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Matsui, J.K.;  Perlow, H.K.;  Baiyee, C.;  Ritter, A.R.;  Mishra, M.V.;  Bovi, J.A.;  Gondi, V.;  Brown, P.D.;  Loughan, A.R.;  Leeper, H.E.; et al. HRQOL and Cognition Evaluations for Brain Metastases Patients. Encyclopedia. Available online: https://encyclopedia.pub/entry/26918 (accessed on 22 April 2025).
Matsui JK,  Perlow HK,  Baiyee C,  Ritter AR,  Mishra MV,  Bovi JA, et al. HRQOL and Cognition Evaluations for Brain Metastases Patients. Encyclopedia. Available at: https://encyclopedia.pub/entry/26918. Accessed April 22, 2025.
Matsui, Jennifer K., Haley K. Perlow, Cyril Baiyee, Alex R. Ritter, Mark V. Mishra, Joseph A. Bovi, Vinai Gondi, Paul D. Brown, Ashlee R. Loughan, Heather E. Leeper, et al. "HRQOL and Cognition Evaluations for Brain Metastases Patients" Encyclopedia, https://encyclopedia.pub/entry/26918 (accessed April 22, 2025).
Matsui, J.K.,  Perlow, H.K.,  Baiyee, C.,  Ritter, A.R.,  Mishra, M.V.,  Bovi, J.A.,  Gondi, V.,  Brown, P.D.,  Loughan, A.R.,  Leeper, H.E.,  Dawson, E., & Palmer, J.D. (2022, September 06). HRQOL and Cognition Evaluations for Brain Metastases Patients. In Encyclopedia. https://encyclopedia.pub/entry/26918
Matsui, Jennifer K., et al. "HRQOL and Cognition Evaluations for Brain Metastases Patients." Encyclopedia. Web. 06 September, 2022.
HRQOL and Cognition Evaluations for Brain Metastases Patients
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This entry is adapted from the peer-reviewed paper 10.3390/cancers14174301

Brain metastases (BMs) are the most common brain malignancy and are projected to increase in incidence. Historically, brain metastasis studies have focused on improving survival outcomes, but the importance of evaluating health-related quality of life (HRQOL) and cognitive function has gained recognition.

brain metastases radiotherapy quality of life cognitive function

1. Introduction

Brain metastases (BMs) occur in approximately 20% of all cancer patients and are the most common brain neoplasm [1]. Survival outcomes are improving for Stage IV cancers, which are unfortunately associated with higher BM incidence [2]. The life expectancy of BM patients has increased due to advances in radiation treatment (RT) and systemic therapy [3]; therefore, maintaining health-related quality of life (HRQOL) and cognitive function during and after treatment are imperative. Many clinical trials have included HRQOL and cognitive function assessments, but there is not yet a standardized clinical approach to assessing these patients in modern clinical practice. There is a pressing need to (1) identify tools tailored to BM patients and (2) adopt a uniform set of tests that measure HRQOL and cognition that will facilitate the design of high-quality studies that can improve the lives of BM patients.

2. Measuring Quality of Life and Neurocognitive Function in the Radiation Oncology Clinic

Historically, improving QOL was secondary to the goals of improving survival outcomes in numerous clinical trials. Although there is still a focus on maximizing survival outcomes, clinicians are recognizing that QOL and cognitive preservation are essential [4]. Measuring QOL is challenging due to the subjectivity of physical and psychosocial factors [5]. Additionally, many patients with BMs experience neurocognitive dysfunction at the time of diagnosis; therefore, establishing an accurate premorbid baseline is often not feasible, yet striving for a pretreatment baseline is essential. Researchers and practitioners in modern clinical practices have sought to design neurocognitive tests that balance practicality (e.g., can be administered by staff who do not require neuropsychological expertise) and sensitivity [6][7][8]. Below, the most common tools for measuring cognition and quality of life are discussed, although this is not all-encompassing of all available testing options for patients. Moreover, cognitive assessments are a burgeoning area of focus internationally, where greater variability in educational attainment/language spoken make this a particular challenge and area of great interest in neuropsychology.

2.1. Patient-Reported Outcome Questionnaires

2.1.1. EQ-5D

The EQ-5D is a series of QOL questionnaires that have been validated as a tool for cancer patients [9][10][11][12]. The questionnaires are brief and include items measuring mobility, self-care, completion of usual activities, pain/discomfort, and anxiety/depression. On the simplest form, items are simply marked as being present or absent, whereas on other forms, patients can indicate symptom severity. There is also an item measuring overall perceived health, rated on a scale of 0–100.

