Abstract
The present study examined the long-term cognitive implications of cancer treatment among breast cancer survivors aged 65 years and older. Fifty-seven women survivors were compared to 30 healthy older female adult comparisons, matched in terms of age and education, with no history of cancer. Cancer survivors were also compared based on treatment intervention, involving chemotherapy (n = 27) versus local therapy through surgery and radiation (n = 30). As a group, the breast cancer survivors scored lower on measures of general cognitive function, working memory, psychomotor speed, and executive function, when compared to the normal comparisons. Among the cancer survivors, those who received local therapy scored lower than the other survivors and normal comparisons on measures of verbal learning, visual perception and construction, as well as visual attention and short-term retention. Our findings suggest that cognitive outcomes may involve more age-related deficits among older cancer survivors compared to matched healthy subjects.
Keywords: breast cancer, chemotherapy, cognition, neuropsychological assessment
According to the American Cancer Society there are almost two and a half million survivors of breast cancer and the median age at the time of diagnosis is 61 years. As the number of breast cancer survivors increase due to expanded treatment options, such as chemotherapy, the impact of such treatments on cognitive function becomes an increasing concern. For older breast cancer survivors successfully treated after diagnosis, there may remain residual concerns regarding whether exposure to cancer treatments may have latent effects on cognitive function as these individuals approach late-life. Neuropsychological evaluations on effects of treatments for all forms of cancer in adults have shown deleterious effects on cognitive functioning that tend to persist in longitudinal follow-up (e.g., [1]). Other reviews featuring breast cancer patients have also suggested adverse effects of chemotherapy on cognition [2, 3, 4, 5, 6].
The possible neuropsychological side effects of these treatments may include difficulty concentrating, impaired memory, difficulty organizing information, processing speed, and decreased motor skills, and language problems. For example, a meta-analysis of 30 studies, encompassing 29 eligible samples across cancer groups (838 adults) by Anderson-Hanley et al. [7] indicated that patients who underwent chemotherapy showed the greatest changes in executive function and verbal memory when compared with matched comparisons. Furthermore, the analysis indicated that cancer patients consistently showed impairments in domains of executive functioning, verbal memory, and motor functioning compared to published normative data. In another meta-analysis, Falleti et al. [3] reported that breast cancer patients who received chemotherapy demonstrated decline in several cognitive domains (with small to medium effect sizes), including motor function, memory, executive functioning, and attention. A last meta-analysis [6], also with breast cancer participants, evaluated seven studies involving more than 300 participants and determined that breast cancer patients treated with chemotherapy displayed decline in language, spatial ability, and short-term memory.
There has been a variety of methodologies utilized to examine the possible deleterious effects on cognition in breast cancer patients. For example, some studies have compared breast cancer patients who have received chemotherapy to those who have received other forms of treatment and healthy matched comparisons (e.g., [8, 9]). Other studies have compared breast cancer patients based on chemotherapy dose, such as standard-dose versus higher doses of chemotherapy (e.g., [10, 11]). Many of these studies have been longitudinal (e.g., [9, 12, 13, 14, 15]), but some have been retrospective (e.g., [1, 16, 17]).
Two recent studies [13, 19] have specifically compared breast cancer patients who have received chemotherapy to breast cancer patients who have not received chemotherapy (e.g., local or radiotherapy only), and healthy controls. A study conducted in Canada [13] compared four groups (chemotherapy group, control group for chemotherapy group, radiotherapy group, and control group for radiotherapy group) of women prior to the start of chemotherapy, right after chemotherapy, and at a three-month follow-up. Each participant completed a neuropsychological battery and self-report questionnaires. Results across the three time points were mixed with breast cancer groups performing both better and worse compared to each other and their respective healthy comparison group. For example, both cancer groups demonstrated a decline in verbal memory between the first two time points, whereas nonverbal memory improved. Between the last two time points, participants demonstrated improvement on most cognitive measures.
