Department of Geriatric Medicine, Eastern Health, Box Hill, Victoria.
Cognitive impairment presents unique clinical challenges in the management of older adults with cancer. With an ageing population, the recognition and management of cognitive impairment is likely to become more important in oncology practice. Currently, screening for cognitive impairment is not routinely performed in oncology. However, screening has been shown to detect cognitive deficits in a significant proportion of older adults with cancer. This can have a significant impact on treatment decisions, including determining suitability for cancer therapy and capacity to provide informed consent. In addition, cognitive impairment can enhance the risk of complications from cancer and its treatment. Early identification can facilitate appropriate decision-making and interventions to minimise its consequences. Further research is needed on recognition and management of cognitive impairment in older adults with cancer. This article provides an overview of cognitive impairment in older adults with cancer, with the aim of informing clinicians on the importance of assessing cognition.
The incidence of both cancer and cognitive impairment increases with age.1-3 With population ageing occurring globally, clinicians are more likely to encounter older adults with both cancer and cognitive impairment. In developed countries, more than 60% of all cancers are diagnosed in persons aged 65 years and older.4,5 In low and middle income countries, the percentage of cancers diagnosed in people aged 65 and older is lower, but population ageing is progressing fastest.6 Almost one in 10 persons aged 65 years and older, and three in 10 of those aged 85 years and older have dementia.7 Currently, screening for cognitive impairment is not routinely performed in most oncology centres. However, several studies examining cognition as part of a comprehensive geriatric assessment demonstrate that between 24% and 38% of older adults with cancer have cognitive deficits.8-13
Identifying these individuals is important, as cognitive impairment is associated with significant clinical consequences, including increased emergency department visits, treatment-related complications, morbidity and mortality.14-16 In cancer patients, the presence of cognitive impairment poses unique clinical challenges and can influence treatment decisions. Cognitive deficits can impact on the patient’s decision-making capacity, adherence to treatment and ability to seek help if problems arise. Identifying individuals with cognitive impairment allows for more informed decision-making and implementation of measures to minimise its consequences. However, despite its potential importance, cognitive impairment remains significantly under-recognised in cancer patients. This review aims to summarise the syndromes of cognitive impairment and evaluation of patients with this condition. It describes the implications of cognitive impairment on clinical decision-making capacity and treatment decisions, and discusses strategies to minimise its impact on older adults with cancer.
Cognitive impairment describes a syndrome of impaired brain function related to the ability to think, concentrate, formulate ideas, reason and remember. Cognitive impairment can be broadly divided into three groups: delirium, mild cognitive impairment and dementia.
Delirium is a medical condition characterised by disturbance of attention, disorientation and altered cognition (eg. memory, orientation, language). The disturbance develops over a short period of time (usually hours to days) and tends to have a fluctuating course. Delirium is a direct physiological consequence of physical disease, brain injury or drug effect.
Mild cognitive impairment (classified as mild neurocognitive disorder in diagnostic and statistical manual of mental disorders (DSM-5)) is a term used when there is significant cognitive decline that exceeds normal ageing, but not sufficient to cause significant functional impairment. Cognitive impairment is considered to be a transitional state between normal ageing and early dementia. It is important to recognise mild cognitive impairment because it is a risk factor for developing early dementia. Depending on clinical setting and definition, between 30% and 50% of individuals with mild cognitive impairment progress to dementia over 10 years.19
Dementia is a syndrome of memory impairment and at least one other cognitive deficit (eg. aphasia, apraxia, agnosia or executive dysfunction) that is sufficient to cause significant functional impairment and represents a decline from previous functioning.17 Dementia usually has a slow, progressive course (over months to years). Alzheimer’s disease is the most common cause of dementia but there are numerous other known causes such as vascular dementia, Lewy body dementia and frontotemporal dementia.
Mood disorders such as depression can also be associated with cognitive deficits. Because delirium, dementia and depression can present with overlapping features and often co-exist in older adults with cancer, careful clinical evaluation is essential (table 1).
Older adults with cancer are particularly vulnerable to developing cognitive impairment. The cause is often multifactorial (table 2). The ageing process is associated with physiological changes in the nervous system, including altered neurotransmitter function, decreased cerebral blood flow, reduction in nerve conduction and decreased sensory perception.20 In addition, pathological changes due to neurodegenerative diseases and vascular ischaemia contribute to cognitive decline and development of dementia. The overall reduction in cognitive reserve predisposes older adults to developing cognitive dysfunction from cancer or its therapy.
