Non‐pharmacological interventions for cognitive impairment due to systemic cancer treatment
It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non‐pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis.
To evaluate the cognitive effects, non‐cognitive effects, duration and safety of non‐pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments).
We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015.
Randomised controlled trials (RCTs) of non‐pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult‐onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non‐melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied.
Data collection and analysis
Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta‐analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well‐being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes.
Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer‐assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed‐ and immediate‐ memory), subjectively reported cognitive function and mental well‐being. Compensatory strategy training demonstrated improvements on objectively assessed delayed‐, immediate‐ and verbal‐memory, self‐reported cognitive function and spiritual quality of life (QoL). The meta‐analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well‐being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) ‐0.59 to 0.83; I2= 67%) or two months post‐intervention (SMD ‐ 0.21, 95% CI ‐0.89 to 0.47; I2 = 63%) or on mental well‐being two months post‐intervention (SMD ‐0.38, 95% CI ‐1.10 to 0.34; I2 = 67%). Lower mental well‐being immediately post‐intervention appeared to be observed in patients who received compensatory strategy training compared to wait‐list controls (SMD ‐0.57, 95% CI ‐0.98 to ‐0.16; I2 = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear.
Overall, the, albeit low‐quality evidence may be interpreted to suggest that non‐pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi‐site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer.
Charlene J Treanor, Una C McMenamin, Roisin F O'Neill, Chris R Cardwell, Mike J Clarke, Marie M Cantwell, Michael Donnelly
Plain language summary
Interventions for cognitive impairment due to non‐localised cancer treatment such as chemotherapy or hormonal therapy
An increasing number of people are surviving and living longer with cancer due to earlier diagnosis, better treatments and an aging population. In turn, there is an increasing number of people with long‐term or long‐lasting effects of cancer and its treatment. For example, up to seven in 10 cancer survivors experience changes in ability regarding memory, learning new things, concentrating, planning and making decisions about their everyday life, as a result of cancer treatment. This is known as cognitive impairment and has a significant impact on the daily activities of cancer survivors. These changes may be caused by non‐localised, systemic cancer treatment, such as chemotherapy and is often called 'chemo‐fog' or 'chemobrain'.
The aim of the review
We reviewed studies that have tested interventions intended to improve cognitive impairment or to maintain cognitive function among people who have been treated with systemic cancer treatments.
What are the main findings?
We identified five eligible studies that described six interventions. These included two studies of computerised cognitive skills practice, two cognitive coping skills training programmes, one meditation intervention and one exercise intervention. All five studies included a total of 235 women who had been treated for breast cancer. The findings suggest that cognitive skills practice and cognitive coping skills training may be useful in improving patient reports and formal assessments of cognition, as well as quality of life. There was insufficient evidence to know if meditation and exercise interventions had any effect on cognition.
What is the quality of the evidence?
The quality of the evidence was low. There were problems with study designs and, so, we need to be cautious about our conclusions.
What are the conclusions?
There is not enough good quality evidence to know if any interventions improve cognitive impairment or maintain cognitive functioning among people who have received systemic treatment for cancer. There are several ongoing trials in the field, which may provide the necessary evidence in the future.
Charlene J Treanor, Una C McMenamin, Roisin F O'Neill, Chris R Cardwell, Mike J Clarke, Marie M Cantwell, Michael Donnelly
Implications for practice
The limited evidence available at present makes it difficult to draw firm recommendations for healthcare providers that would help patients maintain or recover cognitive functions following receipt of chemotherapy. Further research is needed to resolve uncertainties about the effects of available interventions. Tentatively, the review findings suggest that cognitive‐ and compensatory strategy‐training may have potential benefits for improving cognitive functioning and quality of life outcomes among breast cancer survivors. Also, evidence on the effectiveness of physical activity and meditation interventions on cognitive function outcomes is too weak to extract any implications for clinical practice. Although, not an objective of the review, it is not clear if face‐to‐face or group‐delivered interventions would have most benefit or which type of healthcare professional would be best placed to deliver such interventions.
Implications for research
We identified only a small number of trials and these were not of high quality. Nevertheless, the number of ongoing, registered trials, suggest that more rigorous research in this area might be available in future. Larger, multi‐site trials are needed with longer follow‐up periods in order to test robustly the effectiveness of interventions. Moreover, trials that are adequately powered with a formal sample size calculation conducted a priori are needed. Future studies should consider methods to blind participants to group allocation such as the use of attentional control groups. It is recognised that due to the cognitive rehabilitation nature of the interventions identifying an appropriate attentional control may be difficult. It is important to consider the extent to which practice effects may occur as a result of multiple neuropsychological testing and how this factor may lead to improvements in test scores which may be independent of any true intervention effects. For example, if patients remember the content and responses of neuropsychological tests, develop strategies or have increased confidence to complete the tests, this may contribute to practice effects. Future studies should continue to consider use of alternative test battery forms, test measures with good test‐retest reliability to capture with more precision true changes in cognition which may help to control or lessen the impact of practice effects (Calamia 2012; Vardy 2008; Wefel 2011).
Many of the included studies required participants to self‐report deterioration in cognitive functioning since cancer diagnosis and cancer treatment. It is widely known that self‐reported cognitive functioning demonstrates a stronger association with fatigue, distress and related factors than objective measures of cognitive functioning (Green 2005). Whilst some of the studies assessed retrospectively the proportion of study participants who demonstrated objectively assessed cognitive impairment, there is a need also to do so prior to study enrolment in future trials. As with most cancer survivorship research and, indeed, research on treatment‐related cognitive impairment among non‐CNS adult‐onset cancers, breast cancer represents the most widely studied cancer survivor cohort. However, cognitive impairment following systemic cancer treatment is a phenomenon relevant to survivors of other cancers and they too should be considered in future trials.
Further work is needed to determine the psychometric properties of measures of cognitive functioning within cancer patient or survivor populations to ensure that they are appropriate for use, as cognitive impairments among this group occur more subtly than the groups for which the measures were initially designed. There was little agreement across trials about the choice of outcome measures for specific cognitive domains and often, measures were used to assess more than one cognitive domain. The International Cognition and Cancer Task Force published recommendations for outcome measure selection (Wefel 2011) and adherence to these would permit ease of comparison and meta‐analysis in future reviews. Measuring activities of daily living (ADLs) and instrumental ADLs are important outcomes to be captured in future trials.
Future research should consider also incorporating neuroimaging techniques into their evaluation design to demonstrate structural and functional changes in the brain as an additional objective assessment of changes in cognitive functioning. Although research in this area is in its infancy, in the future it may be beneficial to test the effectiveness of interventions targeting maintenance of cognitive function or amelioration of cognitive impairment in a preventative setting, particularly among cancer patients who may have increased susceptibility to the neurotoxic effects of chemotherapy (e.g. presence of apoE ε4 allele). At present, there is no standard care for treatment‐related cognitive impairment and the cost‐effectiveness of implementing cognitive rehabilitation interventions in clinical practice is warranted in future studies, given limited healthcare resources.