title: Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation.
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.
  
  
  OBJECTIVE
  To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adult patients treated with cranial irradiation.
  
  
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Edinburgh Centre for Neuro-Oncology (ECNO),Western General Hospital,Crewe Road South, Edinburgh, Scotland, EH4 2XU, UK. Julia.day@ed.ac.uk. Julia.day@nhslothian.scot.nhs.uk.
authors.forename: Julia
authors.initials: J
authors.lastname: Day
authors.forename: Karolis
authors.initials: K
authors.lastname: Zienius
authors.forename: Karin
authors.initials: K
authors.lastname: Gehring
authors.forename: David
authors.initials: D
authors.lastname: Grosshans
authors.forename: Martin
authors.initials: M
authors.lastname: Taphoorn
authors.forename: Robin
authors.initials: R
authors.lastname: Grant
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Paul D
authors.initials: PD
authors.lastname: Brown
mesh_terms: D000328:Adult; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control* / Q000628:therapy*; D016371:Cranial Irradiation / Q000009:adverse effects*; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000627:therapeutic use; D008559:Memantine / Q000627:therapeutic use; D008774:Methylphenidate / Q000627:therapeutic use; D000077408:Modafinil; D018697:Nootropic Agents / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic
chemical_list: D001559:Benzhydryl Compounds; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D008774:Methylphenidate; D000077265:Donepezil; D000077408:Modafinil; D008559:Memantine