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Original research
Lisa M. Hess PhD
Abstract
Change in cognitive function is increasingly being recognized as an adverse outcome related to chemotherapy treatment. These changes need not be severe to impact patient functional ability and quality of life. The primary goal of this study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and response time among women with newly diagnosed advanced ovarian cancer who receive chemotherapy. Eligible patients were women diagnosed with stage III–IV epithelial ovarian or primary peritoneal cancer who had not yet received chemotherapy but who were prescribed a minimum of six cycles (courses) of chemotherapy treatment. Cognitive function was assessed by a computerized, Web-based assessment (attention, processing speed, and reaction time) and by patient self-report. Cognitive function was assessed at three time points: prior to the first course (baseline), course three, and course six. Medical records were reviewed to abstract information on chemotherapy treatment, concomitant medications, and blood test results (eg, hemoglobin, CA-125). Of the 27 eligible participants, 92% and 86% demonstrated cognitive impairments from baseline to course three and from baseline to course six of chemotherapy, respectively. Impairment was detected in two or more cognitive domains among 48% (12 of 25) and 41% (9 of 22) of participants at course three and course six of chemotherapy, respectively. This study shows evidence of decline in cognitive function among women being treated for ovarian cancer. There is a need for additional, prospective research to better understand the impact of chemotherapy on cognitive function among ovarian cancer patients so that effective preventive and treatment strategies can be developed.
Article Outline
Although the perception of cognitive decline is a common complaint among individuals treated with chemotherapy, it is poorly understood and limited efforts have been made to identify the extent of this problem among women with ovarian cancer. To date, the few studies documenting the neuropsychological consequences of ovarian cancer and its treatment have shown that patients report cognitive problems but that these problems were not quantifiable using objective measures due to the lack of sensitivity of standard instruments to the subtle changes that occur during cancer treatment.[5], [6] and [7]
Although studies of cognitive function among oncology patients have used instruments that have been validated in their own disciplines and with a variety of diseases, the evidence is emerging that they are not comprehensive or appropriate tools for the detection and evaluation of chemotherapy-related change in cognitive function.8 Furthermore, the likelihood of having these tests conducted in a similar manner across multiple institutions, sites, and interviewers with any degree of consistency is very low. This study was designed as a pilot study of the identification of chemotherapy-related changes in cognitive function among women with advanced ovarian cancer using a Web-based assessment tool (Headminder, Inc., New York, NY).7 The primary goal of the current study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and reaction time as well as self-reported changes in the memory, sensory-perception, and cognitive-intellectual domains of cognitive function during chemotherapy among women with newly diagnosed advanced ovarian cancer.
Materials and Methods
All study methods and procedures were reviewed and approved by the University of Arizona Institutional Review Board. Eligible patients included women with a histologically or pathologically confirmed diagnosis of stage III–IV epithelial ovarian or primary peritoneal cancer who were prescribed at least six courses of platinum-based therapy. Patients were excluded if they had a prior history of any cancer (other than nonmelanoma skin cancer), chemotherapy, radiation therapy, erythropoietin treatment (within the last 6 months), or severe head injury. Initially, patients were excluded if they received intraperitoneal therapy, but the protocol was later amended to permit the use of any platinum-based therapy, regardless of route of administration.
Assessment Tools
After providing informed consent, patients completed a neurocognitive battery of tests and the Functional Assessment of Cancer Therapy—Neurotoxicity (FACT-Ntx, to assess patient-reported neuropathy).[9] and [10] The neurocognitive evaluation included both a computerized, Web-based and a patient-reported assessment. The Web-based assessment was provided by HeadMinders, Inc.[7] and [11] and was a modified version of the Cognitive Stability Index. The modified battery was comprised of two warm-up tasks and three empirically-derived cognitive factors: Processing Speed (Animal Decoding and Symbol Scanning subtests), Attention (Number Recall and Number Sequencing subtests), and Reaction Time (Response Direction 1 and Response Direction 2 subtests). The subtests have been validated against traditional neuropsychological tests in healthy and clinical populations, including cancer patients.12 Cognitive domain correlations in the battery's healthy normative sample range from 0.52 to 0.74, and correlations are similar or higher in clinical populations. Test–retest reliability of the factor scores between first and second administrations ranges from 0.74 to 0.82.12 This Web-based neurocognitive assessment tool is 21 CFR Part 11– and Health on the Net (HON)–compliant to ensure patient confidentiality. Prior to undergoing the Web-based cognitive tests, all study participants completed a keyboard proficiency test as a “warm-up task” to the computerized assessment.
The patient-reported cognitive function tool used was the Patient Assessment of Own Functioning Scale (PAF).[13], [14] and [15] The PAF includes eight scales that are grouped into the nature of the ability being considered. The Memory, Sensory-Perceptual, and Cognitive-Intellectual subscales of the PAF are included in this self-assessment questionnaire. Respondents are asked to rate on a six-point scale, from almost always to almost never, how often they experience a particular kind of difficulty in their everyday lives. For this study, the Memory and Cognitive-Intellectual subscales of the PAF were used, similar to other clinical research protocols investigating cognitive changes during chemotherapy treatment.15 The PAF has been shown to be directly related to the Minnesota Multiphasic Personality Inventory (MMPI)13 and to be highly correlated with other cognitive impairment indices, such as the American College of Rheumatology neuropsychology research battery of tests.16 Of note, self-reported cognitive change has not been shown to correlate formal assessments of cognitive function among individuals who have experienced cancer.[17], [18], [19], [20] and [21]
The FACT-Ntx is a validated instrument[9] and [10] that was used to evaluate neurotoxicity. This scale includes 11 items: nine to assess neurotoxicity, one to assess bodily weakness, and one to assess anemia. Neurotoxicity may affect a patient's ability to use the keyboard in the computerized neurocognitive evaluation. This complete assessment battery of tests was completed at baseline (within 5 days of initiation of chemotherapy) and again during follow-up assessments at cycle three and cycle six of chemotherapy. The medical record was reviewed and data were abstracted related to chemotherapy medications, all concomitant medications, and blood test results (eg, hemoglobin, CA-125).
Statistical Plan
This prospective study was exploratory in nature and designed to collect pilot data to determine if there is evidence of neurocognitive change in attention, processing speed, response time, or self-reported cognitive function during the course of chemotherapy among women being treated for advanced ovarian cancer. The purpose of this study was to obtain preliminary estimates of the incidence and degree of cognitive decline to aid in the planning of future studies. While prior estimates of cognitive function were not available for this population, power analyses demonstrate that with a target recruitment goal of 30 patients, a McNemar's test has 78% power at the 0.05 level of significance to detect a significant decline in impairment in a cognitive domain if 12 patients are found to have impairment prior to course six of treatment (but not at course three) and if as few as two patients demonstrate impairment prior to course three but not at course six. This study was therefore powered to detect declines in one or more of the domains that may have occurred at less than both of the study time points following the baseline assessment.