A second study from the United Kingdom [18] sought to compare breast cancer patients being treated with chemotherapy, breast cancer patients being treated with radiotherapy, and a healthy control group at baseline, one month post-chemotherapy and 12 months post-chemotherapy. Results indicated that 22% of chemotherapy patients, 26% of radiotherapy patients, and 18% of healthy controls showed reliable decline on most neuropsychological measures. There were significant differences between the radiotherapy and control group on measures of memory and attention with the control group performing better.
While past research has established that a cohort of breast cancer patients frequently experience short-term cognitive deficits in the initial months and years following cancer treated with chemotherapy, the research has been variable in both the cognitive domain affected and severity. Furthermore, comparatively little has been done to systematically assess the growing cohort of long-term aging survivors who may be disease-free for several decades after treatment. Specifically, it would be useful to understand whether cancer survivors are at greater risk for increased age-related brain changes or dementia secondary to cancer treatment. Although there have been longitudinal studies that have followed cancer survivors after treatment, very little has been done to examine the role of cognitive functioning in older breast cancer patients who are more than a decade post-chemotherapy. The present research attempts to assess long-term survivors over age 65 to determine whether any sustained cognitive liability is incurred from exposure to cancers treatments.
The primary goal of the present study was to determine whether a history of chemotherapy would be associated with cognitive deficits in excess of those observed in demographically matched healthy comparison women. Previous investigations from our laboratory have indicated that breast cancer patients, more than a decade post-chemotherapy, demonstrated significant differences and performed worse in the domains of attention, working memory, psychomotor speed, and aspects of executive functioning when compared to matched healthy community-dwelling older adults [17]. However, given that suffering from cancer may have independent effects beyond the impact of chemotherapy, it is also important to examine women with a history of breast cancer but treated with local therapy (as opposed to chemotherapy). Therefore, a second group of cancer survivors were recruited and comprised of women treated with surgical removal and local radiation for breast cancer. We hypothesized that a history of cancer would be associated with greater cognitive deficits when compared to an age-, education, and intellect-matched sample of healthy, community-dwelling older adults. Also, women who were exposed to chemotherapy would endorse greater cognitive deficits when compared to women who had been treated with surgical removal and local radiation.
Methods
Participants
Fifty-seven breast cancer survivors (hereafter referred to as BCS) participated in the study. The BCS were recruited in collaboration with the Iowa Cancer Registry, a statewide registry of cancer patients begun in 1973. Notably, the registry collects information on diagnosis of all cancers in the State of Iowa, including tissue type, stage of cancer and type of treatment. The registry undergoes continuous updates so the recurrence of breast cancer or other cancers would be noted. Enrollment criteria specified that the participants were women over the age of 65 years, at least 50 years of age at the time of cancer diagnosis, and at least 10 years post-cancer treatment without recurrence. Participants for this study were diagnosed and treated for early malignant breast cancer Stage I through Stage IIIA without evidence of metastasis. Participants were excluded if there had been a recurrence of any kind of cancer in the 10–15 year period since initial diagnosis, excluding basal cell or relatively benign skin lesions. Participants were also excluded if they possessed a central nervous system (CNS) disorder, such as multiple sclerosis, Parkinson’s disease, closed head trauma with an extended loss of consciousness, or other CNS lesion. All breast cancer survivors were free of currently active and unstable metabolic, psychiatric, and cardiovascular diseases, including cerebrovascular events and substance abuse.
The participants in the chemotherapy group had received a standard multi-agent chemotherapy regimen involving cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or an anthracycline (doxorubicin) following their initial surgical excision of the cancer. Participants in the local-therapy group had all received surgery and/or received local radiation to the affected breast.
Non-cancer comparison participants were identified from an existing database. These “comparisons” (hereafter referred to as NC) were previously recruited in the community for an ongoing study examining the effects of aging on decision-making behavior. As such, only healthy, community-dwelling adults were included. Participants met inclusionary criteria if they were free of neurological and psychiatric illness.