2.1.2. Functional Assessment of Cancer Therapy-General

The Functional Assessment of Cancer Therapy-General is a 33-item questionnaire that was designed to measure QOL in cancer patients [13]. Symptom domains include physical, social/family, emotional, and functional well-being. Each item is rated on a scale from 0 to 4, and some items are reverse-scored.

2.1.3. Functional Assessment of Cancer Therapy-Brain

A supplementary set of items, referred to as the FACT-Brain (FACT-Br), assesses neurological symptoms that can occur secondary to primary central nervous system tumors, such as cognitive and sensory complaints [14]. Although the tool was originally designed for patients with primary brain tumors, the FACT-Br demonstrated effectiveness for assessing patients with BM [15].

2.1.4. EORTC Quality of Life Questionnaire

The EORTC QLQ-C30 is a questionnaire designed to assess the QOL of cancer patients [16][17]. This tool is a multi-dimensional HRQOL that is composed of six functional scales (e.g., ability to walk, wash self), three symptom scales (e.g., shortness of breath, trouble sleeping), and additional single-item scales. There is a variety of validated models for specific disease sites (e.g., cervical cancer, colorectal cancer), including one dedicated to brain cancer (EORTC QLQ-BN20). Numerous studies have utilized the QLQ-C30 alongside the QLQ-BN20 for BM patients [18][19]. Other studies have suggested that the QLQ-BN20 in conjunction with the QLQ-C15-PAL (Core 15 Palliative) is an effective way to measure QOL in BM patients with a lower question burden [20].
A summary of the patient-reported outcome questionnaires is outlined in Table 1.
Table 1. Tools for measuring QOL in BM patients.
Screening Tools Description Number of Questions/Time to Complete
EQ-5D Measures mobility, self-care, usual activities, pain/discomfort, and anxiety/depression [21]. 5 questions, <5 min
FACT-G Questionnaire measuring physical, social, emotional, and functional well-being [22]. 33 questions, 10–15 min
FACT-Br Composed of the FACT-G and brain cancer subscale. 50 questions, 15–20 min
EORTC QLQ EORTC QLQ-C30 is used to measure cancer patients’ physical, psychological, and social functioning [23]. Other forms are available; EORTC QLQ-BN20 is designed for brain cancer patients. 30 questions, 10 min

2.2. Neurocognitive Tests

2.2.1. Mini-Mental State Examination

The Mini-Mental State Examination (MMSE) is a popular tool for measuring neurocognitive outcomes. This exam consists of 30 question items and can be completed in under 10 min [24]. This test measures orientation to time and place, short-term memory recall, attention, working memory, language, and other basic neurocognitive skills. Although large differences in MMSE scores can reliably indicate clinically significant deterioration in cognitive function, it is often not a suitable tool for detecting changes in memory function, executive function, and psychomotor speed seen in patients with brain tumors due to limited sensitivity [25]. In fact, in patients with primary CNS tumors, the MMSE was no more sensitive to cognitive impairment than a coin toss [26]. Further, the RTOG 0214 demonstrated the limitations of the MMSE. A phase III randomized trial compared non-small cell lung cancer patients who either underwent observation or prophylactic cranial irradiation (PCI) [27]. While the Hopkins Verbal Learning Test (HVLT) indicated deterioration in memory, the MMSE demonstrated no between-group differences [28].

2.2.2. The Montreal Cognitive Assessment

The Montreal Cognitive Assessment (MoCA) is another widely utilized cognitive test that assesses short-term memory recall, visuospatial abilities (clock drawing and copying a three-dimensional cube), executive function, attention, language, abstract reasoning, and orientation to time and place [29]. The MoCA was hypothesized to be an effective cognitive assessment tool for brain tumors for the following reasons: (1) the MoCA has greater sensitivity than the MMSE in capturing mild cognitive impairment; (2) the test is less than 10 min (potentially increasing compliance); (3) the test is more extensive than the MMSE (e.g., assesses attention, learning, and executive function at a greater depth) [30]. Olson et al. compared the MMSE and the MoCA and found that the MoCA had greater sensitivity and better correlation with self-reported quality of life measures (61.9% vs. 19.0%, p < 0.005) [31]. Although this test has greater sensitivity than the MMSE, it may not be an ideal screening tool for detecting small changes in cognitive function experienced by patients with brain tumors [32].