To be considered fully evaluable, patients had to have completed at least one follow-up neurocognitive evaluation and may not have received antipsychotic neuropsychological medications during the study (eg, chlorpromazine, haloperidol, clozapine). Antidepressants and antianxiety medications (eg, serotonin/norepinephrine reuptake inhibitors or benzodiazepines) were permitted and use was recorded throughout study participation. A summary score for each cognitive domain (processing speed, reaction time, and attention) was recorded at each assessment time point using the HeadMinder Web-based assessment. This summary score was assessed by time (processing speed and reaction time), measured to the hundredth of a second, and by number of errors (attention). If a cognitive domain summary score at a follow-up assessment time declined at least one standard error of measurement (SEM) from baseline, the patient was considered to have experienced a decline at that time point. For the purposes of this article, such declines are referred to as “impairments” within the cognitive domain under investigation. A cognitive index score (CIS) was calculated as the number of cognitive domains impaired for the time point. The range of a CIS is 0–3, with zero equal to no impairment on any cognitive domain and three equal to impairment on all cognitive domains. Patients with only one cognitive domain decline (CIS = 1) at any one of the follow-up assessment time points were considered as having possible cognitive function decline. Patients with more than one cognitive domain impairment (CIS >1) at any follow-up assessment time points were considered as having evidence of cognitive function decline. The incidence of cognitive function impairment was determined by the percentage of patients who experienced any cognitive domain impairment (including possible and evidence of decline) at any follow-up assessment.
A repeated-measures analyses of variance (ANOVA) was used to further explore the neurocognitive values at the various time points during the study. Many of the neurocognitive values were not normally distributed but skewed either positively or negatively, so the square roots of the values were used in the analyses. Since this is an exploratory analysis, no corrections for multiple comparisons were performed.
The patient-reported cognitive function instrument (PAF) contains items scored on a Likert-type scale from almost never to almost always (range 0–5). Patient-reported outcomes as measured with the PAF are measured as mean scale values, ranging from 0, indicating no impairment, to 5.0, indicating complete impairment. PAF score ranges indicate low (≤1.25), medium (1.26–1.92), and high (≥1.93) levels of cognitive impairment.13 A total FACT-Ntx score was obtained; lower scores represent greater neurotoxicity, ranging from 0 (extreme neurotoxicity) to 44 (no neurotoxicity). The total score was reported, with adjustments made for missing values as described elsewhere.22
Results
Thirty patients were enrolled in this study; however, two were later deemed ineligible, and one was unable to complete the baseline neurocognitive assessment prior to chemotherapy and was withdrawn from the study, resulting in 27 patients available for assessment. Five of these patients did not complete all neurocognitive assessments. The primary reason for nonadherence to the study schedule was clinical scheduling (eg, chemotherapy was administered prior to the neurocognitive assessment). The characteristics of eligible patients are provided in Table 1. The majority of patients were receiving intravenous chemotherapy (intraperitoneal therapy was at first not permitted but later was allowable following an amendment to the protocol) and taking concomitant sleep, antianxiety, and/or antidepressant medications outside of every 3- to 4-week chemotherapy regimen (primarily zolpidem, lorazepam, sertraline, and/or trazodone).
| n = 27 | |
| Mean age, years (range) | 59.3 (40.3–81.5) |
| Education, n (%) | |
| High school or less | 3 (11.1%) |
| Some college | 12 (44.4%) |
| College graduate | 12 (44.4%) |
| Race/ethnicity, n (%) | |
| White, non-Hispanic | 25 (92.6%) |
| Hispanic | 1 (3.7%) |
| Native American | 1 (3.7%) |
| Marital status, n (%) | |
| Married/cohabitating | 19 (70.4%) |
| Divorced/separated | 1 (3.7%) |
| Widowed | 5 (18.5%) |
| Never married | 2 (7.4%) |
| Mean courses of chemotherapy, n (range) | 5.9 (4–6) |
| Chemotherapy route, n (%) | |
| Intraperitoneal | 5 (18.5%) |
| Intravenous | 22 (81.5%) |
| Concurrent medication use, n (%) | |
| Antidepressant | 7 (25.9%) |
| Antianxiety | 16 (59.3%) |
| Sleep aids | 5 (18.5%) |
Web-Assessed Cognitive Function
Keyboard proficiency remained unchanged over time (P = 0.39). As shown in Table 2, most participants demonstrated cognitive impairments in at least one of the three cognitive domains assessed during this study (92% and 86% at course 3 and course 6, respectively). Nearly half of the study participants demonstrated impairment from baseline in two or more of the three cognitive domains assessed (Table 3). Table 4 shows a detailed summary of the subscales within the Web-based cognitive tests that comprised the CIS.This table demonstrates the statistically significant increase in test subscale errors, despite the test-taking improvements over time, as shown by reduction in testing time.
| CIS | COURSE 3 | COURSE 6 |
|---|---|---|
| No decline (CIS = 0) | 2 (8%) | 3 (14%) |
| One impairment (CIS = 1) | 11 (44%) | 10 (45%) |
| Two impairments (CIS = 2) | 11 (44%) | 7 (32%) |
| Three impairments (CIS = 3) | 1 (4%) | 2 (9%) |
| COGNITIVE IMPAIRMENT SCALE (CIS) FACTORS | BASELINE | COURSE 3 | COURSE 6 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N | MEAN | SD | N | MEAN | SD | N | MEAN | SD | P | |
| Attention | ||||||||||
| Number recall (number correct) | 25 | 7.08 | 1.75 | 25 | 7.16 | 2.03 | 22 | 7.45 | 1.92 | 0.887 |
| Number sequencing (number correct) | 26 | 6.23 | 0.98 | 25 | 5.96 | 2.65 | 23 | 5.61 | 2.29 | 0.476 |
| Processing speed | ||||||||||
| Animal decoding (number of errors) | 25 | 0.4 | 0.5 | 25 | 0.72 | 0.84 | 23 | 3.26 | 0.86 | <0.0001 |
| Animal decoding (number correct) | 25 | 32.48 | 6.48 | 25 | 32.96 | 8.90 | 23 | 32.22 | 8.70 | 0.678 |
| Symbol scanning (number correct) | 27 | 18.59 | 1.15 | 25 | 18.76 | 1.2 | 21 | 18.67 | 1.35 | 0.883 |
| Symbol scanning (response time) | 27 | 4.38 | 1.37 | 25 | 4.26 | 1.66 | 21 | 3.61 | 0.84 | 0.002 |
| Reaction time | ||||||||||
| Response direction 1 (number of omissions) | 27 | 0.04 | 0.19 | 26 | 0.62 | 2.35 | 23 | 0 | 0 | 0.028 |
| Response direction 1 (response time, seconds) | 27 | 0.52 | 0.06 | 26 | 0.55 | 0.22 | 23 | 0.52 | 0.07 | 0.567 |
| Response direction 2 (number of omissions) | 27 | 0.63 | 1.33 | 26 | 0.5 | 2.18 | 23 | 0.43 | 0.95 | 0.135 |
| Response direction 2 (response time, seconds) | 27 | 0.75 | 0.13 | 26 | 0.72 | 0.20 | 23 | 0.71 | 0.17 | 0.467 |
| Response direction, shift failures (number) | 27 | 4.33 | 3.13 | 26 | 2.77 | 2.29 | 23 | 3.04 | 2.58 | 0.007 |
Patient-Reported Cognitive Function
The mean values and 95% confidence intervals of the patient-reported cognitive function outcomes are presented in Figure 1. Mean values remained within the low impairment range (less than 1.25) during chemotherapy.
