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:
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.
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).
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 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).
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.