Neurocognitive Effects Following Cranial Irradiation for Brain Metastases

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Neurocognitive Effects Following Cranial Irradiation for Brain Metastases M.B. Pinkham *y, P. Sanghera z, G.K. Wall x, B.D. Dawson x, G.A. Whitfield * * Clinical

Oncology, The University of Manchester, Manchester Cancer Research Centre, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester, UK y School of Medicine, University of Queensland, Brisbane, Australia z Hall Edwards Radiotherapy Research Group, Queen Elizabeth Hospital, Birmingham, UK x Neuropsychology, Salford Royal NHS Foundation Trust, Salford, UK Received 1 April 2015; accepted 3 June 2015

Abstract About 90% of patients with brain metastases have impaired neurocognitive function at diagnosis and up to two-thirds will show further declines within 2e6 months of whole brain radiotherapy. Distinguishing treatment effects from progressive disease can be challenging because the prognosis remains poor in many patients. Omitting whole brain radiotherapy after local therapy in good prognosis patients improves verbal memory at 4 months, but the effect of higher intracranial recurrence and salvage therapy rates on neurocognitive function beyond this time point is unknown. Hippocampal-sparing whole brain radiotherapy and postoperative stereotactic radiosurgery are investigational techniques intended to reduce toxicity. Here we describe the changes that can occur and review technological, pharmacological and practical approaches used to mitigate their effect in clinical practice. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Key words: Brain metastases; hippocampus; neurocognitive function; quality of life; radiotherapy; stereotactic radiosurgery

Statement of Search Strategies Used and Sources of Information Searches for original and review articles were conducted on Pubmed and Google Scholar databases. Search terms included ‘neurocognitive’, ‘cognitive’, ‘brain metastases’, ‘whole brain radiotherapy’, ‘stereotactic radiosurgery’ and ‘quality of life’. Individual bibliographies were reviewed for additional relevant references.

Introduction Brain metastases occur in around 25% of patients with a malignancy originating outside the central nervous system Author for correspondence: M. Pinkham, Clinical Oncology, Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. Tel: þ44-161-446-3977; Fax: þ44-161-446-8111. E-mail address: [email protected] (M.B. Pinkham).

(CNS) [1,2]. Deficits in neurocognitive function (NCF) may relate to intracranial disease progression or toxicity from treatment. Whole brain radiotherapy (WBRT) is a standard therapy [3,4] expected to improve neurological signs and symptoms in about 50% of patients [5e7]. Treatment for patients with brain metastases is individualised because WBRT may be associated with both declines [8e10] and improvements [11] in NCF depending on the clinical circumstances. Declining NCF increases caregiver burden [12] and impairs financial, work and social activities [13,14] in those who are able to remain independent. Changes in NCF precede and predict for changes in quality of life (QoL) and functional independence [15], but a causal relationship has not yet been proven. As systemic therapies continue to improve, the potential sequelae of cranial irradiation in this population become increasingly relevant. Here we describe changes in NCF that can occur, summarise how they are assessed and review technological, pharmacological and practical approaches used to mitigate their effect in clinical practice.

http://dx.doi.org/10.1016/j.clon.2015.06.005 0936-6555/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Pinkham MB, et al., Neurocognitive Effects Following Cranial Irradiation for Brain Metastases, Clinical Oncology (2015), http://dx.doi.org/10.1016/j.clon.2015.06.005

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Characterising Neurocognitive Changes after Cranial Radiotherapy The functional organisation of major cognitive domains within the brain is illustrated in Figure 1. NCF in patients with brain metastases is influenced by multiple interdependent factors (Table 1). Neurocognitive dysfunction is characterised by diminished learning and memory, attention, executive function, processing speed and motor dexterity [16]. However, defining the incidence of these deficits is challenging because of the way NCF is assessed and the timing of assessments has varied between studies. A number of expert groups recommend a core battery of sensitive, validated tests to assess NCF in brain metastases trials [17e19]. These include Hopkins Verbal Learning TestRevised (HVLT-R), Trail Making Test (TMT) parts A and B and the Controlled Oral Word Association (COWA) test (Table 2). Together these tests should take no longer than 30 minutes to complete, facilitating compliance [19]. The Mini-Mental State Examination (MMSE) is a dementia screening tool that has been used in older studies of cranial irradiation to measure NCF. However, it lacks sensitivity to detect changes relevant to many patients with brain tumours [19,20]. For example after cranial irradiation, HVLT-R [21] and TMT part B [22] scores show changes in NCF that MMSE does not. Impaired performance in at least one NCF test is apparent in up to 90% of self-caring adults at diagnosis of brain metastases, with verbal memory and fine motor deficits the most common [8]. Severity of impairment correlates with volume but not number of intracranial metastases [8,22,23]. Using sensitive neurocognitive tests, further reductions in NCF are detectable in up to 65% of patients within 2e6