Blood Chemistries and Toxicity
The mean values and 95% confidence intervals of significant differences in blood chemistries and toxicities are presented in [Figure 2] and [Figure 3]. Total patient-reported neurotoxicity increased significantly during chemotherapy (ANOVA; F = 6.851, P = 0.002), while several mean blood chemistry values decreased during chemotherapy treatment (hemoglobin F = 2.465, P = 0.09; white blood cell count F = 16.95, P < 0.001; platelets F = 13.72, P < 0.001; and CA-125 F = 4.91, P = 0.01). One study participant received a blood transfusion at the final course of chemotherapy, and two and three participants received cytokines (erythropoietin or darbepoietin) at course 3 and course 6, respectively.
Discussion
This study shows preliminary evidence that cognitive decline is a significant factor experienced by women who are treated for advanced ovarian cancer. Most participants self-reported mild declines, and these were detectable by a sensitive Web-based assessment tool. There are many potential mechanisms of cognitive decline during chemotherapy, ranging from oxidative damage to reduced blood oxygenation due to anemia to stress and anxiety. While it is outside of the scope of this small pilot study to examine the causative factors of decline, it does suggest the need for further investigation of the effect and potential mechanisms of cognitive decline in this population. While most of the prior work in cognitive function has been conducted among breast cancer patients, ovarian cancer patients appear to experience cognitive decline as well. There is a need to further understand this issue so that effective preventive or treatment strategies can be developed.
The significant increase in patient-reported neurotoxicity across each study visit may be a concern for computerized assessments that require dexterity. However, the keyboard proficiency tests did not decline over time, suggesting that the neurotoxicity reported by patients in this study was not great enough to affect their ability to use the computer keyboard. Patients appear to report higher levels of difficulty with memory (eg, forgetfulness) following diagnosis than following the initiation of chemotherapy; however, higher-level cognitive processes (eg, logic, organizational abilities, calculations) reported by patients appear to decline following the initiation of chemotherapy. Although larger, adequately powered trials are needed to determine the extent of this decline, this suggests that patients experience increasing challenges that may interfere with their ability to perform necessary tasks at work and in the household. Further work is needed to examine the duration of these effects following chemotherapy. Since the cognitive impact of chemotherapy reported by patients is mild, investigators must ensure the use of appropriate patient-reported tools that are able to detect these differences. While reported decline may occur, this is likely to remain within the mild category of traditional assessment tools. It is of benefit to use patient-reported tools such as the PAF that also permit the analysis of continuous data.
This study is limited by its design as a pilot study and was challenged by several logistical issues. Four patients were unable to complete all the neurocognitive evaluations. This was due to remote study staff, who would visit various clinics in the Tucson and Phoenix metropolitan regions in Arizona (range of travel more than 120 miles). The lack of completion was entirely due to communication and travel complications. When a patient was rescheduled to a different chemotherapy date, it was not always possible for this to be communicated to the Arizona Cancer Center researchers in a timely manner, resulting in missed visits. It is recommended for future studies that require strict timelines for study assessments (such as this cognitive function study) that the assessments be conducted by staff in those practices who can identify changes in infusion dates when they occur. This will reduce the communication barriers and rate of missed visits. This study was also not designed to be a comprehensive assessment of neurocognitive function but was focused on assessing three domains: attention, processing speed, and response time. It is possible that many other domains of cognitive function could be impacted by chemotherapy that were not evaluated in this study. Many patients were also taking antidepressant medications during the study; however, these were generally not new prescriptions and were also being taken at the baseline assessment. Nevertheless, future studies should incorporate assessments of mood, depression, and anxiety to account for the potential effect of these factors on cognitive assessment scores.
Despite these limitations, the study provides preliminary data demonstrating cognitive decline during chemotherapy among ovarian cancer patients treated in the front-line setting of advanced disease. More than 90% of all patients experienced measurable impairments in cognitive function during primary chemotherapy. More than half of all patients demonstrated impairment on two or more cognitive domains. Prior work has shown that even mild cognitive impairments can influence quality of life and the ability to perform routine daily activities (eg, taking medications, returning to work, managing household finances).23 The data emphasize the critical need to further understand the impact of chemotherapy on cognitive function among ovarian cancer patients so that effective preventive and treatment strategies can be developed. Additional research is needed to understand how long these declines may persist following chemotherapy treatment.
Acknowledgments
This study was funded by an investigator-initiated grant from Ortho Biotech, Inc., to the University of Arizona Cancer Center. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect those of Ortho Biotech.
References1
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12 D.M. Erlanger, T. Kaushik, D. Broshek, J. Freeman, D. Feldman and J. Festa, Development and validation of a Web-based screening tool for monitoring cognitive status, J Head Trauma Rehabil 17 (5) (2002), pp. 458–476. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (22)
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20 S.B. Schagen, M.J. Muller and W. Boogerd et al., Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients, Ann Oncol 13 (9) (2002), pp. 1387–1397. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (99)
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Original research
Lisa M. Hess PhD
Abstract
Change in cognitive function is increasingly being recognized as an adverse outcome related to chemotherapy treatment. These changes need not be severe to impact patient functional ability and quality of life. The primary goal of this study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and response time among women with newly diagnosed advanced ovarian cancer who receive chemotherapy. Eligible patients were women diagnosed with stage III–IV epithelial ovarian or primary peritoneal cancer who had not yet received chemotherapy but who were prescribed a minimum of six cycles (courses) of chemotherapy treatment. Cognitive function was assessed by a computerized, Web-based assessment (attention, processing speed, and reaction time) and by patient self-report. Cognitive function was assessed at three time points: prior to the first course (baseline), course three, and course six. Medical records were reviewed to abstract information on chemotherapy treatment, concomitant medications, and blood test results (eg, hemoglobin, CA-125). Of the 27 eligible participants, 92% and 86% demonstrated cognitive impairments from baseline to course three and from baseline to course six of chemotherapy, respectively. Impairment was detected in two or more cognitive domains among 48% (12 of 25) and 41% (9 of 22) of participants at course three and course six of chemotherapy, respectively. This study shows evidence of decline in cognitive function among women being treated for ovarian cancer. There is a need for additional, prospective research to better understand the impact of chemotherapy on cognitive function among ovarian cancer patients so that effective preventive and treatment strategies can be developed.
Article Outline
Although the perception of cognitive decline is a common complaint among individuals treated with chemotherapy, it is poorly understood and limited efforts have been made to identify the extent of this problem among women with ovarian cancer. To date, the few studies documenting the neuropsychological consequences of ovarian cancer and its treatment have shown that patients report cognitive problems but that these problems were not quantifiable using objective measures due to the lack of sensitivity of standard instruments to the subtle changes that occur during cancer treatment.[5], [6] and [7]
Although studies of cognitive function among oncology patients have used instruments that have been validated in their own disciplines and with a variety of diseases, the evidence is emerging that they are not comprehensive or appropriate tools for the detection and evaluation of chemotherapy-related change in cognitive function.8 Furthermore, the likelihood of having these tests conducted in a similar manner across multiple institutions, sites, and interviewers with any degree of consistency is very low. This study was designed as a pilot study of the identification of chemotherapy-related changes in cognitive function among women with advanced ovarian cancer using a Web-based assessment tool (Headminder, Inc., New York, NY).7 The primary goal of the current study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and reaction time as well as self-reported changes in the memory, sensory-perception, and cognitive-intellectual domains of cognitive function during chemotherapy among women with newly diagnosed advanced ovarian cancer.