Measures
Each participant completed a comprehensive neuropsychological battery of approximately 3-hours duration consisting of standardized clinical instruments designed to assess a broad range of cognitive skills and emotional functioning, including current and premorbid intellect, mental status, attention and working memory, psychomotor speed, language, visuospatial skills, memory, executive functioning, mood, and medical comorbidity. Table 1 display individual names of neuropsychological measures by cognitive domain.
TABLE 1.
Neuropsychological Measures by Cognitive Domain
| Cognitive Domain | Neuropsychological Measures |
|---|---|
| Intelligence and Mental Status | Wechsler Abbreviated Scale of Intelligence (WASI; [19]) |
| Wide Range Achievement Test–III Reading subtest (WRAT-III; [20]) | |
| Folstein Mini Mental State examination (MMSE; [21]) | |
| Attention and Working Memory | Digit Span, Letter-Number Sequencing, and Arithmetic subtests from the Wechsler Adult Intelligence Scale–Third Edition (WAIS-III; [22]) |
| Psychomotor Speed | Trail Making Test, Part A (Trail Making A; [23]) |
| Language | Controlled Oral Word Association Test (COWAT; [24]) |
| Boston Naming Test (BNT; [25]) | |
| Visuospatial | Rey-Osterrieth Complex Figure Test-Copy Condition (Rey-O Copy; [26]) |
| Benton Facial Recognition Test (Benton Faces; [27]) | |
| Memory | Rey Auditory-Verbal Learning Test (RAVLT; [28]) |
| Rey-Osterrieth Complex Figure Test-Delay Condition (Rey-O Delay; [26]) | |
| Benton Visual Retention Test-Revised (BVRT-R; [29]) | |
| Executive Functioning | Wisconsin Card Sorting Test (WCST; [30]) |
| Trail Making Test, Part B (Trail Making B; [23]) | |
| Mood | Beck Depression Inventory-II (BDI-II; [31]) |
| Medical Comorbidity | Adult Comorbidity Evaluation-27 (ACE-27; [32]) |
Procedure
Participants signed a written informed consent document approved by the University of Iowa Institutional Review Board and were financially compensated for their involvement.
Statistical Analyses
Preliminary analysis examined data for the presence of outliers and the appropriateness of assumptions of normality, linearity, and homogeneity of variances. A one-way analysis of variance (ANOVA) was computed using the cognitive measures as dependent variables and the participant groups (i.e., chemotherapy, local-therapy, non-cancer) as independent variables. To control for inflation of the experiment-wise type 1 error, the Hochberg procedure [33] was used to account for multiple comparisons. The next set of analyses explored group differences on individual neuropsychological tests, using a series of one-way analyses of covariance (ANCOVA) with age, education, and medical comorbidity as the covariates and each test score as the dependent variable. The ANCOVAs were applied to measures displaying significant group differences after the Hochberg procedure.
Results
The final sample was comprised of 87 subjects. The chemotherapy-exposed group included 27 participants, with a mean age of 72.0 years (SD = 4.9; range [66–85]), a mean education of 14.6 years (SD = 2.8; range [11–20]), a WASI Full-Scale IQ of 114.5 (SD = 12.11), and a WRAT-III reading raw score of 48.1 (SD = 4.7). The local therapy group included 30 participants, with a mean age of 76.7 years (SD = 5.4; range [69–89]), mean education of 14.2 years (SD = 2.1; range [11–19]), a WASI Full-Scale IQ of 111.7 (SD = 14.9), and a WRAT-III reading raw score of 48.7 (SD = 4.1).