months of WBRT [8,9,24e26]. The proportion attributable to treatment-induced neurotoxicity is unclear because progressive disease and pre-terminal decline are also common events during this interval and are confounding factors. In some patients, NCF stabilises or improves after WBRT due to regression of disease [8,11] and/or reduced rates of intracranial recurrence [23,27]. Benefits are greatest in terms of executive function and fine motor co-ordination rather than memory [8]. Data describing neurocognitive effects more than 6 months after WBRT for brain metastases are scant and limited by high dropout rates and confounding factors. An imaging study of nine long-term survivors with a median survival of 6.25 years showed acceleration in the rate of cerebral atrophy after WBRT compared with normal aging [28] but correlation with NCF was not reported. Some evidence suggests early detrimental effects may improve at later time points. In a study of 20 patients, memory function and performance in TMT part B deteriorated 4 months after WBRT but then improved by 8 months [22]. In the subgroup of nine patients surviving at least 12 months, regression of test scores back to baseline may suggest a biphasic pattern. In patients with stage III non-small cell lung cancer without brain metastases undergoing prophylactic cranial irradiation, memory impairment was greatest at 3 months and improved thereafter but did not return to baseline [21]. The proportion of patients with a deterioration in HVLT-R immediate recall score at 3, 6 and 12 months was 45, 19 and 26% patients, respectively. By contrast, the proportion of patients with deterioration at 12 months who did not receive prophylactic cranial irradiation was 7% (P ¼ 0.03). Prohibitively small numbers prevented analyses comparing those who developed intracranial failure versus those who did not.

Fig 1. Organisation of major cognitive domains. The hippocampus lies in the medial temporal lobe (MTL), coronal section shown. Neurogenesis occurs within the subgranular zone (SGZ) of the dentate gyrus (DG) and just below the floor of the temporal horn of the lateral ventricle in the subventricular (SVZ) zone. OT, optic tracts. Please cite this article in press as: Pinkham MB, et al., Neurocognitive Effects Following Cranial Irradiation for Brain Metastases, Clinical Oncology (2015), http://dx.doi.org/10.1016/j.clon.2015.06.005

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Table 1 Factors influencing neurocognitive function in patients with brain metastases Patient factors

Tumour factors

Age, gender Baseline cognitive function, education Fatigue, depression, anxiety

Intracranial disease burden (volume, location, response to treatment) Recurrent seizures Extracranial disease burden Paraneoplastic phenomena

Treatment factors

Other

Craniotomy Cranial radiotherapy (dose, volume) Chemotherapy Hormonal therapy Drugs: dexamethasone, anti-epileptics, opiates

Cerebrovascular disease Unrelated processes (e.g. infective, metabolic, endocrine, psychiatric, pain)

The Relevance of Neurocognitive Function in the Management of Brain Metastases Patients with brain metastases have competing risks for both survival and NCF. Most die from progressive extracranial disease and the median survival after WBRT is in the range 4e6 months [7]. Prognosis varies with the number of brain metastases, age, performance status, primary tumour type and extent of systemic disease [29,30] and can be used to inform treatment decisions. Irrespective of modality, treatment intent remains palliative in nearly all cases. Without randomised studies the survival benefit of WBRT is unknown, but median survival is 1e2 months in patients with the poorest prognosis treated with steroids alone [31,32]. In these patients, WBRT may be withheld on the basis that benefit is unlikely and to avoid early sideeffects such as fatigue and alopecia. Results from a randomised trial assessing QoL in such patients with non-small cell lung cancer are awaited (ClinicalTrials.gov Identifier NCT00403065). Local therapies, including surgery or stereotactic radiosurgery (SRS), may be considered in select patients with more favourable prognoses in an attempt to improve

outcomes [7,33e35]. SRS involves the precise delivery of a single high dose of radiation to the tumour to maximise local control and minimise dose to the surrounding normal brain [35]. Successful randomised comparisons of surgery and SRS have not been possible [36,37]. However both are considered equally efficacious in appropriately selected patients, although their relative effects on NCF are not well defined. In self-caring patients with up to four brain metastases, adding WBRT after local therapy reduces the risk of intracranial progression but does not improve overall survival or the duration of functional independence [38e40]. Due to potential adverse effects on QoL [41], the clinical benefit of WBRT in this setting is therefore disputed [3,42]. In 341 patients randomised to WBRT or observation, Soffieti et al. [41] reported that WBRT led to inferior health-related QoL total scores at 9 months (mean 63.2 versus 52.2, P ¼ 0.015) but not at 3, 6 or 12 months and significant differences in fatigue, physical functioning and role functioning were noted at 8 weeks. NCF was not assessed but differences in patient-reported cognitive functioning at 8 weeks (mean score 81.2 versus 73.9, P ¼ 0.026) and 12 months (80.4 versus 69.7, P ¼ 0.049) favouring observation were observed. Improved intracranial control after WBRT may