Materials and Methods
All study methods and procedures were reviewed and approved by the University of Arizona Institutional Review Board. Eligible patients included women with a histologically or pathologically confirmed diagnosis of stage III–IV epithelial ovarian or primary peritoneal cancer who were prescribed at least six courses of platinum-based therapy. Patients were excluded if they had a prior history of any cancer (other than nonmelanoma skin cancer), chemotherapy, radiation therapy, erythropoietin treatment (within the last 6 months), or severe head injury. Initially, patients were excluded if they received intraperitoneal therapy, but the protocol was later amended to permit the use of any platinum-based therapy, regardless of route of administration.
Assessment Tools
After providing informed consent, patients completed a neurocognitive battery of tests and the Functional Assessment of Cancer Therapy—Neurotoxicity (FACT-Ntx, to assess patient-reported neuropathy).[9] and [10] The neurocognitive evaluation included both a computerized, Web-based and a patient-reported assessment. The Web-based assessment was provided by HeadMinders, Inc.[7] and [11] and was a modified version of the Cognitive Stability Index. The modified battery was comprised of two warm-up tasks and three empirically-derived cognitive factors: Processing Speed (Animal Decoding and Symbol Scanning subtests), Attention (Number Recall and Number Sequencing subtests), and Reaction Time (Response Direction 1 and Response Direction 2 subtests). The subtests have been validated against traditional neuropsychological tests in healthy and clinical populations, including cancer patients.12 Cognitive domain correlations in the battery's healthy normative sample range from 0.52 to 0.74, and correlations are similar or higher in clinical populations. Test–retest reliability of the factor scores between first and second administrations ranges from 0.74 to 0.82.12 This Web-based neurocognitive assessment tool is 21 CFR Part 11– and Health on the Net (HON)–compliant to ensure patient confidentiality. Prior to undergoing the Web-based cognitive tests, all study participants completed a keyboard proficiency test as a “warm-up task” to the computerized assessment.
The patient-reported cognitive function tool used was the Patient Assessment of Own Functioning Scale (PAF).[13], [14] and [15] The PAF includes eight scales that are grouped into the nature of the ability being considered. The Memory, Sensory-Perceptual, and Cognitive-Intellectual subscales of the PAF are included in this self-assessment questionnaire. Respondents are asked to rate on a six-point scale, from almost always to almost never, how often they experience a particular kind of difficulty in their everyday lives. For this study, the Memory and Cognitive-Intellectual subscales of the PAF were used, similar to other clinical research protocols investigating cognitive changes during chemotherapy treatment.15 The PAF has been shown to be directly related to the Minnesota Multiphasic Personality Inventory (MMPI)13 and to be highly correlated with other cognitive impairment indices, such as the American College of Rheumatology neuropsychology research battery of tests.16 Of note, self-reported cognitive change has not been shown to correlate formal assessments of cognitive function among individuals who have experienced cancer.[17], [18], [19], [20] and [21]
The FACT-Ntx is a validated instrument[9] and [10] that was used to evaluate neurotoxicity. This scale includes 11 items: nine to assess neurotoxicity, one to assess bodily weakness, and one to assess anemia. Neurotoxicity may affect a patient's ability to use the keyboard in the computerized neurocognitive evaluation. This complete assessment battery of tests was completed at baseline (within 5 days of initiation of chemotherapy) and again during follow-up assessments at cycle three and cycle six of chemotherapy. The medical record was reviewed and data were abstracted related to chemotherapy medications, all concomitant medications, and blood test results (eg, hemoglobin, CA-125).
Statistical Plan
This prospective study was exploratory in nature and designed to collect pilot data to determine if there is evidence of neurocognitive change in attention, processing speed, response time, or self-reported cognitive function during the course of chemotherapy among women being treated for advanced ovarian cancer. The purpose of this study was to obtain preliminary estimates of the incidence and degree of cognitive decline to aid in the planning of future studies. While prior estimates of cognitive function were not available for this population, power analyses demonstrate that with a target recruitment goal of 30 patients, a McNemar's test has 78% power at the 0.05 level of significance to detect a significant decline in impairment in a cognitive domain if 12 patients are found to have impairment prior to course six of treatment (but not at course three) and if as few as two patients demonstrate impairment prior to course three but not at course six. This study was therefore powered to detect declines in one or more of the domains that may have occurred at less than both of the study time points following the baseline assessment.
To be considered fully evaluable, patients had to have completed at least one follow-up neurocognitive evaluation and may not have received antipsychotic neuropsychological medications during the study (eg, chlorpromazine, haloperidol, clozapine). Antidepressants and antianxiety medications (eg, serotonin/norepinephrine reuptake inhibitors or benzodiazepines) were permitted and use was recorded throughout study participation. A summary score for each cognitive domain (processing speed, reaction time, and attention) was recorded at each assessment time point using the HeadMinder Web-based assessment. This summary score was assessed by time (processing speed and reaction time), measured to the hundredth of a second, and by number of errors (attention). If a cognitive domain summary score at a follow-up assessment time declined at least one standard error of measurement (SEM) from baseline, the patient was considered to have experienced a decline at that time point. For the purposes of this article, such declines are referred to as “impairments” within the cognitive domain under investigation. A cognitive index score (CIS) was calculated as the number of cognitive domains impaired for the time point. The range of a CIS is 0–3, with zero equal to no impairment on any cognitive domain and three equal to impairment on all cognitive domains. Patients with only one cognitive domain decline (CIS = 1) at any one of the follow-up assessment time points were considered as having possible cognitive function decline. Patients with more than one cognitive domain impairment (CIS >1) at any follow-up assessment time points were considered as having evidence of cognitive function decline. The incidence of cognitive function impairment was determined by the percentage of patients who experienced any cognitive domain impairment (including possible and evidence of decline) at any follow-up assessment.
A repeated-measures analyses of variance (ANOVA) was used to further explore the neurocognitive values at the various time points during the study. Many of the neurocognitive values were not normally distributed but skewed either positively or negatively, so the square roots of the values were used in the analyses. Since this is an exploratory analysis, no corrections for multiple comparisons were performed.