The non-cancer comparison group had a mean age of 72.6 years (SD = 5.5; range [65–85]), a mean education of 14.3 years (SD = 2.2; range [11–18]), a WASI Full-Scale IQ of 112.9 (SD = 9.9), and a WRAT-III reading raw score of 50.2 (SD = 5.0). We observed significant differences among the three participants groups in terms of age, such that the surgery group were significantly older than both the chemotherapy and NCs [F(2, 86) = 7.07, p = .001]. The three groups did not significantly differ in terms of education, overall premorbid and current intelligence, self-reported mood, or medical comorbidity. Demographic variables are presented in Table 2.
TABLE 2.
Between-Subjects Effects from ANOVA
| Measure | Chemotherapy (n=27) | Local-therapy (n=30) | Non-Cancer (n=30) | F | P |
|---|---|---|---|---|---|
| Age (years) | 72.0 (4.9) | 76.7 (5.4) | 72.6 (5.5) | 7.07 | .001* |
| Education (years) | 14.6 (2.8) | 14.2 (2.1) | 14.3 (2.2) | .18 | .838 |
| Wechsler Abbreviated Scale of Intelligence | |||||
| Vocabulary | 64.5 (7.8) | 60.9 (8.2) | 63.7 (6.9) | 1.65 | .198 |
| Block Design | 33.9 (12.3) | 32.0 (13.4) | 34.8 (11.9) | .14 | .871 |
| Similarities | 36.8 (4.8) | 35.8 (5.2) | 36.6 (3.0) | .133 | .893 |
| Matrix Design | 20.6 (6.5) | 17.9 (7.1) | 21.8 (6.8) | 2.45 | .093 |
| Wide Range Achievement Test–III reading subtest | 48.1 (4.7) | 48.7 (4.1) | 50.2 (5.0) | 1.697 | .191 |
| Folstein Mini-Mental State Examination | 28.0 (1.7) | 27.5 (2.1) | 29.4 (0.7) | 10.72 | .000* |
| Digit span total raw score | 15.5 (3.4) | 15.2 (3.2) | 16.9 (4.4) | 1.93 | .151 |
| Letter-Number Sequencing total raw score | 9.1 (2.1) | 8.7 (2.0) | 11.0 (2.0) | 10.58 | .000* |
| Arithmetic total raw score | 12.4 (2.8) | 12.3 (3.8) | 13.7 (3.2) | 1.56 | .216 |
| Trail Making test | |||||
| A – time (s) | 37.8 (8.9) | 39.4 (12.2) | 29.27 (8.7) | 8.75 | .000* |
| B – time (s) | 97.0 (35.5) | 100.3 (53.4) | 72.4 (26.6) | 4.28 | .017 |
| Controlled Oral Word Association Test | 39.4 (15.1) | 37.0 (9.8) | 38.8 (11.1) | .31 | .731 |
| Boston Naming Test total raw score | 57.0 (2.5) | 52.8 (10.3) | 56.1 (3.0) | 3.37 | .039 |
| Rey-Osterrieth Complex Figure | |||||
| Total copy score | 33.3 (2.0) | 29.2 (2.9) | 32.0 (2.9) | 18.68 | .000* |
| Total delay score | 15.9 (5.1) | 11.6 (6.0) | 15.6 (5.6) | 5.46 | .006 |
| Benton Faces total raw score | 44.4 (3.4) | 43.2 (3.6) | 45.5 (3.8) | 3.13 | .049 |
| Benton Visual Retention Test total error score | 5.3 (2.2) | 6.8 (2.3) | 4.4 (2.8) | 5.92 | .004* |
| Rey Auditory-Verbal Learning Test total recall | 48.6 (8.3) | 41.8 (9.8) | 49.4 (8.7) | 6.42 | .003* |
| Rey Auditory-Verbal Learning Test 30 minute delay | 10.2 (2.6) | 8.7 (3.4) | 10.6 (2.3) | 3.85 | .025 |
| IED Stage 5 errors | 3.2 (4.2) | 2.1 (1.5) | 1.3 (1.0) | 3.59 | .032 |
| Wisconsin Card Sorting Test | |||||
| Perseverative | 12.5 (6.9) | 12.8 (9.3) | 16.6 (12.2) | 1.452 | .241 |
| Errors | 11.0 (5.7) | 11.1 (7.7) | 14.9 (11.0) | 1.754 | .180 |
| Categories | 2.9 (1.6) | 2.8 (1.5) | 5.0 (1.9) | 14.46 | .000* |
| Beck Depression Inventory-II total raw score | 5.7 (5.1) | 6.4 (5.4) | 4.0 (3.4) | 1.99 | .143 |
| Adult Comorbidity Evaluation index | .96 (.66) | .97 (.56) | .84 (.69) | .242 | .786 |
Significant P-value after Hochberg correction for multiple comparisons.