Table 2 Neurocognitive assessment in patients with brain metastases Test

Domain

Time

Administration

HVLT-R

Verbal memory and learning

8 min

TMT part A

Visuo-motor speed

5 min

TMT part B

Executive function

5 min

COWA

Verbal fluency and executive function

5 min

Immediate recall assessed using 12 word list rehearsed 3 times (maximum score 36). Delayed recall assessed after 20 min (maximum score 12). Recognition of words from a longer list (maximum score 12). There are 6 alternative versions to avoid practice effects. Subtle deficits may not be reliably detected. Connect 25 dots numbered 1 to 25 in order. Score is number of seconds to complete task (range 0e300). Connect 25 dots alternating numerical and alphabetical order (e.g. 1, A, 2, B, etc.). Score is number of seconds to complete task (range 0e300). There may be practice effects and variability of performance with time of day in older adults. Subject names as many words as possible in 1 min beginning with a specific letter (phenomic fluency) or from specific category (semantic fluency). Repeated 3 times using different letter or category each time. Age and gender adjusted raw score (range; 0e no upper limit).

HVLT-R, Hopkins Verbal Learning TesteRevised; TMT, Trail Making Test; COWA, Controlled Oral Word Association Test. Please cite this article in press as: Pinkham MB, et al., Neurocognitive Effects Following Cranial Irradiation for Brain Metastases, Clinical Oncology (2015), http://dx.doi.org/10.1016/j.clon.2015.06.005

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not have translated into a QoL benefit due to the use of surveillance magnetic resonance imaging and early salvage of recurrent disease. Typically the decision to withhold WBRT rests with physician and patient preferences based on the anticipated balance of risks between early, diffuse and/or symptomatic intracranial recurrence versus unacceptable radiotherapyinduced toxicities in that individual. The overall effect of withholding WBRT on NCF is uncertain. Aoyama et al. [23] assessed NCF using MMSE in 92 patients randomised to SRS þ WBRT or SRS alone and reported that the median time to deterioration in MMSE score by  3 points was 12.0 versus 6.6 months (P ¼ 0.05). Chang et al. [10] randomised 58 patients to the same treatment arms and assessed NCF using HVLT-R. The study was stopped early based on an interim analysis of 31 patients when NCF was shown to be inferior after SRS þ WBRT at 4 months with 52% versus 24% likelihood of decline in HVLT-R total recall score by  5 points. Adding WBRT reduced the risk of intracranial recurrence at 1 year from 73 to 27% (P ¼ 0.0003). However, unexpected imbalances in median survival between the arms confound interpretation of the data and the clinical significance of NCF assessed shortly before death in a large proportion of the patients receiving SRS þ WBRT is controversial. The effect of recurrence and salvage therapy on NCF in this cohort remains unknown and may be relevant [43]. These issues illustrate the complexities in NCF assessment in a heterogeneous population over time. Although no single cognitive domain, NCF test and/or assessment time point can remain universally the most relevant to all patients, clinically meaningful neurocognitive end points are essential in modern trials of brain metastases because benefits beyond overall survival and time to intracranial progression are needed to assess new treatments.

Supporting Patients with Neurocognitive Dysfunction Patients with brain metastases and cognitive impairment are best managed in a multidisciplinary team. This ensures that input is tailored to the stage of each patient’s cancer journey. A holistic approach enables separate but related issues including fatigue, pain, anxiety and depression to be addressed, which can negatively affect cognitive function. In addition support and practical advice for affected carers, family members and employers may be required. Local charitable organisations may be helpful in this regard [44,45]. Cognitive rehabilitation [46] attempts to overcome or ameliorate deficits in NCF by restoring and strengthening compensatory strategies. Evidence of benefit is growing for patients with primary CNS tumours although not all received cranial irradiation [47e50]. Evidence for patients with brain metastases is lacking, but it may be considered on an individual basis for patients with a favourable prognosis. A thorough neuropsychological assessment and full appreciation of the environmental context of impairment in

each individual is essential. External memory tools or aides (such as electronic alarms/reminder, diary or dosette box) may also be of benefit. For patients managed in the community, internet-based computer training programs such as www.lumosity.com could be considered [51,52]. However, efficacy has not been assessed in this specific population.