Cancer can affect cognition through direct effects on the brain such as brain metastases or indirectly through complications such as organ failure, electrolyte imbalance, malnutrition. In addition, cancer therapy can also exacerbate cognitive deterioration through adverse effects such as infection, dehydration, electrolyte imbalance, hormonal dysregulation. Important variables known to influence the risk of cognitive side-effects include: type, dose, duration and combination chemotherapy; brain radiotherapy; advanced age; and cognitive function prior to treatment.21 In addition, symptoms such as fatigue, anxiety and depression can negatively influence cognitive performance. Cancer patients also typically receive multiple medications for co-morbid conditions or as part of cancer therapy. This can increase the risk of cognitive impairment, especially with the use of opioids, corticosteroids and benzodiazepines.22
Apart from acute cognitive changes that commonly occur during cancer therapy, there is growing evidence that some individuals experience long-term cognitive deficits following cancer therapy. The risk of dementia is increased in long-term cancer survivors aged 65 years and older compared with their cancer-free twins, suggesting that cancer and its treatment increases the risk of long-term cognitive dysfunction.23 Several studies show that cognitive impairment can occur in cancer survivors following brain radiotherapy and chemotherapy.24,25 The evidence for chemotherapy-induced cognitive impairment is greatest in breast cancer patients, where numerous studies suggest that 20-40% of patients demonstrate cognitive deficits in post-treatment evaluation.26-28 Recognising cognitive impairment and its risk factors is important, as it allows for strategies to be implemented to reduce their clinical consequences.
Because of the potential impact of cognitive impairment on treatment decisions and tolerance of treatment, clinicians should consider cognitive screening in older adults with cancer. Many cognitively impaired individuals compensate for their deficits and can appear cognitively intact on routine evaluation, hence the use of a standardised screening instrument is recommended.
Of the many screening instruments available, the Mini-Mental State Examination (MMSE) is one of the most commonly used instruments for assessing cognitive function.29 The MMSE can be used to screen for dementia, track changes in cognitive function over time and assess the effects of therapeutic agents on cognition.30 It consists of 11 items designed to assess five areas of cognitive function: orientation; registration; calculation and attention; recall; and language. The MMSE is fairly lengthy and takes 10 minutes to administer, with a sensitivity of 71-92% and specificity of 56-96% for detecting dementia.31,32 Limitations of the MMSE include poor sensitivity to frontal lobe dysfunction and its influence by age, education level and culture.33-35 This can lead to failure to detect dementia in well-educated people and low scores in patients with language barriers, poor education, depression and anxiety, or who are feeling unwell at time of assessment.
Newer cognitive screening instruments, such as the Rowland Universal Dementia Assessment Scale (RUDAS) and the Montreal Cognitive Assessment (MoCA), are gaining more widespread use. In patients of non-English speaking background, the RUDAS should be utilised as it is designed to minimise the effects of cultural learning and language diversity.36,37 However, when mild cognitive impairment is suspected, the MoCA should be performed as it has been shown to be superior to the MMSE in detection mild cognitive impairment.38-40
In a busy clinical practice, a more rapid screening test may be desirable. The Clock Drawing Test (CDT) and Mini-Cognitive Assessment (Mini-Cog) are simple and quick screening instruments for gross abnormalities of cognition.41-43 CDT, when combined with three-item recall, forms the Mini-Cog. These tests takes less than three minutes to administer and compare well against other longer cognitive screening instruments. Abnormal findings on initial brief screening should trigger more detailed assessment.
When cognitive impairment has developed rapidly, delirium should be suspected. Use of a validated instrument such as the Confusion Assessment Method or the Memorial Delirium Assessment Scale can assist with screening, diagnosis and monitoring severity of delirium.44,45 The presence of delirium should prompt urgent assessment and treatment of the underlying cause and concurrent management of symptoms of delirium.46 Drugs and infection are the most common causes of delirium in the elderly. In most patients, delirium improves over time if the underlying cause is treated. Aggressive supportive care with appropriate non-pharmacological and pharmacological interventions should be instated until the patient recovers.
Depression can present as cognitive impairment (‘pseudodementia’), hence older adults with cancer who experience cognitive impairment should also be screened for depressive symptoms with a standardised screening instrument such as the Hospital Anxiety and Depression Scale or the Geriatric Depression Scale.47,48 The presence of depression warrants prompt intervention and treatment, which may include counselling, cognitive behavioural therapy, antidepressant therapy or referral to specialised psychiatry services.
It is important to emphasise that the diagnosis of cognitive impairment should not be based solely on abnormal cognitive screen results. Screening tests should be used to complement clinical judgement in assessing a patient’s cognition. If cognitive screen was abnormal, clinicians should obtain a structured history from the patient and an informant, perform a physical examination and mental state assessment, review medications and perform blood investigations for medical conditions that may contribute to cognitive impairment including vitamin B12, folate, thyroid function and calcium levels (table 3). Neuro-imaging such as CT or MRI, may be indicated if there is focal neurology to exclude structural brain lesions, such as brain metastasis, subdural haemorrhage and stroke. If diagnosis is uncertain, cognitive impairment persists, or cognition continues to deteriorate, patients should be referred to a memory clinic for specialist evaluation and detailed neuropsychological testing. The role of memory clinic is to provide expert clinical diagnosis, information on appropriate treatments, education, support and direction in future planning. As various types of dementia have different treatment options and rate of progression, accurate diagnosis is important to determine appropriate management and future planning.
