Day Julia, Zienius Karolis, Gehring Karin, Grosshans David, Taphoorn Martin, Grant Robin, Li Jing, Brown Paul D
Edinburgh Centre for Neuro-Oncology (ECNO),Western General Hospital,Crewe Road South, Edinburgh, Scotland, EH4 2XU, UK.
Cochrane Database Syst Rev. 2014 Dec 18;2014(12):CD011335. doi: 10.1002/14651858.CD011335.pub2.
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.
To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adult patients treated with cranial irradiation.
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.
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.
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.
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.
认知缺陷在接受过颅脑照射的人群中很常见，对日常功能和生活质量有严重影响。该人群中认知缺陷的药物和非药物治疗的益处尚不清楚。
评估干预措施对接受颅脑照射的成年患者预防或改善认知缺陷的有效性。
2014年8月，我们检索了Cochrane对照试验注册库（CENTRAL）、MEDLINE、EMBASE和PsycINFO，并检查了纳入研究的参考文献列表。我们还通过ClinicalTrials.gov、医师数据查询和对照试验元注册库搜索了正在进行的试验。
我们纳入了评估对接受颅脑照射的成年人进行药物或非药物干预的随机对照试验（RCT），将客观认知功能作为主要或次要结局指标。
两位综述作者（JD、KZ）独立从选定研究中提取数据，并进行“偏倚风险”评估。报告了认知功能、疲劳和情绪结局。未进行数据合并。
确定了16项可能纳入综述的研究，其中6项被纳入。3项研究调查了预防措施，3项研究调查了改善措施。由于所评估的干预措施在研究之间存在差异，无法进行荟萃分析。2项研究调查了预防认知缺陷的药物干预；美金刚与安慰剂比较，盐酸d-苏式甲基苯丙胺与安慰剂比较。在第一项研究中，6个月时记忆的主要认知结局未达到显著性，但与安慰剂相比，总体认知功能有显著改善，各组不良事件相似。第二项研究发现两组之间无统计学显著差异，不良事件较少。第三项研究调查了预防认知缺陷的康复计划，但未对组间认知表现进行统计学比较。3项研究调查了治疗认知缺陷的药物干预；哌甲酯与莫达非尼比较、两种不同剂量的莫达非尼、多奈哌齐与安慰剂比较。第一项研究发现哌甲酯组和莫达非尼组的认知功能均有改善；报告的不良事件较少。第二项研究合并了治疗组，发现所有认知测试均有改善，然而，报告了一些不良事件。两项研究均受样本量小的限制。第三项研究未发现总体表现的主要认知结局有改善，但与安慰剂相比，在一项记忆单项测试中发现有改善；未报告不良事件。没有符合条件的关于改善认知缺陷的非药物研究。各项研究存在一些局限性，但很少没有高偏倚风险。
有支持性证据表明，美金刚可能有助于预防接受颅脑照射的脑转移瘤成年患者的认知缺陷。有支持性证据表明，多奈哌齐可能在治疗接受过颅脑照射的原发性或转移性脑肿瘤成年患者的认知缺陷中发挥作用。患者退出影响了两项研究的统计效力。进一步的研究若能尽量减少同意退出的情况，进而减少插补程序的需求，可能会提供更高质量的证据。没有有力证据支持任何非药物干预措施（医学或认知/行为）用于预防或改善认知缺陷。非随机研究似乎很有前景，但通过转化为高质量证据仍未得出定论。需要进一步研究。