Pathogenesis of Radiotherapy-induced Neurocognitive Dysfunction Conventional radiobiology considered the brain a lateresponding, radioresistant organ, possibly attributable to an expected lack of mitosis after embryonal and early postnatal development. However, a strong body of evidence now indicates that adult mammalian brains do generate new cells, a process known as neurogenesis. Furthermore, clinically it is clear that radiotherapy-induced deficits in NCF follow a subacute, biphasic pattern that can occur within weeks or a few months of WBRT [8e10] and recover thereafter [21]. Adult mammalian neurogenesis is localised to regions with distinct micro-environments, including the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone within the hippocampal dentate gyrus (Figure 1) [53]. Animal experiments show that neural progenitor cells (NPC) in the SVZ actively cycle to yield new neurons that migrate to the olfactory bulb. However, the dentate gyrus seems to be the most active region of neurogenesis in humans [53,54]. This is of particular interest given the association between the hippocampus and new memory formation [55]. Neurogenesis has been implicated in new memory formation [56] and can be influenced by several factors. Animal and human data indicate that radiotherapy impairs neurogenesis [57e59] and induces a neuroinflammatory response. In young adult rats, cranial irradiation leads to deficits in spatial learning and memory that are associated with reductions in proliferating NPC, increased activated microglia and changes in the microvasculature of the hippocampus [59]. Microglia are immune cells within the brain that also regulate NPC biology and interact with multiple other cell types [60]. Hippocampal neurogenesis seems to be unaffected in older rats with radiotherapy-induced cognitive impairment [61] but activated microglia appear to release pro-inflammatory cytokines that can directly inhibit NPC [62]. This may be relevant in a wider context because not all hippocampaldependent learning depends on neurogenesis [63] and deficits in non-hippocampal-dependent domains of cognitive function also occur [64]. Drawing conclusions from animal data may be limited in part by the more rapid reduction in neurogenesis that seems to occur in aging rodents compared with humans [54]. However, the above characteristics fit well with the notion that an early-responding compartment responsible for brain function exists. It also offers one explanation why neurotoxicity can occur in the absence of structural abnormalities such as demyelination or necrosis. Functional magnetic resonance imaging techniques are being explored

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as a method of assessing neurogenesis in vivo and could provide further insights into the effect of radiotherapy [65]. As mechanisms underlying these changes become clear, molecular targets and pathways that can be modulated to mitigate these unwanted effects may emerge.

Alternative Radiotherapy Approaches to Mitigate Neurocognitive Effects To optimise NCF after cranial radiotherapy, manipulations of total dose, dose per fraction and volume of normal brain treated have been considered. Reducing the volume of normal brain treated can be achieved through omitting WBRT altogether, exclusively targeting at risk regions and/ or avoiding unaffected ones. Each approach bears distinct pros and cons. No difference in overall survival or symptom control has been shown for commonly used WBRT dose-fractionation schemes (such as 30 Gy in 10 fractions and 20 Gy in five fractions) or compared with altered fractionation [3,4]. The effects on QoL and NCF are not well described within these studies. No significant difference in MMSE score at 2 and 3 months was apparent in 445 patients with brain metastases randomised to 30 Gy in 10 fractions versus 54.4 Gy in 34 fractions twice daily [24]. Using more sensitive NCF tests in a randomised phase II study of 264 patients with limited stage small cell lung cancer undergoing prophylactic cranial irradiation, the incidence of cognitive decline at 12 months was 85, 89 and 62% in those receiving 36 Gy in 18 fractions, 36 Gy in 24 fractions twice daily and 25 Gy in 10 fractions (P ¼ 0.03), respectively [66].

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The omission of WBRT through the use of SRS for good prognosis patients with up to four metastases is an increasingly common approach. After surgery, the risk of intracranial recurrence remains greatest locally and WBRT reduces this from 59 to 27% at 2 years [40]. Local radiotherapy, whether fractionated [67] or SRS [68], to the surgical cavity may improve local control while limiting dose to other areas of the brain. However, target localisation and cavity dynamics may make this challenging in some cases, particularly for SRS when margins of normal tissue included in the high dose volume should be kept small. The efficacy of postoperative SRS compared with WBRT is currently under assessment in a phase III randomised trial and NCF at 6 months is a co-primary end point (ClinicalTrials.gov identifier NCT01372774). Given that WBRT improves both local and distant intracranial disease control, novel ways of delivering cranial radiotherapy while reducing the effect on NCF are being explored. Hippocampal NPC located within the SVZ and dentate gyrus represent a radiosensitive organ at risk and the dose delivered to them can be reduced using intensitymodulated radiotherapy [69,70] in the hope of preserving NCF (Figure 2). The dose response of human hippocampal NPC is unknown, but even 1 Gy has demonstrable effects on neurogenesis in rats [71]. A potential consequence of hippocampal-sparing WBRT (hsWBRT) is an increased risk of recurrent disease within the temporal lobes. However, only 5e8% of metastases are located within 5 mm of the hippocampi at diagnosis [72,73]. Gondi et al. [74] evaluated changes in NCF and QoL in 42 patients who received hsWBRT as part of a multiinstitutional phase II study. Patients with metastases within 5 mm of either hippocampus or metastatic small cell

Fig 2. Hippocampal-sparing whole brain radiotherapy can restrict the dose to bilateral hippocampi while maintaining homogenous dose elsewhere in the brain. Please cite this article in press as: Pinkham MB, et al., Neurocognitive Effects Following Cranial Irradiation for Brain Metastases, Clinical Oncology (2015), http://dx.doi.org/10.1016/j.clon.2015.06.005

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lung cancer or germ cell tumours were not eligible. The dose prescribed was 30 Gy in 10 fractions and the dose to the hippocampi was restricted (minimum dose 10 Gy and maximum point dose 17 Gy). The mean relative decline in HVLT-R delayed recall score at 4 months was 7% (95% confidence interval e5 to 19%) compared with 30% in a historic control group [75]. Patients aged 60 years were more likely to experience a decline in HVLT-R delayed recall with time. QoL remained stable during the study period.

