Neurocognitive Performance in Adults Treated With Radiation for a Primary Brain Tumor.

Purpose: The contributory effects of radiation dose to different brain regions on neurocognitive performance after radiation therapy (RT) for primary brain tumors is not well known. Methods and Materials: In this retrospective cohort study, 30 patients with brain tumors treated with photon RT were identified, and radiation dosimetric parameters across brain regions were calculated. All patients had longitudinal neurocognitive evaluations at baseline and after treatment. Generalized estimating equations were used to model each neurocognitive endpoint over time in a multivariable analysis, while adjusted for multiple comparisons of brain regions. Results: Median follow-up from RT to last assessment was 4.1 years. Fewer years of formal education and older age at the time of RT were associated with lower scores in language, verbal memory, and working memory, after adjustment for baseline scores in multivariable analyses. Higher radiation dose to specific brain regions was not associated with declines in any of the evaluated cognitive domains. On average, there was no clinically significant decline (magnitude of z score change >1) between first and last neurocognitive evaluation. Across each individual cognitive domain, fewer than 15% of patients were impaired at most recent follow-up. Conclusions: In this small study of 30 patients treated with RT for a primary brain tumor, brain region dosimetry was not associated with decline in cognitive performance. Older age at time of RT and fewer years of formal education were associated with declines in cognitive performance, suggesting that effects of nondosimetric factors on cognitive performance should be considered alongside treatment factors and dosimetry in neuro-oncology research.

Factors associated with cognitive impairment and cognitive concerns in patients with metastatic non-small cell lung cancer.

BACKGROUND: Knowledge regarding cognitive problems in metastatic non-small cell lung cancer (mNSCLC) is limited. Such problems may include both patient-reported cognitive concerns and demonstrable cognitive impairment. Greater understanding of these outcomes is needed to inform rehabilitation strategies for these difficulties. We aimed to identify the frequency of cognitive problems and associated factors in patients with mNSCLC. METHODS: In this cross-sectional study, adults with mNSCLC completed validated neuropsychological tests and self-report questionnaires measuring cognitive concerns, neurobehavioral concerns, depression, demoralization, illness intrusiveness, self-esteem, and physical symptoms. Cognitive impairment (performance based) was defined according to International Cancer and Cognition Task Force criteria. Clinically significant cognitive concerns were defined by a score ≥1.5 SD below the normative mean on the Functional Assessment of Cancer Therapy-Cognitive Function Perceived Cognitive Impairment (FACT-Cog PCI). Univariate and multivariate logistic regression analyses were performed to identify associated factors. RESULTS: Of 238 patients approached, 77 participated (median age: 62 years; range: 37-82). Brain metastases were present in 41 patients (53%), and 23 (29%) received cranial irradiation. Cognitive impairment and cognitive concerns were present in 31 (40%) and 20 patients (26%), respectively. Cognitive impairment and cognitive concerns co-occurred in 10 patients (13%), but their severity was unrelated. Cognitive impairment was associated with cranial irradiation (odds ratio [OR] = 2.89; P = .04), whereas cognitive concerns were associated with greater illness intrusiveness (OR = 1.04; P = .03) and lower self-esteem (OR = 0.86; P = .03). CONCLUSIONS: Cognitive impairment and cognitive concerns are both common in patients with mNSCLC but are not necessarily related, and their risk factors differ. The association of illness intrusiveness and self-esteem with cognitive concerns can inform therapeutic interventions in this population.

Death Anxiety in Patients With Metastatic Non-Small Cell Lung Cancer With and Without Brain Metastases.

CONTEXT: Death anxiety is common in patients with metastatic cancer, but its relationship to brain metastases and cognitive decline is unknown. Early identification of death anxiety and its determinants allows proactive interventions to be offered to those in need. OBJECTIVES: To identify psychological, physical, and disease-related (including brain metastases and cognitive impairment) factors associated with death anxiety in metastatic non-small cell lung cancer (mNSCLC) patients. METHODS: A cross-sectional pilot study with mNSCLC outpatients completing standardized neuropsychological tests and validated questionnaires measuring death anxiety, cognitive concerns, illness intrusiveness, depression, demoralization, self-esteem, and common cancer symptoms. We constructed a composite for objective cognitive function (mean neuropsychological tests z-scores). RESULTS: Study measures were completed by 78 patients (50% females; median age 62 years [range 37-82]). Median time since mNSCLC diagnosis was 11 months (range 0-89); 53% had brain metastases. At least moderate death anxiety was reported by 43% (n = 33). Objective cognitive impairment was present in 41% (n = 32) and perceived cognitive impairment in 27% (n = 21). Death anxiety, objective, and perceived cognitive impairment did not significantly differ between patients with and without brain metastases. In univariate analysis, death anxiety was associated with demoralization, depression, self-esteem, illness intrusiveness, common physical cancer symptoms, and perceived cognitive impairment. In multivariate analysis, demoralization (P < 0.001) and illness intrusiveness (P = 0.001) were associated with death anxiety. CONCLUSION: Death anxiety and brain metastases are common in patients with mNSCLC but not necessarily linked. The association of death anxiety with both demoralization and illness intrusiveness highlights the importance of integrated psychological and symptom management. Further research is needed on the psychological impact of brain metastases.