Table 2 displays the results of between-subjects effects from ANOVA analysis. After applying the Hochberg procedure, we observed significant differences among the three participant groups on the following neuropsychological measures: MMSE [F(2, 86) = 10.72, p < .001]; Letter-Number Sequencing [F(2, 86) = 10.58, p < .001]; WCST categories [F(2, 86) = 14.46, p < .001]; Trail Making A [F(2, 86) = 8.75, p < .001]. Tukey post-hoc comparisons of the three groups indicated that the NC group outperformed the BCS in the aforementioned measures of mental status, attention and working memory, psychomotor speed, and executive function.
In the domain of verbal learning and visual perception, there were significant differences among the three participant groups on the RAVLT total recall [F(2, 86) = 6.42, p = .003] and Rey-O Copy [F(2, 86) = 18.68, p < .001], such that local-therapy group underperformed in comparison to the chemotherapy and NC groups. Group differences were also observed in the aspects of visual attention and short-term retention. Specifically, there were group differences in BVRT [F(2, 86) = 5.92, p = .004], such that local-therapy group performed worse in comparison to the NC group. Results of the ANOVA post-hoc analyses are presented in Table 3.
TABLE 3.
Tukey HSD Comparison from ANOVA and ANCOVA
| Measure | Group (I) | Group (J) | ANOVA | ANCOVA | ||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Mean Diff (I-J) | Std. Error | Sig. | Mean Diff (I-J) | Std. Error | Sig. | |||
| MMSE | Chemo | Local-therapy | .500 | .428 | .475 | .270 | .487 | .581 |
| Non-Cancer | −1.367* | .428 | .006 | −1.458* | .511 | .006 | ||
| Local-therapy | Chemo | −.500 | .428 | .475 | −.270 | .487 | .581 | |
| Non-Cancer | −1.867* | .416 | .000 | −1.727* | .525 | .002 | ||
| Non-Cancer | Chemo | 1.367* | .428 | .006 | 1.727* | .525 | .002 | |
| Local-therapy | 1.867* | .416 | .000 | 1.458* | .511 | .006 | ||
| LN - Total raw score | Chemo | Local-therapy | .333 | .549 | .816 | .180 | .587 | .760 |
| Non-Cancer | −1.926* | .535 | .002 | −1.882* | .611 | .003 | ||
| Local-therapy | Chemo | −.333 | .549 | .816 | −.180 | .587 | .760 | |
| Non-Cancer | −2.259* | .535 | .000 | −2.062* | .635 | .002 | ||
| Non-Cancer | Chemo | 1.926* | .535 | .002 | 2.062* | .635 | .002 | |
| Local-therapy | 2.259* | .535 | .000 | 1.882* | .611 | .003 | ||
| Trail A – time (s) | Chemo | Local-therapy | −1.619 | 2.672 | .817 | 1.805 | 2.853 | .529 |
| Non-Cancer | 8.548* | 2.672 | .005 | 8.856* | 2.995 | .004 | ||
| Local-therapy | Chemo | 1.619 | 2.672 | .817 | −1.805 | 2.853 | .529 | |
| Non-Cancer | 10.167* | 2.600 | .001 | 7.051* | 3.079 | .025 | ||
| Non-Cancer | Chemo | −8.548* | 2.672 | .005 | −7.051* | 3.079 | .025 | |