Pharmacological Approaches to Mitigate Neurocognitive Effects Drugs used to maintain NCF after cranial irradiation can be broadly classified as radioprotectors, radiosensitisers, neuromodulators or CNS stimulants. There is some evidence to support the use of memantine in preventing cognitive decline after WBRT and donepezil to treat established deficits [26,76,77]. However, in general, further work is needed in this area because most studies are inconclusive and limited by poor accrual and high participant attrition [78]. Memantine is a non-competitive antagonist for the Nmethyl-D-aspartate (NMDA) receptor, which is licensed in Alzheimer’s disease and has also been shown to have some benefit in vascular dementia [79], possibly by blocking ischaemia-induced NMDA stimulation and excitotoxicity. Brown et al. [26] hypothesised that it might have radioprotective effects by blocking pathological excitotoxicity associated with radiotherapy-induced small vessel disease. They randomised 508 patients with brain metastases and MMSE >18 to receive memantine or placebo during and after WBRT for 24 weeks in total [26]. There was no statistically significant difference in HVLT-R delayed recall score at 4 months between the arms (the primary end point, P ¼ 0.059) although the study was underpowered with only 149 patients available for analysis at this time. Small but statistically significant improvements in HVLT-R delayed recognition, COWA, overall NCF and time to cognitive failure were observed. The adverse events of memantine resembled those of placebo. Donepezil is a neuromodulatory agent that increases cholinergic transmission in the brain by reversible inhibition of acetyl cholinesterase. Shaw et al. [76] reported a phase II trial administering donepezil for 6 months to 24 patients with primary brain tumours who had received cranial irradiation previously. They noted statistically significant improvements in a range of NCF tests compared with baseline and acceptable toxicity. They have since presented results from a phase III randomised placebocontrolled trial in abstract form [77]; full publication is awaited. There were 198 patients, including 27% with brain metastases and all had received cranial irradiation at least 6 months previously. There was no difference in improvement in overall cognitive function between the two arms but statistically significant gains in HVLT-R recognition, HVLT-R discrimination and psychomotor tests favouring donepezil.

Methylphenidate [80] and modafinil [80,81] are CNS stimulants that have been evaluated in small uncontrolled studies of patients with primary CNS tumours, but high quality data on efficacy and toxicity are lacking. Combining WBRT with radiosensitisers, such as motexafin gadolinium (MGd) [8,75] or thalidomide [25], to maximise intracranial control has not shown a clear benefit in NCF or overall survival. Trends to prolonged neurocognitive progression in patients with brain metastases from non-small cell lung cancer have been observed with WBRT þ MGd [8,75,82]. Preclinical data suggest a number of drugs including ramipril [64], lithium [83], indomethacin [84] and pioglitazone [85] that are already widely available for other indications, improve cognitive outcomes after WBRT in tumour-free rats. Careful evaluation in the clinic is needed to ensure they do not radioprotect the tumour.

Future Directions Advances in radiotherapy technology should be properly assessed before routine clinical use with efficacy (in terms of quality of survival and NCF) and cost-effectiveness the priorities. For patients with between one and four brain metastases undergoing local therapy, the neurocognitive effects beyond 4 months of adding WBRT remain uncertain and the role of hsWBRT in this setting is yet to be defined. A randomised phase II trial comparing WBRT and hsWBRT in patients with one to four brain metastases after SRS or surgery with HVLT-R total recall score at 4 months as the primary end point and longitudinal NCF assessment to 2 years post-treatment is about to open in the UK (ClinicalTrials.gov ID NCT02147028). A similar trial is ongoing in France in breast cancer patients after surgery to a single metastasis (ClinicalTrials.gov NCT01942980). A phase III trial evaluating NCF in patients receiving memantine and WBRT versus memantine and hsWBRT is also planned (ClinicalTrials.gov ID NCT02360215). Together these trials should help to clarify whether the additional resources associated with hsWBRT can be justified. For patients with at least five brain metastases, highquality data are needed to inform treatment recommendations. At present most of these patients still have a very poor prognosis but select patients, for example with low volume brain metastases and controllable extracranial disease, may survive longer. SRS [86] and/or systemic therapy [87e92] may be considered in some patients instead of upfront WBRT, but current data are biased by patient selection and the effect on NCF using sensitive neurocognitive tests is unknown. A phase III randomised trial of Gamma Knife SRS versus WBRT is currently recruiting patients with 5 brain metastases and total tumour volume 15 cm3 to evaluate differences in NCF at 6 months (ClinicalTrials.gov ID NCT01731704). As the management of brain metastases becomes increasingly individualised, neurocognitive and QoL end points in future trials should reflect this to ensure they remain relevant to patients from a range of prognostic

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groups, primary tumour types and social backgrounds. Distinguishing between screen-detected and self-reported or carer-reported cognitive outcomes could become relevant. Decision analysis tools [93] may help to quantify and examine the overall balance of pros and cons in different populations. Together with further work in functional imaging and biomarkers to predict those at greatest risk of intracranial progression and/or neurotoxicity, this may help to refine and inform the selection of patients for different treatments.