Cognitive rehabilitation for cancer-related cognitive dysfunction: a systematic review.

PURPOSE: Individuals with non-central nervous system (CNS) cancers can experience cancer-related cognitive dysfunction (CRCD), negatively impacting daily functioning and quality of life. This systematic review examined cognitive rehabilitation programs aimed at improving cognitive function. METHODS: PsychInfo and PubMed were searched in February 2019. Eligible studies evaluated a cognitive rehabilitation program for adults with non-CNS cancers and included at least one objective cognitive measure. Across studies, we assessed methodological quality using relevant criteria based on published intervention-related review guidelines and examined findings from performance-based and self-reported outcome measures. RESULTS: 19 studies met inclusion criteria, totalling 1124 participants altogether. These studies included randomized controlled trials (n = 12), partial, quasi or non-randomized controlled trials (n = 3) and single-arm pilot studies (n = 4). All studies found improvements on at least one cognitive measure (performance-based or self-reported). By cognitive domain, objective improvements in memory were most commonly reported, followed by executive functions and processing speed. In terms of methodological quality, studies generally provided clear descriptions of participants and interventions. However, limitations included lack of standardized terminology for interventions, discrepancies in outcome measures, and incomplete statistical reporting. CONCLUSIONS: The available evidence supports clinical implementation of cognitive rehabilitation to improve CRCD, with further work in program development, dissemination, and feasibility recommended. We provide specific recommendations to facilitate future research and integration in this field.

The Impact of Brain Metastases and Associated Neurocognitive Aspects on Health Utility Scores in EGFR Mutated and ALK Rearranged NSCLC: A Real World Evidence Analysis.

BACKGROUND: In lung cancer, brain metastases (BM) and their treatment are associated with high economic burden and inferior health-related quality of life. In the era of targeted therapy, real world evidence through health utility scores (HUS) is critical for economic analyses. MATERIALS AND METHODS: In a prospective observational cohort study (2014-2016), outpatients with stage IV lung cancer completed demographic and EQ-5D-3L surveys (to derive HUS). Health states and clinicopathologic variables were obtained from chart abstraction. Patients were categorized by the presence or absence of BM; regression analyses identified factors that were associated with HUS. A subset of patients prospectively completed neurocognitive function (NCF) tests and/or the FACT-brain (FACT-Br) questionnaire, which were then correlated with HUS (Spearman coefficients; regression analyses). RESULTS: Of 519 patients with 1,686 EQ-5D-3L-derived HUS, 94 (18%) completed NCF tests and 107 (21%) completed FACT-Br; 301 (58%) never developed BM, 24 (5%) developed first BM during study period, and 194 (37%) had BM at study entry. The sample was enriched (46%) for EGFR mutations (EGFRm) and ALK-rearrangements (ALKr). There were no HUS differences by BM status overall and in subsets by demographics. In multivariable analyses, superior HUS was associated with having EGFRm/ALKr (p < .0001), no prior radiation for extracranial disease (p < .001), and both intracranial (p = .002) and extracranial disease control (p < .01). HUS correlated with multiple elements of the FACT-Br and tests of NCF. CONCLUSION: Having BM in lung cancer is not associated with inferior HUS in a population enriched for EGFRm and ALKr. Patients exhibiting disease control and those with oncogene-addicted tumors have superior HUS. IMPLICATIONS FOR PRACTICE: In the setting of EGFR mutations or ALK rearrangement non-small cell lung cancer (NSCLC), a diagnosis of brain metastases no longer consigns the patient to an inferior health state suggesting that new economic analyses in NSCLC are needed in the era of targeted therapies. Additionally, the EQ-5D questionnaire is associated with measures of health-related quality of life and neurocognitive scores suggesting this tool should be further explored in prospective clinical studies.

Cognitive rehabilitation for executive dysfunction in brain tumor patients: a pilot randomized controlled trial.