2.2.3. Repeatable Battery for the Assessment of Neuropsychological Status

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) consists of 12 subtests that assess immediate memory, visuospatial abilities, language, attention, and delayed memory [33]. The test takes approximately 30 min to administer and has two forms for serial testing. Historically, this test has been extensively used for patients with dementia, multiple sclerosis, Parkinson disease, and other neurological disorders [34]. Although there is currently limited studies utilizing the RBANS in neuro-oncology, some studies have found the RBANS to be an effective screening tool for patients with primary brain tumors [35].

2.2.4. Trail Making Test

The Trail Making Test (TMT) is a timed neuropsychological test that assesses processing speed and attention shifting. There are two parts to the test. Part A tests visual scanning and sequencing; patients are asked to connect numbers 1–25 in ascending order, which are scattered on a piece of paper. Part B tests attention shifting [36]; patients are asked to connect numbers and letters in alternating sequencing in ascending and alphabetical order, which are also scattered on a piece of paper. The test is scored based on completion time (including time necessary to correct errors), balancing speed and accuracy. Although this test was originally designed to detect cognitive impairment in dementia patients, it is extensively used across patient populations, including BM patients [37].

2.2.5. Hopkins Verbal Learning Test-Revised

The Hopkins Verbal Learning Test-Revised (HVLT-R) includes three learning trials of 12 orally presented words, a 25-min delayed recall trial, and a recognition trial during which patients are asked to identify words with a “yes” or non-target words with a “no”. Over the past two decades, the HVLT-R has demonstrated reliability and validity across clinical populations [38][39]. Numerous RT BM trials have utilized this test to assess the effects of RT on neurocognitive function [6][28][40].

2.2.6. Controlled Oral Word Association Test

The Controlled Oral Word Association Test (COWAT) is a measure of verbal fluency. During the phonemic fluency trials, patients are given three 1 min opportunities to state as many words as possible that begin with a specified letter [41]. The test is scored based on the summation of different words produced for all three letter trials. Error patterns (e.g., repetition of a word) are also noted [42]. The resulting scores are useful in evaluating patients with stroke, traumatic brain injury, and dementia, but have also demonstrated sensitivity in patients with BMs [43].
A summary of the neurocognitive tests are outlined in Table 2.
Table 2. Tools for measuring cognitive function in BM patients.
Screening Tools Description Number of Questions/Time to Complete
MMSE Brief screen measuring mental status, including orientation, language, memory, and other abilities [24]. 30 questions, 10 min [44]
MoCA Assesses short-term memory recall, visuospatial abilities (clock drawing and copying a 3-dimensional cube), executive function, attention, language, abstract reasoning, and orientation to time and place. 30 points, <10 min
RBANS Tests immediate memory, visuospatial abilities, language, attention, and delayed memory. 12 subtests, 30 min
TMT Assesses visual scanning, graphomotor speed, and executive function [45]. 2 tests, 3–5 min
HVLT-R Assesses verbal learning, immediate recall, delayed recall, and recognition [46]. Various forms available. 12 items for 3 learning trials, a free recall and recognition section, 10–15 min plus delayed recall time
COWAT Measures phonemic verbal fluency [41]. 3 letters, 3 min total

3. Current Recommendations for Assessing HRQOL and Neurocognition

Neuropsychological evaluations are considered the “gold standard” for evaluating cognitive function, especially for clinical purposes [47]. Neuropsychological evaluations are particularly powerful given the flexibility of tailoring tests administered to assess specific cognitive functions combined with patient-specific treatment recommendations rendered based on each individual’s neuropsychological profile [48]. The primary drawback of these assessments is accessibility, particularly for research purposes [49]. In the context of research, specifically, there has been an effort to establish standardized neurocognitive tests that can be completed in a reasonable amount of time with adequate sensitivity by appropriately trained research staff.
The current recommendations for evaluating HRQOL and neurocognitive function in patients with BMs stem from previous recommendations for patients with non-CNS and glioma tumors; these recommendations are briefly discussed below to provide greater context. The recommendations for patients with BMs are outlined at the end of this section.

3.1. Patients with Non-CNS Tumors

The International Cognition and Cancer Task Force (ICCTF) has presented cognitive test recommendations for patients with non-CNS tumors; these tests include the HVLT-R, Trail Making Test (TMT), and Controlled Oral Word Association Test (COWAT) for patients with non-CNS tumors [50]. When choosing specific tests, the ICCTF focused on measuring learning and memory; processing speed; and executive function. The goal was assessing cognitive domains that would be affected by chemotherapy (e.g., frontal subcortical circuitry). Additionally, the ICCTF selected tests with adequate sensitivity that require little overall time to administer.