Conclusions Most patients with brain metastases have impaired NCF at diagnosis. Therefore baseline assessment is essential to understand changes with time. Separating the effects of treatment from disease progression is challenging and to date few studies have included detailed NCF assessments. Deficits in verbal memory can occur around 2e4 months after WBRT, although the significance for patients with favourable prognoses is uncertain because partial recovery may occur and regression of disease can lead to stabilisation or improvements in NCF. In patients undergoing local therapy, WBRT may be omitted due to concerns regarding QoL but the effect of increased intracranial recurrence on NCF is yet to be defined. Advanced radiotherapy techniques, including hsWBRT and postoperative cavity SRS, are currently under evaluation as ways to minimise toxicity. Future trials should assess both NCF and QoL as measures of efficacy.

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[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

Acknowledgements The authors are grateful to Sara Robson for advice regarding the support of patients with neurocognitive dysfunction in the community.

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[17]

References [1] Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004;22(14): 2865e2872. [2] Gavrilovic IT, Posner JB. Brain metastases: epidemiology and pathophysiology. J Neurooncol 2005;75(1):5e14. [3] Tsao MN, Rades D, Wirth A, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 2012;2(3):210e225. [4] Tsao MN, Lloyd N, Wong RKS, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev Online 2012;4. CD003869. [5] Borgelt B, Gelber R, Kramer S, et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980;6(1):1e9. [6] Borgelt B, Gelber R, Larson M, Hendrickson F, Griffin T, Roth R. Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: final results of the first two studies by the

[18]

[19]

[20]

[21]

[22]

7

Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981;7(12):1633e1638. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004;363(9422):1665e1672. Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol 2004;22(1): 157e165. Welzel G, Fleckenstein K, Schaefer J, et al. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys 2008;72(5):1311e1318. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10(11):1037e1044. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol 2007;25(10):1260e1266. Germain S, Adam S, Olivier C, et al. Does cognitive impairment influence burden in caregivers of patients with Alzheimer’s disease? J Alzheimers Dis 2009;17(1):105e114. Griffith HR, Belue K, Sicola A, et al. Impaired financial abilities in mild cognitive impairment: a direct assessment approach. Neurology 2003;60(3):449e457. Meyers CA. Functional outcomes. In: Berger MS, Prados M, editors. Textbook of neuro-oncology. Philadelphia: Elsevier; 2005. p. 101e104. Li J, Bentzen SM, Li J, Renschler M, Mehta MP. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys 2008;71(1):64e70. Klein M, Heimans JJ, Aaronson NK, et al. Effect of radiotherapy and other treatment-related factors on mid-term to longterm cognitive sequelae in low-grade gliomas: a comparative study. Lancet 2002;360(9343):1361e1368. Meyers CA, Brown PD. Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol 2006;24(8):1305e1309. Preusser M, Winkler F, Collette L, et al. Trial design on prophylaxis and treatment of brain metastases: lessons learned from the EORTC Brain Metastases Strategic Meeting 2012. Eur J Cancer 2012;48(18):3439e3447. Lin NU, Wefel JS, Lee EQ, et al. Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group. Lancet Oncol 2013;14(10):e407ee416. Meyers CA, Wefel JS. The use of the mini-mental state examination to assess cognitive functioning in cancer trials: no ifs, ands, buts, or sensitivity. J Clin Oncol 2003;21(19): 3557e3558. Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 2011;29(3):279e286. Onodera S, Aoyama H, Tha KK, et al. The value of 4-month neurocognitive function as an endpoint in brain metastases trials. J Neurooncol 2014;120(2):311e319.