Decision-making capacity is an important issue to consider in cancer patients with cognitive impairment, especially when cancer therapy often involves complex treatment decisions. The presence of cognitive impairment does not necessarily mean a lack of decision-making capacity, but further careful evaluation is required. To have decision-making capacity, an individual must be able to understand relevant information, appreciate the situation and its consequences, reason about treatment options and communicate a choice.49 If all these criteria are true, a person is capable of making a decision, even if that person has cognitive impairment. It is also possible for a person to lack capacity to make a specific decision, but not about another.
A person with cognitive impairment should be supported in making decisions for themselves where possible. Helpful strategies include involving close family members in decisions, repeating key points, using simple language, asking targeted questions and obtaining verbal feedback about their understanding. If the person is still unable to make an informed decision, then medical decisions can be made by a substitute decision-maker, which is usually a close family member, unless prior arrangements such as a medical power of attorney or advance directives have been made. In cancer patients, capacity can change rapidly due to complications from cancer or its treatment. Therefore, early on while the patient still has capacity, it is important to discuss issues such as the goals of care, treatment preference, advance directives and enduring power of attorney.
While the presence of cognitive impairment should not dictate treatment decisions, it is an important factor that needs to be considered. Cognitive impairment can shift the overall risk-benefit ratio of cancer treatment through its effects on life expectancy, morbidity, tolerance of therapy and adherence to treatment plan. The degree of impact of cognitive impairment depends on its severity and rate of progression. Individuals with mild cognitive impairment may not progress to dementia and may remain suitable to receive life-sustaining treatment.19 By contrast, individuals with moderate-to-severe cognitive impairment (MMSE<17) can have a five year mortality equivalent to the diagnosis of cancer.50 Estimating the trajectory of cognitive decline and overall life expectancy may contribute to planning for patients and families. Knowledge that dementia is a progressive, incurable disease with high morbidity and significant caregiver burden, or that certain treatments can exacerbate cognitive deterioration exemplified by brain radiotherapy and increase the level of care, could influence the patient’s preference for cancer treatment. Discussions with patients should take into consideration the patient’s priorities, prognosis and risk-benefit assessment of the intervention. Interventions should be tailored to maximise the effective dose and minimise toxicity in older cancer patients.
Recognising cognitive impairment early allows clinicians to anticipate problems and implement preventative measures. Cognitive impairment increases the risk of delirium during hospitalisation. Prevention strategies such as reorientation sleep enhancement, early mobilisation, vision optimisation, hearing optimisation and early correction of dehydration can significantly reduce the risk of delirium in hospitalised patients.51 In community patients undergoing chemotherapy, cognitive impairment may impact on the ability to recognise symptoms of toxicity or seek prompt medical attention. Proper education and social support can ameliorate some of these risks. Cognitive impairment should be taken into consideration when prescribing medications. Strategies to improve medication adherence should be considered, such as tailored medication information, systems to organise medications or enlisting social supports to monitor adherence or administer medications. Medications should be reviewed and inappropriate medications discontinued. Oral chemotherapy should be avoided if adherence is unreliable. Cognitive impairment can affect the patient’s ability to compensate for functional decline, perhaps indicated by poor mobility or psychosocial issues which are more common in elderly patients undergoing cancer therapy. Cognitive impairment also places significantly increased demands on caregivers and may limit the ability of families to support a patient through a complex treatment regimen. A comprehensive multidisciplinary approach to support patients and facilitate access to services can reduce some of the impact of cognitive impairment.
There is currently no established treatment for cognitive impairment due to chemotherapy or radiotherapy. Possible reversible causes, such as anaemia, vitamin deficiencies, endocrine dysfunction, metabolic abnormalities and medication side-effects should be addressed. Improvement of fatigue, pain and mood are also likely to improve cognitive performance. Cognitive and behavioural treatment strategies may also be employed, focusing on compensatory strategy training, stress management, energy conservation and psychoeducation.21 There is growing evidence that cognitive training through crosswords, Sudoku or the like, regular exercise, social engagement and good nutrition may correlate with improved cognitive performance.52 There are no known risks associated with using these non-pharmacological interventions, however the current evidence is insufficient to recommend them routinely in older adults with cancer.
The number of older adults with both cancer and cognitive impairment is predicted to increase due to an ageing population. The challenge faced by clinicians will be to identify and manage patients with these co-existing problems. Early identification can facilitate appropriate decision-making and interventions to reduce the effects of cognitive impairment on patients and their caregivers. Clinicians should be aware of methods of cognitive screening, availability of specialist diagnostic clinics and management strategies for cognitive impairment. Finally, further research is required to determine the optimal way to identify cognitive impairment in older cancer patients, to understand the relationship between cancer therapy and cognitive impairment, and to develop treatment options and preventative strategies to minimise the impact of cognitive impairment.