The patient-reported cognitive function instrument (PAF) contains items scored on a Likert-type scale from almost never to almost always (range 0–5). Patient-reported outcomes as measured with the PAF are measured as mean scale values, ranging from 0, indicating no impairment, to 5.0, indicating complete impairment. PAF score ranges indicate low (≤1.25), medium (1.26–1.92), and high (≥1.93) levels of cognitive impairment.13 A total FACT-Ntx score was obtained; lower scores represent greater neurotoxicity, ranging from 0 (extreme neurotoxicity) to 44 (no neurotoxicity). The total score was reported, with adjustments made for missing values as described elsewhere.22
Results
Thirty patients were enrolled in this study; however, two were later deemed ineligible, and one was unable to complete the baseline neurocognitive assessment prior to chemotherapy and was withdrawn from the study, resulting in 27 patients available for assessment. Five of these patients did not complete all neurocognitive assessments. The primary reason for nonadherence to the study schedule was clinical scheduling (eg, chemotherapy was administered prior to the neurocognitive assessment). The characteristics of eligible patients are provided in Table 1. The majority of patients were receiving intravenous chemotherapy (intraperitoneal therapy was at first not permitted but later was allowable following an amendment to the protocol) and taking concomitant sleep, antianxiety, and/or antidepressant medications outside of every 3- to 4-week chemotherapy regimen (primarily zolpidem, lorazepam, sertraline, and/or trazodone).
| n = 27 | |
| Mean age, years (range) | 59.3 (40.3–81.5) |
| Education, n (%) | |
| High school or less | 3 (11.1%) |
| Some college | 12 (44.4%) |
| College graduate | 12 (44.4%) |
| Race/ethnicity, n (%) | |
| White, non-Hispanic | 25 (92.6%) |
| Hispanic | 1 (3.7%) |
| Native American | 1 (3.7%) |
| Marital status, n (%) | |
| Married/cohabitating | 19 (70.4%) |
| Divorced/separated | 1 (3.7%) |
| Widowed | 5 (18.5%) |
| Never married | 2 (7.4%) |
| Mean courses of chemotherapy, n (range) | 5.9 (4–6) |
| Chemotherapy route, n (%) | |
| Intraperitoneal | 5 (18.5%) |
| Intravenous | 22 (81.5%) |
| Concurrent medication use, n (%) | |
| Antidepressant | 7 (25.9%) |
| Antianxiety | 16 (59.3%) |
| Sleep aids | 5 (18.5%) |
Web-Assessed Cognitive Function
Keyboard proficiency remained unchanged over time (P = 0.39). As shown in Table 2, most participants demonstrated cognitive impairments in at least one of the three cognitive domains assessed during this study (92% and 86% at course 3 and course 6, respectively). Nearly half of the study participants demonstrated impairment from baseline in two or more of the three cognitive domains assessed (Table 3). Table 4 shows a detailed summary of the subscales within the Web-based cognitive tests that comprised the CIS.This table demonstrates the statistically significant increase in test subscale errors, despite the test-taking improvements over time, as shown by reduction in testing time.
| CIS | COURSE 3 | COURSE 6 |
|---|---|---|
| No decline (CIS = 0) | 2 (8%) | 3 (14%) |
| One impairment (CIS = 1) | 11 (44%) | 10 (45%) |
| Two impairments (CIS = 2) | 11 (44%) | 7 (32%) |
| Three impairments (CIS = 3) | 1 (4%) | 2 (9%) |
| COGNITIVE IMPAIRMENT SCALE (CIS) FACTORS | BASELINE | COURSE 3 | COURSE 6 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N | MEAN | SD | N | MEAN | SD | N | MEAN | SD | P | |
| Attention | ||||||||||
| Number recall (number correct) | 25 | 7.08 | 1.75 | 25 | 7.16 | 2.03 | 22 | 7.45 | 1.92 | 0.887 |
| Number sequencing (number correct) | 26 | 6.23 | 0.98 | 25 | 5.96 | 2.65 | 23 | 5.61 | 2.29 | 0.476 |
| Processing speed | ||||||||||
| Animal decoding (number of errors) | 25 | 0.4 | 0.5 | 25 | 0.72 | 0.84 | 23 | 3.26 | 0.86 | <0.0001 |
| Animal decoding (number correct) | 25 | 32.48 | 6.48 | 25 | 32.96 | 8.90 | 23 | 32.22 | 8.70 | 0.678 |
| Symbol scanning (number correct) | 27 | 18.59 | 1.15 | 25 | 18.76 | 1.2 | 21 | 18.67 | 1.35 | 0.883 |
| Symbol scanning (response time) | 27 | 4.38 | 1.37 | 25 | 4.26 | 1.66 | 21 | 3.61 | 0.84 | 0.002 |
| Reaction time | ||||||||||
| Response direction 1 (number of omissions) | 27 | 0.04 | 0.19 | 26 | 0.62 | 2.35 | 23 | 0 | 0 | 0.028 |
| Response direction 1 (response time, seconds) | 27 | 0.52 | 0.06 | 26 | 0.55 | 0.22 | 23 | 0.52 | 0.07 | 0.567 |
| Response direction 2 (number of omissions) | 27 | 0.63 | 1.33 | 26 | 0.5 | 2.18 | 23 | 0.43 | 0.95 | 0.135 |
| Response direction 2 (response time, seconds) | 27 | 0.75 | 0.13 | 26 | 0.72 | 0.20 | 23 | 0.71 | 0.17 | 0.467 |
| Response direction, shift failures (number) | 27 | 4.33 | 3.13 | 26 | 2.77 | 2.29 | 23 | 3.04 | 2.58 | 0.007 |
Patient-Reported Cognitive Function
The mean values and 95% confidence intervals of the patient-reported cognitive function outcomes are presented in Figure 1. Mean values remained within the low impairment range (less than 1.25) during chemotherapy.
Blood Chemistries and Toxicity
The mean values and 95% confidence intervals of significant differences in blood chemistries and toxicities are presented in [Figure 2] and [Figure 3]. Total patient-reported neurotoxicity increased significantly during chemotherapy (ANOVA; F = 6.851, P = 0.002), while several mean blood chemistry values decreased during chemotherapy treatment (hemoglobin F = 2.465, P = 0.09; white blood cell count F = 16.95, P < 0.001; platelets F = 13.72, P < 0.001; and CA-125 F = 4.91, P = 0.01). One study participant received a blood transfusion at the final course of chemotherapy, and two and three participants received cytokines (erythropoietin or darbepoietin) at course 3 and course 6, respectively.
Discussion
This study shows preliminary evidence that cognitive decline is a significant factor experienced by women who are treated for advanced ovarian cancer. Most participants self-reported mild declines, and these were detectable by a sensitive Web-based assessment tool. There are many potential mechanisms of cognitive decline during chemotherapy, ranging from oxidative damage to reduced blood oxygenation due to anemia to stress and anxiety. While it is outside of the scope of this small pilot study to examine the causative factors of decline, it does suggest the need for further investigation of the effect and potential mechanisms of cognitive decline in this population. While most of the prior work in cognitive function has been conducted among breast cancer patients, ovarian cancer patients appear to experience cognitive decline as well. There is a need to further understand this issue so that effective preventive or treatment strategies can be developed.