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[23] Aoyama H, Tago M, Kato N, et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys 2007;68(5):1388e1395. [24] Regine WF, Scott C, Murray K, Curran W. Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. accelerated-hyperfractionated radiotherapy: an analysis from Radiation Therapy Oncology Group Study 91-04. Int J Radiat Oncol Biol Phys 2001; 51(3):711e717. [25] Corn BW, Moughan J, Knisely JPS, et al. Prospective evaluation of quality of life and neurocognitive effects in patients with multiple brain metastases receiving whole-brain radiotherapy with or without thalidomide on Radiation Therapy Oncology Group (RTOG) trial 0118. Int J Radiat Oncol Biol Phys 2008;71(1):71e78. [26] Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving wholebrain radiotherapy: a randomized, double-blind, placebocontrolled trial. Neuro-Oncology 2013;15(10):1429e1437. [27] Penitzka S, Steinvorth S, Sehlleier S, Fuss M, Wannenmacher M, Wenz F. Assessment of cognitive function after preventive and therapeutic whole brain irradiation using neuropsychological testing. Strahlenther Onkol 2002; 178(5):252e258. [28] Sanghera P, Gardner SL, Scora D, Davey P. Early expansion of the intracranial CSF volume after palliative whole-brain radiotherapy: results of a longitudinal CT segmentation analysis. Int J Radiat Oncol Biol Phys 2010;76(4):1171e1176. [29] Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37(4):745e751. [30] Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012;30(4):419e425. [31] Horton J, Baxter DH, Olson KB. The management of metastases to the brain by irradiation and corticosteroids. Am J Roentgenol 1971;111(2):334e336. [32] Langley RE, Stephens RJ, Nankivell M, et al. Interim data from the Medical Research Council QUARTZ Trial: does whole brain radiotherapy affect the survival and quality of life of patients with brain metastases from non-small cell lung cancer? Clin Oncol 2013;25(3):e23ee30. [33] Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322(8):494e500. [34] Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al. The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994;29(4):711e717. [35] Pinkham MB, Whitfield GA, Brada M. New developments in intracranial stereotactic radiotherapy for metastases. Clin Oncol 2015;27:316e323. [36] Muacevic A, Wowra B, Siefert A, Tonn J-C, Steiger H-J, Kreth FW. Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial. J Neurooncol 2008;87(3):299e307. [37] Roos DE, Smith JG, Stephens SW. Radiosurgery versus surgery, both with adjuvant whole brain radiotherapy, for solitary brain metastases: a randomised controlled trial. Clin Oncol 2011;23(9):646e651.

[38] Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998;280(17):1485e1489. [39] Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006;295(21):2483e2491. [40] Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011;29(2):134e141. [41] Soffietti R, Kocher M, Abacioglu UM, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol 2013;31(1):65e72. [42] Choosing Wisely. ASTRO releases second list of five radiation oncology treatments to question, as part of national Choosing WiselyÒ campaign. Available at: http://www.choosingwisely. org/astro-releases-second-list/. [43] Regine WF, Huhn JL, Patchell RA, et al. Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery alone in patients with newly diagnosed brain metastases: results and implications. Int J Radiat Oncol Biol Phys 2002;52(2):333e338. [44] Macmillan Cancer Support. Available at: http://www. macmillan.org.uk/. [45] Headway e the Brain Injury Association. Available at: https:// www.headway.org.uk/home.aspx. [46] Cicerone KD, Langenbahn DM, Braden C, et al. Evidence-based cognitive rehabilitation: updated review of the literature from 2003 through 2008. Arch Phys Med Rehabil 2011;92(4): 519e530. [47] Locke DEC, Cerhan JH, Wu W, et al. Cognitive rehabilitation and problem-solving to improve quality of life of patients with primary brain tumors: a pilot study. J Support Oncol 2008;6(8):383e391. [48] Gehring K, Sitskoorn MM, Gundy CM, et al. Cognitive rehabilitation in patients with gliomas: a randomized, controlled trial. J Clin Oncol 2009;27(22):3712e3722. [49] Zucchella C, Capone A, Codella V, et al. Cognitive rehabilitation for early post-surgery inpatients affected by primary brain tumor: a randomized, controlled trial. J Neurooncol 2013;114(1):93e100. [50] Hassler MR, Elandt K, Preusser M, et al. Neurocognitive training in patients with high-grade glioma: a pilot study. J Neurooncol 2010;97(1):109e115. [51] Kesler S, Hadi Hosseini SM, Heckler C, et al. Cognitive training for improving executive function in chemotherapy-treated breast cancer survivors. Clin Breast Cancer 2013;13(4): 299e306. [52] Finn M, McDonald S. Computerised cognitive training for older persons with mild cognitive impairment: a pilot study using a randomised controlled trial design. Brain Impair 2011;12(03):187e199. €rk-Eriksson T, et al. Neurogenesis [53] Eriksson PS, Perfilieva E, Bjo in the adult human hippocampus. Nat Med 1998;4(11): 1313e1317. [54] Spalding KL, Bergmann O, Alkass K, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 2013;153(6): 1219e1227. [55] Scoville W, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 1957; 20(1):11e21.

Please cite this article in press as: Pinkham MB, et al., Neurocognitive Effects Following Cranial Irradiation for Brain Metastases, Clinical Oncology (2015), http://dx.doi.org/10.1016/j.clon.2015.06.005