3.2. Patients with a Glioma

The Response Assessment in Neuro-oncology (RANO) criteria suggest that the assessment of clinical benefit or deterioration in low-grade gliomas should include cognitive function tests and HRQOL (e.g., measuring symptom burden) [51]. To assess cognitive dysfunction, they recommend using the MMSE to stratify patients at baseline. Additionally, the RANO suggests utilizing a series of more sensitive neurocognitive tests (HVLT-R, TMT (Parts A and B), COWAT) at baseline and at longitudinal follow-up time points. These tests are designed to measure memory, executive function, and processing speed in a reasonable timeframe (20–30 min). Regarding the measurements of HRQOL, the EORTC QLQ-C30 with QLQBN-20, EQ-5D-3L or -5L, or FACT-BR have each demonstrated robust psychometric properties and can be completed within 5-20 min [52][53]. The HRQOL questionnaires should be administered before treatment initiation, at regular intervals during and after treatment, and continued in the event of tumor progression [50][51][54].

3.3. Patients with Brain Metastases

For the patients with BMs, the RANO-BM and ICCTF recommend using the HVLT-R, TMT (Parts A and B), and COWAT to assess neurocognitive function [55]. These tests should be administered at various time points to distinguish acute versus long-term treatment toxicity. Although neurocognitive tests do not always correlate with QOL, there is evidence that neurocognitive decline is associated with a reduction in HRQOL and ADLs [25]. To assess HRQOL in patients with BMs, the RANO recommends using the following validated tools: the EORTC QLQ C30 and QLQ BN-20, FACT-Br, or EQ-5D-3L or -5L. The RANO recommends clinical trials include endpoints of QOL and neurocognitive function in later-phase studies.

4. Challenges Measuring and Interpreting Quality of Life and Cognitive Outcomes

From the early 2000s, neurocognitive tests post-RT have been included in randomized control trials, but the actual impact of RT has been difficult to define due to the lack of standardized measurements. There is also a lack of standardized HRQOL tools specifically designed for patients with BM that measure important factors (e.g., well-being, pain, mood).
Existing neurocognitive evaluations and QOL measurements available for cancer patients are typically lengthy, which may limit feasibility by increasing participant burden in clinical trials. One study found the compliance rate was 56% at 6 months for cancer patients completing self-reported QOL examinations [56]. Clinicians have recognized the importance of using succinct tools to lower question burden for patients. Walker et al. found the largest cause of missing data was administrative failure; they recommended that studies monitoring QOL find avenues to minimize sources of missing data and record reasons for non-compliance. Bae et al. evaluated patient factors associated with missing data using a variety of brain cancer trials and found institutional error and request to not be contacted were frequent causes for missing data, but a majority of cases were unspecified [44].
Verhaak et al. conducted a systematic review of HRQOL outcomes for BM patients who received SRS [57]. Although some studies reported stable HRQOL scores at the group level, individual changes have been challenging to deduce given that test scores can remain constant in the event of improvement in some symptoms and declines in others [58]. Furthermore, different questionnaires were utilized across studies (e.g., EQ-5D, FACT-Br), leading to incongruent results; studies that used EQ-5D reported a decline in physical HRQOL [59][60][61], whereas studies using FACT-Br reported stable scores over time [62][63][64]. This lack of standardization prevents the pooling of study results for meta-analyses.
The setting where the questionnaire is completed may also affect the results. In some studies, follow-up questionnaires are sent via mail [62]. Although there is a possibility that completing the forms at home could induce less stress or anxiety than in the hospital setting, there is also a possibility that the patients will be influenced by others or not complete the test correctly [57]. Patients may also lose the questionnaires and/or be unmotivated to complete the questionnaires once returning home.
Furthermore, interpreting HRQOL data from patients can be complicated by a range of other factors including the effects of non-radiation treatment (e.g., chemotherapy, immunotherapy, surgery), additional medication (e.g., steroids, anti-depressants), and disease progression.

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Subjects: Oncology
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Jennifer K. Matsui
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Haley K. Perlow
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Cyril Baiyee
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Alex R. Ritter
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Mark V. Mishra
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Joseph A. Bovi
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Vinai Gondi
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Paul D. Brown
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Ashlee R. Loughan
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Heather E. Leeper
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Erica Dawson
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Joshua D. Palmer
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