The significant increase in patient-reported neurotoxicity across each study visit may be a concern for computerized assessments that require dexterity. However, the keyboard proficiency tests did not decline over time, suggesting that the neurotoxicity reported by patients in this study was not great enough to affect their ability to use the computer keyboard. Patients appear to report higher levels of difficulty with memory (eg, forgetfulness) following diagnosis than following the initiation of chemotherapy; however, higher-level cognitive processes (eg, logic, organizational abilities, calculations) reported by patients appear to decline following the initiation of chemotherapy. Although larger, adequately powered trials are needed to determine the extent of this decline, this suggests that patients experience increasing challenges that may interfere with their ability to perform necessary tasks at work and in the household. Further work is needed to examine the duration of these effects following chemotherapy. Since the cognitive impact of chemotherapy reported by patients is mild, investigators must ensure the use of appropriate patient-reported tools that are able to detect these differences. While reported decline may occur, this is likely to remain within the mild category of traditional assessment tools. It is of benefit to use patient-reported tools such as the PAF that also permit the analysis of continuous data.
This study is limited by its design as a pilot study and was challenged by several logistical issues. Four patients were unable to complete all the neurocognitive evaluations. This was due to remote study staff, who would visit various clinics in the Tucson and Phoenix metropolitan regions in Arizona (range of travel more than 120 miles). The lack of completion was entirely due to communication and travel complications. When a patient was rescheduled to a different chemotherapy date, it was not always possible for this to be communicated to the Arizona Cancer Center researchers in a timely manner, resulting in missed visits. It is recommended for future studies that require strict timelines for study assessments (such as this cognitive function study) that the assessments be conducted by staff in those practices who can identify changes in infusion dates when they occur. This will reduce the communication barriers and rate of missed visits. This study was also not designed to be a comprehensive assessment of neurocognitive function but was focused on assessing three domains: attention, processing speed, and response time. It is possible that many other domains of cognitive function could be impacted by chemotherapy that were not evaluated in this study. Many patients were also taking antidepressant medications during the study; however, these were generally not new prescriptions and were also being taken at the baseline assessment. Nevertheless, future studies should incorporate assessments of mood, depression, and anxiety to account for the potential effect of these factors on cognitive assessment scores.
Despite these limitations, the study provides preliminary data demonstrating cognitive decline during chemotherapy among ovarian cancer patients treated in the front-line setting of advanced disease. More than 90% of all patients experienced measurable impairments in cognitive function during primary chemotherapy. More than half of all patients demonstrated impairment on two or more cognitive domains. Prior work has shown that even mild cognitive impairments can influence quality of life and the ability to perform routine daily activities (eg, taking medications, returning to work, managing household finances).23 The data emphasize the critical need to further understand the impact of chemotherapy on cognitive function among ovarian cancer patients so that effective preventive and treatment strategies can be developed. Additional research is needed to understand how long these declines may persist following chemotherapy treatment.
Acknowledgments
This study was funded by an investigator-initiated grant from Ortho Biotech, Inc., to the University of Arizona Cancer Center. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect those of Ortho Biotech.
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Original research
Lisa M. Hess PhD
Abstract
Change in cognitive function is increasingly being recognized as an adverse outcome related to chemotherapy treatment. These changes need not be severe to impact patient functional ability and quality of life. The primary goal of this study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and response time among women with newly diagnosed advanced ovarian cancer who receive chemotherapy. Eligible patients were women diagnosed with stage III–IV epithelial ovarian or primary peritoneal cancer who had not yet received chemotherapy but who were prescribed a minimum of six cycles (courses) of chemotherapy treatment. Cognitive function was assessed by a computerized, Web-based assessment (attention, processing speed, and reaction time) and by patient self-report. Cognitive function was assessed at three time points: prior to the first course (baseline), course three, and course six. Medical records were reviewed to abstract information on chemotherapy treatment, concomitant medications, and blood test results (eg, hemoglobin, CA-125). Of the 27 eligible participants, 92% and 86% demonstrated cognitive impairments from baseline to course three and from baseline to course six of chemotherapy, respectively. Impairment was detected in two or more cognitive domains among 48% (12 of 25) and 41% (9 of 22) of participants at course three and course six of chemotherapy, respectively. This study shows evidence of decline in cognitive function among women being treated for ovarian cancer. There is a need for additional, prospective research to better understand the impact of chemotherapy on cognitive function among ovarian cancer patients so that effective preventive and treatment strategies can be developed.
Article Outline
Although the perception of cognitive decline is a common complaint among individuals treated with chemotherapy, it is poorly understood and limited efforts have been made to identify the extent of this problem among women with ovarian cancer. To date, the few studies documenting the neuropsychological consequences of ovarian cancer and its treatment have shown that patients report cognitive problems but that these problems were not quantifiable using objective measures due to the lack of sensitivity of standard instruments to the subtle changes that occur during cancer treatment.[5], [6] and [7]
Although studies of cognitive function among oncology patients have used instruments that have been validated in their own disciplines and with a variety of diseases, the evidence is emerging that they are not comprehensive or appropriate tools for the detection and evaluation of chemotherapy-related change in cognitive function.8 Furthermore, the likelihood of having these tests conducted in a similar manner across multiple institutions, sites, and interviewers with any degree of consistency is very low. This study was designed as a pilot study of the identification of chemotherapy-related changes in cognitive function among women with advanced ovarian cancer using a Web-based assessment tool (Headminder, Inc., New York, NY).7 The primary goal of the current study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and reaction time as well as self-reported changes in the memory, sensory-perception, and cognitive-intellectual domains of cognitive function during chemotherapy among women with newly diagnosed advanced ovarian cancer.
Materials and Methods
All study methods and procedures were reviewed and approved by the University of Arizona Institutional Review Board. Eligible patients included women with a histologically or pathologically confirmed diagnosis of stage III–IV epithelial ovarian or primary peritoneal cancer who were prescribed at least six courses of platinum-based therapy. Patients were excluded if they had a prior history of any cancer (other than nonmelanoma skin cancer), chemotherapy, radiation therapy, erythropoietin treatment (within the last 6 months), or severe head injury. Initially, patients were excluded if they received intraperitoneal therapy, but the protocol was later amended to permit the use of any platinum-based therapy, regardless of route of administration.
Assessment Tools
After providing informed consent, patients completed a neurocognitive battery of tests and the Functional Assessment of Cancer Therapy—Neurotoxicity (FACT-Ntx, to assess patient-reported neuropathy).[9] and [10] The neurocognitive evaluation included both a computerized, Web-based and a patient-reported assessment. The Web-based assessment was provided by HeadMinders, Inc.[7] and [11] and was a modified version of the Cognitive Stability Index. The modified battery was comprised of two warm-up tasks and three empirically-derived cognitive factors: Processing Speed (Animal Decoding and Symbol Scanning subtests), Attention (Number Recall and Number Sequencing subtests), and Reaction Time (Response Direction 1 and Response Direction 2 subtests). The subtests have been validated against traditional neuropsychological tests in healthy and clinical populations, including cancer patients.12 Cognitive domain correlations in the battery's healthy normative sample range from 0.52 to 0.74, and correlations are similar or higher in clinical populations. Test–retest reliability of the factor scores between first and second administrations ranges from 0.74 to 0.82.12 This Web-based neurocognitive assessment tool is 21 CFR Part 11– and Health on the Net (HON)–compliant to ensure patient confidentiality. Prior to undergoing the Web-based cognitive tests, all study participants completed a keyboard proficiency test as a “warm-up task” to the computerized assessment.
