeks following RT. Patients completed assessments at baseline, at the end of RT, and 4 weeks after the end of RT. Intervention toxicity was recorded.
Participants	Patients with a primary brain tumour receiving a total RT dose of 45 Gy during participation.
Interventions	Arm I: 150 mg/day Armodafinil Arm II: Placebo
Outcomes	Fatigue (BFI, FACIT‐Fatigue) Sleepiness (ESS) Quality of life (FACT, FACT‐brain) Cognitive function (Wake Forest Cognitive Function Battery)
Notes	In the armodafinil treatment arm, fatigue, sleepiness and quality of life scores significantly improved at the end of RT, compared with the placebo arm.

Trial name or title	Armodafinil in reducing cancer‐related fatigue in patients with high grade glioma
Methods	Phase III double‐blind placebo‐controlled RCT. Patients are randomly assigned to receive one of two doses of armodafinil or a placebo for 8 weeks.
Participants	Inclusion criteria: aged ≥ 18yrs; glioblastoma multiforme, anaplastic astrocytoma, gliosarcoma, or anaplastic oligodendroglioma; clinically stable (stable/improved KPS compared to the prior month); completed radiation therapy > 21 days and ≤ 24 months prior to enrolment; ≥ 6 score on the worst fatigue question of the BFI (Brief Fatigue Inventory); previous surgery (gross total or subtotal resection) or biopsy; negative serum pregnancy test done ≤ 7 days prior to registration; ability to complete questionnaire(s) by themselves or with assistance, ECOG PS 0, 1, 2 or 3; provide informed written consent; willing to return to enrolling institution for follow‐up (during the Active Monitoring Phase of the study) ; stable dose of corticosteroid ≤ 28 days prior to registration. Exclusion criteria: History of hypersensitivity to other psychostimulants; history of steroid psychosis; history of/currently taking medications for attention deficit hyperactivity disorder, severe anxiety disorder, schizophrenia, or substance abuse by patient record and/or self‐report; currently taking medications to treat fatigue including psychostimulants, antidepressants, acupuncture (antidepressants used to treat items other than fatigue (such as hot flushes or depression) are allowed if the patient has been on a stable dose for ≥ 30 days and plans to continue for the duration of the trial); anticipating surgery; laboratory evidence of hypothyroidism with an elevated thyroid stimulating hormone (TSH) concentration in the blood > 5.0 mlU/L; profound anaemia (haemoglobin level of < 10 g/dL) ≤ 28 days prior to registration; clinical depression per physician discretion; active/history of Tourette's syndrome or tic disorder, glaucoma, intractable epilepsy or uncontrolled seizure disorder; history of myocardial infarction, unstable angina, left ventricular hypertrophy or mitral valve prolapse syndrome; use of strong or moderate inhibitors of cytochrome P450 3A4 (CYP3A4) ≤ 7 days prior to registration; use of medications or substances that are inducers of CYP3A4 ≤ 7 days prior to registration. Follow‐up: 8 weeks Setting: 92 centres in the United States.
Interventions	Arm I: 150 mg Armodafinil Arm II: 250 mg Armodafinil Arm III: Placebo
Outcomes	Patient‐reported fatigue (BFI) Cognitive functioning (SDM, COWA, TMT, FACT‐Cog) Quality of life (LASA).
Starting date	2013
Contact information	Recruitment is being carried out in 92 centres. Study Chair: Alyx Umphrey Mayo Clinic Rochester Minnesota United States 55905 507‐538‐7623
Notes	ClinicalTrials.gov Identifier: NCT01781468 Current status: Recruiting participants.

Develop and run the search strategy	JD, KZ, KG
Obtain copies of trials	JD, KZ
Select which trials to include	JD, KZ, KG
Extract data from trials (2 people)	JD, KZ
Enter data into RevMan	JD, KZ
Carry out the analyses	JD, KZ
Interpret the analyses	All authors
Draft the final review	All authors
Update the review	All authors

PERMALINK

Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation

Julia Day

Karolis Zienius

Karin Gehring

David Grosshans

Martin Taphoorn

Robin Grant

Jing Li

Paul D Brown

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation

Background

Description of the condition

Neurotoxic effects of cranial irradiation

The mechanism of cranial irradiation‐induced cognitive impairment

Measuring cognitive deficits

Description of the intervention

Pharmacological

Non‐pharmacological

How the intervention might work

Pharmacological

Non‐pharmacological

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Prevention

Amelioration

Types of participants

Prevention

Amelioration

Types of interventions

Pharmacological interventions

Non‐pharmacological interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Data extraction

Data management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Figure 1.

Included studies

Prevention

Pharmacological Studies

Non‐Pharmacological Studies

Amelioration

Pharmacological Studies

Non‐Pharmacological Studies

Excluded studies

Studies Awaiting Classifications

Ongoing Studies

Risk of bias in included studies

Figure 2.

Figure 3.

Allocation