M.B. Pinkham et al. / Clinical Oncology xxx (2015) 1e10 [56] Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. Neurogenesis in the adult is involved in the formation of trace memories. Nature 2001;410(6826):372e376. [57] Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med 2002;8(9):955e962. [58] Monje ML, Vogel H, Masek M, Ligon KL, Fisher PG, Palmer TD. Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies. Ann Neurol 2007;62(5):515e520. [59] Raber J, Rola R, LeFevour A, et al. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res 2004;162(1):39e47. [60] Tofilon PJ, Fike JR. The radioresponse of the central nervous system: a dynamic process. Radiat Res 2000;153(4):357e370. [61] Schindler MK, Forbes ME, Robbins ME, Riddle DR. Agingdependent changes in the radiation response of the adult rat brain. Int J Radiat Oncol Biol Phys 2008;70(3):826e834. [62] Dong X, Luo M, Huang G, et al. Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of mice. Int J Radiat Biol 2015;91(3):224e239. [63] Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 2002;12(5): 578e584. [64] Lee TC, Greene-Schloesser D, Payne V, et al. Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiationinduced perirhinal cortex-dependent cognitive impairment. Radiat Res 2012;178(1):46e56. [65] Manganas LN, Zhang X, Li Y, et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 2007;318(5852):980e985. [66] Wolfson AH, Bae K, Komaki R, et al. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81(1):77e84. [67] Minniti G, D’Angelillo RM, Scaringi C, et al. Fractionated stereotactic radiosurgery for patients with brain metastases. J Neurooncol 2014;117(2):295e301. [68] Soltys SG, Adler JR, Lipani JD, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys 2008;70(1):187e193. [69] Gondi V, Tolakanahalli R, Mehta MP, et al. Hippocampalsparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2010;78(4):1244e1252. [70] Shen J, Bender E, Yaparpalvi R, et al. An efficient volumetric arc therapy treatment planning approach for hippocampalavoidance whole-brain radiation therapy (HA-WBRT). Med Dosim Jan 17, 2015 [Epub ahead of print]. [71] Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 2003;63(14):4021e4027. [72] Gondi V, Tome WA, Marsh J, et al. Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. Radiother Oncol 2010;95(3):327e331. [73] Hong AM, Suo C, Valenzuela M, et al. Low incidence of melanoma brain metastasis in the hippocampus. Radiother Oncol 2014;111(1):59e62.

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[74] Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stemcell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 2014;32(34):3810e3816. [75] Mehta MP, Rodrigus P, Terhaard CHJ, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 2003;21(13):2529e2536. [76] Shaw EG, Rosdhal R, D’Agostino RB, et al. Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol 2006;24(9):1415e1420. [77] Rapp SR, Case D, Peiffer A, et al. Phase III randomized, double-blind, placebo-controlled trial of donepezil in irradiated brain tumor survivors. ASCO Meet Abstr 2013;31(Suppl. 15):2006. [78] Day J, Zienius K, Gehring K, et al. Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation. Cochrane Database Syst Rev 2014;12. CD011335. €ffler A, Mo € bius H-J, Forette F. Ef[79] Orgogozo J-M, Rigaud A-S, Sto ficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebocontrolled trial (MMM 300). Stroke J Cereb Circ 2002;33(7):1834e1839. [80] Gehring K, Patwardhan SY, Collins R, et al. A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor. J Neurooncol 2012;107(1): 165e174. [81] Kaleita TA, Wellisch DK, Graham CA, et al. Pilot study of modafinil for treatment of neurobehavioral dysfunction and fatigue in adult patients with brain tumors. ASCO Meet Abstr 2006;24(Suppl. 18):1503. [82] Mehta MP, Shapiro WR, Phan SC, et al. Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial. Int J Radiat Oncol Biol Phys 2009;73(4):1069e1076. [83] Huo K, Sun Y, Li H, et al. Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain. Mol Cell Neurosci 2012;51(1e2):32e42. [84] Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302(5651):1760e1765. [85] Zhao W, Payne V, Tommasi E, Diz DI, Hsu F-C, Robbins ME. Administration of the peroxisomal proliferator-activated receptor gamma agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys 2007;67(1):6e9. [86] Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014;15(4):387e395. [87] Gerber NK, Yamada Y, Rimner A, et al. Erlotinib versus radiation therapy for brain metastases in patients with EGFRmutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys 2014;89(2):322e329. [88] Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol 2013;14(1):64e71.

Please cite this article in press as: Pinkham MB, et al., Neurocognitive Effects Following Cranial Irradiation for Brain Metastases, Clinical Oncology (2015), http://dx.doi.org/10.1016/j.clon.2015.06.005

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M.B. Pinkham et al. / Clinical Oncology xxx (2015) 1e10

[89] Bartsch R, Berghoff AS, Preusser M. Breast cancer brain metastases responding to primary systemic therapy with T-DM1. J Neurooncol 2014;116(1):205e206. [90] Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13(11):1087e1095. [91] Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13(5):459e465.

[92] Lim ZD, Mahajan A, Weinberg J, Tannir NM. Outcome of patients with renal cell carcinoma metastatic to the brain treated with sunitinib without local therapy. Am J Clin Oncol 2013;36(3):258e260. [93] Lee JJ, Bekele BN, Zhou X, Cantor SB, Komaki R, Lee JS. Decision analysis for prophylactic cranial irradiation for patients with small-cell lung cancer. J Clin Oncol 2006;24(22): 3597e3603.

Please cite this article in press as: Pinkham MB, et al., Neurocognitive Effects Following Cranial Irradiation for Brain Metastases, Clinical Oncology (2015), http://dx.doi.org/10.1016/j.clon.2015.06.005