The patient-reported cognitive function tool used was the Patient Assessment of Own Functioning Scale (PAF).[13], [14] and [15] The PAF includes eight scales that are grouped into the nature of the ability being considered. The Memory, Sensory-Perceptual, and Cognitive-Intellectual subscales of the PAF are included in this self-assessment questionnaire. Respondents are asked to rate on a six-point scale, from almost always to almost never, how often they experience a particular kind of difficulty in their everyday lives. For this study, the Memory and Cognitive-Intellectual subscales of the PAF were used, similar to other clinical research protocols investigating cognitive changes during chemotherapy treatment.15 The PAF has been shown to be directly related to the Minnesota Multiphasic Personality Inventory (MMPI)13 and to be highly correlated with other cognitive impairment indices, such as the American College of Rheumatology neuropsychology research battery of tests.16 Of note, self-reported cognitive change has not been shown to correlate formal assessments of cognitive function among individuals who have experienced cancer.[17], [18], [19], [20] and [21]
The FACT-Ntx is a validated instrument[9] and [10] that was used to evaluate neurotoxicity. This scale includes 11 items: nine to assess neurotoxicity, one to assess bodily weakness, and one to assess anemia. Neurotoxicity may affect a patient's ability to use the keyboard in the computerized neurocognitive evaluation. This complete assessment battery of tests was completed at baseline (within 5 days of initiation of chemotherapy) and again during follow-up assessments at cycle three and cycle six of chemotherapy. The medical record was reviewed and data were abstracted related to chemotherapy medications, all concomitant medications, and blood test results (eg, hemoglobin, CA-125).
Statistical Plan
This prospective study was exploratory in nature and designed to collect pilot data to determine if there is evidence of neurocognitive change in attention, processing speed, response time, or self-reported cognitive function during the course of chemotherapy among women being treated for advanced ovarian cancer. The purpose of this study was to obtain preliminary estimates of the incidence and degree of cognitive decline to aid in the planning of future studies. While prior estimates of cognitive function were not available for this population, power analyses demonstrate that with a target recruitment goal of 30 patients, a McNemar's test has 78% power at the 0.05 level of significance to detect a significant decline in impairment in a cognitive domain if 12 patients are found to have impairment prior to course six of treatment (but not at course three) and if as few as two patients demonstrate impairment prior to course three but not at course six. This study was therefore powered to detect declines in one or more of the domains that may have occurred at less than both of the study time points following the baseline assessment.
To be considered fully evaluable, patients had to have completed at least one follow-up neurocognitive evaluation and may not have received antipsychotic neuropsychological medications during the study (eg, chlorpromazine, haloperidol, clozapine). Antidepressants and antianxiety medications (eg, serotonin/norepinephrine reuptake inhibitors or benzodiazepines) were permitted and use was recorded throughout study participation. A summary score for each cognitive domain (processing speed, reaction time, and attention) was recorded at each assessment time point using the HeadMinder Web-based assessment. This summary score was assessed by time (processing speed and reaction time), measured to the hundredth of a second, and by number of errors (attention). If a cognitive domain summary score at a follow-up assessment time declined at least one standard error of measurement (SEM) from baseline, the patient was considered to have experienced a decline at that time point. For the purposes of this article, such declines are referred to as “impairments” within the cognitive domain under investigation. A cognitive index score (CIS) was calculated as the number of cognitive domains impaired for the time point. The range of a CIS is 0–3, with zero equal to no impairment on any cognitive domain and three equal to impairment on all cognitive domains. Patients with only one cognitive domain decline (CIS = 1) at any one of the follow-up assessment time points were considered as having possible cognitive function decline. Patients with more than one cognitive domain impairment (CIS >1) at any follow-up assessment time points were considered as having evidence of cognitive function decline. The incidence of cognitive function impairment was determined by the percentage of patients who experienced any cognitive domain impairment (including possible and evidence of decline) at any follow-up assessment.
A repeated-measures analyses of variance (ANOVA) was used to further explore the neurocognitive values at the various time points during the study. Many of the neurocognitive values were not normally distributed but skewed either positively or negatively, so the square roots of the values were used in the analyses. Since this is an exploratory analysis, no corrections for multiple comparisons were performed.
The patient-reported cognitive function instrument (PAF) contains items scored on a Likert-type scale from almost never to almost always (range 0–5). Patient-reported outcomes as measured with the PAF are measured as mean scale values, ranging from 0, indicating no impairment, to 5.0, indicating complete impairment. PAF score ranges indicate low (≤1.25), medium (1.26–1.92), and high (≥1.93) levels of cognitive impairment.13 A total FACT-Ntx score was obtained; lower scores represent greater neurotoxicity, ranging from 0 (extreme neurotoxicity) to 44 (no neurotoxicity). The total score was reported, with adjustments made for missing values as described elsewhere.22
Results
Thirty patients were enrolled in this study; however, two were later deemed ineligible, and one was unable to complete the baseline neurocognitive assessment prior to chemotherapy and was withdrawn from the study, resulting in 27 patients available for assessment. Five of these patients did not complete all neurocognitive assessments. The primary reason for nonadherence to the study schedule was clinical scheduling (eg, chemotherapy was administered prior to the neurocognitive assessment). The characteristics of eligible patients are provided in Table 1. The majority of patients were receiving intravenous chemotherapy (intraperitoneal therapy was at first not permitted but later was allowable following an amendment to the protocol) and taking concomitant sleep, antianxiety, and/or antidepressant medications outside of every 3- to 4-week chemotherapy regimen (primarily zolpidem, lorazepam, sertraline, and/or trazodone).
| n = 27 | |
| Mean age, years (range) | 59.3 (40.3–81.5) |
| Education, n (%) | |
| High school or less | 3 (11.1%) |
| Some college | 12 (44.4%) |
| College graduate | 12 (44.4%) |
| Race/ethnicity, n (%) | |
| White, non-Hispanic | 25 (92.6%) |
| Hispanic | 1 (3.7%) |
| Native American | 1 (3.7%) |
| Marital status, n (%) | |
| Married/cohabitating | 19 (70.4%) |
| Divorced/separated | 1 (3.7%) |
| Widowed | 5 (18.5%) |
| Never married | 2 (7.4%) |
| Mean courses of chemotherapy, n (range) | 5.9 (4–6) |
| Chemotherapy route, n (%) | |
| Intraperitoneal | 5 (18.5%) |
| Intravenous | 22 (81.5%) |
| Concurrent medication use, n (%) | |
| Antidepressant | 7 (25.9%) |
| Antianxiety | 16 (59.3%) |
| Sleep aids | 5 (18.5%) |
Web-Assessed Cognitive Function
Keyboard proficiency remained unchanged over time (P = 0.39). As shown in Table 2, most participants demonstrated cognitive impairments in at least one of the three cognitive domains assessed during this study (92% and 86% at course 3 and course 6, respectively). Nearly half of the study participants demonstrated impairment from baseline in two or more of the three cognitive domains assessed (Table 3). Table 4 shows a detailed summary of the subscales within the Web-based cognitive tests that comprised the CIS.This table demonstrates the statistically significant increase in test subscale errors, despite the test-taking improvements over time, as shown by reduction in testing time.