PURPOSE: Patients with brain tumors face unique quality of life challenges. Executive dysfunction is common and functionally limiting, with no established treatments as standard care. This pilot study evaluated the efficacy of Goal Management Training (GMT), a behavioral intervention combining mindfulness and strategy training, for improving executive and real-life functioning in this population. METHODS: Twenty-five primary brain tumor survivors were randomized to GMT, an active control (Brain Health Program, BHP), or a wait-list (WAIT) control group. The BHP was a supportive care intervention offering education and activities to promote general brain health, without cognitive strategy training. Participants in GMT and BHP completed eight individual sessions and homework between sessions; those in WAIT received usual care. Assessments at baseline, immediately post-training, and 4-month follow-up used a battery of objective and subjective measures, including functional goal attainment. RESULTS: Adherence (% sessions completed) was high for both GMT (98.9%) and BHP (84.4%). Executive functions improved with GMT but not BHP or WAIT (repeated measures analysis of variance, time-by-group interaction, post-training P = 0.077, follow-up P = 0.046). Both intervention groups reported fewer cognitive concerns at post-training (P = 0.049) and follow-up (P < 0.001). Functional goal attainment was greatest with GMT (post-training P = 0.027, follow-up P = 0.064). CONCLUSIONS: GMT improved executive and real-life functioning in brain tumor survivors, with gains maintained at 4-month follow-up. Clinical implementation of this adaptable program merits consideration for clinically stable patients with cognitive dysfunction. Further development and larger prospective cognitive rehabilitation trials appear warranted.

External modulation of the sustained attention network in traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is associated with impairments in processing speed as well as higher-level cognitive functions that depend on distributed neural networks, such as regulating and sustaining attention. Although exogenous alerting cues have been shown to support patients in sustaining attentive, goal-directed behavior, the neural correlates of this rehabilitative effect are unclear. The purpose of this study was to explore the effects of moderate to severe TBI on activity and functional connectivity in the well-documented right-lateralized frontal-subcortical-parietal sustained attention network, and to assess the effects of alerting cues. METHOD: Using multivariate analysis of fMRI data, TBI patients and matched neurologically healthy (NH) comparison participants were scanned as they performed the Sustained Attention to Response Task (SART) in 60-s blocks, with or without exogenous cueing through brief auditory alerting tones. RESULTS: Results documented inefficient voluntary control of attention in the TBI patients, with reduced functional connectivity in the sustained attention network relative to NH participants. When alerting cues were present during the SART, however, functional connectivity increased and became comparable to activity patterns seen in the NH group. CONCLUSIONS: These findings provide novel evidence of a neural mechanism for the facilitatory effects of alerting cues on goal-directed behavior in patients with damaged attentional brain systems, and support their use in cognitive rehabilitation. (PsycINFO Database Record

Neurocognitive impact of cranial radiation in adults with cancer: an update of recent findings.

PURPOSE OF REVIEW: Radiation to the brain is associated with adverse effects on cognition in cancer patients. Advances in technology have improved treatment efficacy, while new or adjuvant approaches continue to be developed. The long-term impact of both established and newer treatments on cognition is an active area of research. RECENT FINDINGS: The article reviews the 15 studies published between January 2015 and October 2016 that include data on neurocognitive functions following radiation to the brain in adults with brain metastases, primary brain tumors, or other cancers. These studies examine neurocognitive outcomes in relation to radiation treatment delivery, pharmacological interventions, and biomarkers of brain injury. SUMMARY: Advances in radiotherapy protocols have reduced neurotoxic side-effects. Implementation of standardized, validated neurocognitive measures and biomarkers of brain injury provide new insights into the impact of cranial radiation on cognitive functions. Several promising new lines of research will benefit from further study to address common challenges in the field, including high rates of attrition in longitudinal trials, absence of control groups, small sample sizes, and heterogeneous patient groups.

In vivo characterization of traumatic brain injury neuropathology with structural and functional neuroimaging.

Quantitative neuroimaging is increasingly used to study the effects of traumatic brain injury (TBI) on brain structure and function. This paper reviews quantitative structural and functional neuroimaging studies of patients with TBI, with an emphasis on the effects of diffuse axonal injury (DAI), the primary neuropathology in TBI. Quantitative structural neuroimaging has evolved from simple planometric measurements through targeted region-of-interest analyses to whole-brain analysis of quantified tissue compartments. Recent studies converge to indicate widespread volume loss of both gray and white matter in patients with moderate-to-severe TBI. These changes can be documented even when patients with focal lesions are excluded. Broadly speaking, performance on standard neuropsychological tests of speeded information processing are related to these changes, but demonstration of specific brain-behavior relationships requires more refined experimental behavioral measures. The functional consequences of these structural changes can be imaged with activation functional neuroimaging. Although this line of research is at an early stage, results indicate that TBI causes a more widely dispersed activation in frontal and posterior cortices. Further progress in analysis of the consequences of TBI on neural structure and function will require control of variability in neuropathology and behavior.