| CIS | COURSE 3 | COURSE 6 |
|---|---|---|
| No decline (CIS = 0) | 2 (8%) | 3 (14%) |
| One impairment (CIS = 1) | 11 (44%) | 10 (45%) |
| Two impairments (CIS = 2) | 11 (44%) | 7 (32%) |
| Three impairments (CIS = 3) | 1 (4%) | 2 (9%) |
| COGNITIVE IMPAIRMENT SCALE (CIS) FACTORS | BASELINE | COURSE 3 | COURSE 6 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N | MEAN | SD | N | MEAN | SD | N | MEAN | SD | P | |
| Attention | ||||||||||
| Number recall (number correct) | 25 | 7.08 | 1.75 | 25 | 7.16 | 2.03 | 22 | 7.45 | 1.92 | 0.887 |
| Number sequencing (number correct) | 26 | 6.23 | 0.98 | 25 | 5.96 | 2.65 | 23 | 5.61 | 2.29 | 0.476 |
| Processing speed | ||||||||||
| Animal decoding (number of errors) | 25 | 0.4 | 0.5 | 25 | 0.72 | 0.84 | 23 | 3.26 | 0.86 | <0.0001 |
| Animal decoding (number correct) | 25 | 32.48 | 6.48 | 25 | 32.96 | 8.90 | 23 | 32.22 | 8.70 | 0.678 |
| Symbol scanning (number correct) | 27 | 18.59 | 1.15 | 25 | 18.76 | 1.2 | 21 | 18.67 | 1.35 | 0.883 |
| Symbol scanning (response time) | 27 | 4.38 | 1.37 | 25 | 4.26 | 1.66 | 21 | 3.61 | 0.84 | 0.002 |
| Reaction time | ||||||||||
| Response direction 1 (number of omissions) | 27 | 0.04 | 0.19 | 26 | 0.62 | 2.35 | 23 | 0 | 0 | 0.028 |
| Response direction 1 (response time, seconds) | 27 | 0.52 | 0.06 | 26 | 0.55 | 0.22 | 23 | 0.52 | 0.07 | 0.567 |
| Response direction 2 (number of omissions) | 27 | 0.63 | 1.33 | 26 | 0.5 | 2.18 | 23 | 0.43 | 0.95 | 0.135 |
| Response direction 2 (response time, seconds) | 27 | 0.75 | 0.13 | 26 | 0.72 | 0.20 | 23 | 0.71 | 0.17 | 0.467 |
| Response direction, shift failures (number) | 27 | 4.33 | 3.13 | 26 | 2.77 | 2.29 | 23 | 3.04 | 2.58 | 0.007 |
Patient-Reported Cognitive Function
The mean values and 95% confidence intervals of the patient-reported cognitive function outcomes are presented in Figure 1. Mean values remained within the low impairment range (less than 1.25) during chemotherapy.
Blood Chemistries and Toxicity
The mean values and 95% confidence intervals of significant differences in blood chemistries and toxicities are presented in [Figure 2] and [Figure 3]. Total patient-reported neurotoxicity increased significantly during chemotherapy (ANOVA; F = 6.851, P = 0.002), while several mean blood chemistry values decreased during chemotherapy treatment (hemoglobin F = 2.465, P = 0.09; white blood cell count F = 16.95, P < 0.001; platelets F = 13.72, P < 0.001; and CA-125 F = 4.91, P = 0.01). One study participant received a blood transfusion at the final course of chemotherapy, and two and three participants received cytokines (erythropoietin or darbepoietin) at course 3 and course 6, respectively.
Discussion
This study shows preliminary evidence that cognitive decline is a significant factor experienced by women who are treated for advanced ovarian cancer. Most participants self-reported mild declines, and these were detectable by a sensitive Web-based assessment tool. There are many potential mechanisms of cognitive decline during chemotherapy, ranging from oxidative damage to reduced blood oxygenation due to anemia to stress and anxiety. While it is outside of the scope of this small pilot study to examine the causative factors of decline, it does suggest the need for further investigation of the effect and potential mechanisms of cognitive decline in this population. While most of the prior work in cognitive function has been conducted among breast cancer patients, ovarian cancer patients appear to experience cognitive decline as well. There is a need to further understand this issue so that effective preventive or treatment strategies can be developed.
The significant increase in patient-reported neurotoxicity across each study visit may be a concern for computerized assessments that require dexterity. However, the keyboard proficiency tests did not decline over time, suggesting that the neurotoxicity reported by patients in this study was not great enough to affect their ability to use the computer keyboard. Patients appear to report higher levels of difficulty with memory (eg, forgetfulness) following diagnosis than following the initiation of chemotherapy; however, higher-level cognitive processes (eg, logic, organizational abilities, calculations) reported by patients appear to decline following the initiation of chemotherapy. Although larger, adequately powered trials are needed to determine the extent of this decline, this suggests that patients experience increasing challenges that may interfere with their ability to perform necessary tasks at work and in the household. Further work is needed to examine the duration of these effects following chemotherapy. Since the cognitive impact of chemotherapy reported by patients is mild, investigators must ensure the use of appropriate patient-reported tools that are able to detect these differences. While reported decline may occur, this is likely to remain within the mild category of traditional assessment tools. It is of benefit to use patient-reported tools such as the PAF that also permit the analysis of continuous data.
This study is limited by its design as a pilot study and was challenged by several logistical issues. Four patients were unable to complete all the neurocognitive evaluations. This was due to remote study staff, who would visit various clinics in the Tucson and Phoenix metropolitan regions in Arizona (range of travel more than 120 miles). The lack of completion was entirely due to communication and travel complications. When a patient was rescheduled to a different chemotherapy date, it was not always possible for this to be communicated to the Arizona Cancer Center researchers in a timely manner, resulting in missed visits. It is recommended for future studies that require strict timelines for study assessments (such as this cognitive function study) that the assessments be conducted by staff in those practices who can identify changes in infusion dates when they occur. This will reduce the communication barriers and rate of missed visits. This study was also not designed to be a comprehensive assessment of neurocognitive function but was focused on assessing three domains: attention, processing speed, and response time. It is possible that many other domains of cognitive function could be impacted by chemotherapy that were not evaluated in this study. Many patients were also taking antidepressant medications during the study; however, these were generally not new prescriptions and were also being taken at the baseline assessment. Nevertheless, future studies should incorporate assessments of mood, depression, and anxiety to account for the potential effect of these factors on cognitive assessment scores.
Despite these limitations, the study provides preliminary data demonstrating cognitive decline during chemotherapy among ovarian cancer patients treated in the front-line setting of advanced disease. More than 90% of all patients experienced measurable impairments in cognitive function during primary chemotherapy. More than half of all patients demonstrated impairment on two or more cognitive domains. Prior work has shown that even mild cognitive impairments can influence quality of life and the ability to perform routine daily activities (eg, taking medications, returning to work, managing household finances).23 The data emphasize the critical need to further understand the impact of chemotherapy on cognitive function among ovarian cancer patients so that effective preventive and treatment strategies can be developed. Additional research is needed to understand how long these declines may persist following chemotherapy treatment.
Acknowledgments
This study was funded by an investigator-initiated grant from Ortho Biotech, Inc., to the University of Arizona Cancer Center. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect those of Ortho Biotech.
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