| Local-therapy | −10.167* | 2.600 | .001 | −8.856* | 2.995 | .004 | ||
| Rey-O Copy | Chemo | Local-therapy | 4.150* | .699 | .000 | 3.584* | .670 | .000 |
| Non-Cancer | 1.317 | .699 | .063 | .203 | .703 | .774 | ||
| Local-therapy | Chemo | −4.150* | .699 | .000 | −3.584* | .670 | .000 | |
| Non-Cancer | −2.833* | .681 | .000 | −3.382 | .722 | .000 | ||
| Non-Cancer | Chemo | −1.317 | .699 | .063 | −.203 | .703 | .774 | |
| Local-therapy | 2.833* | .681 | .000 | 3.382* | .722 | .000 | ||
| BVRT - Total error score | Chemo | Local-therapy | −1.523 | .697 | .081 | −1.446* | .704 | .044 |
| Non-Cancer | .899 | .682 | .390 | 1.347 | .719 | .066 | ||
| Local-therapy | Chemo | 1.523 | .697 | .081 | 1.446* | .704 | .044 | |
| Non-Cancer | 2.423* | .710 | .003 | 2.793* | .761 | .001 | ||
| Non-Cancer | Chemo | −.899 | .682 | .390 | −2.793* | .761 | .001 | |
| Local-therapy | −2.423 | .710 | .003 | −1.347 | .719 | .066 | ||
| RAVLT - Total recall | Chemo | Local-therapy | 6.793* | 2.380 | .015 | 5.504* | 2.473 | .029 |
| Non-Cancer | −.807 | 2.380 | .939 | .026 | 2.596 | .992 | ||
| Local-therapy | Chemo | −6.793* | 2.380 | .015 | −5.504* | 2.473 | .029 | |
| Non-Cancer | −7.600* | 2.317 | .004 | −5.478* | 2.669 | .044 | ||
| Non-Cancer | Chemo | .807 | 2.380 | .939 | 5.478* | 2.669 | .044 | |
| Local-therapy | 7.600* | 2.317 | .004 | −.026 | 2.596 | .992 | ||
| WCST - Categories | Chemo | Local-therapy | .114 | .500 | .972 | −.067 | .481 | .890 |
| Non-Cancer | −2.111* | .460 | .000 | −2.677* | .461 | .000 | ||
| Local-therapy | Chemo | −.114 | .500 | .972 | .067 | .481 | .890 | |
| Non-Cancer | −2.225* | .488 | .000 | −2.610* | .507 | .000 | ||
| Non-Cancer | Chemo | 2.111* | .460 | .000 | 2.610* | .507 | .000 | |
| Local-therapy | 2.225* | .460 | .000 | 2.677* | .461 | .000 | ||
The mean difference is significant at the 0.05 level.
The univariate ANCOVAs presented in Table 4 indicate significant differences between the groups that are consistent with results from the analysis of variance, with the exception of performances on the BVRT and RAVLT. For performance on the BVRT, an ANCOVA revealed a significant main effect, [F(2,86)) = 6.747; p = .002)], with post-hoc analysis using Tukey’s HSD indicated that the local-therapy group underperformed in comparison to both the chemotherapy (p = .04) and NC group (p = .001).
TABLE 4.
Between-Subjects Effects from ANOVA and ANCOVA
| Measure | Chemotherapy (n=27) | Local-therapy (n=30) | Non-Cancer (n=30) | F | P | Sig. Main Effects |
|---|---|---|---|---|---|---|
| MMSE | 28.0 (1.7) | 27.5 (2.1) | 29.4 (0.7) | 10.72 | .000 | Non-Cancer > Chemo & Local-therapy |
| 27.9 (.34) | 27.6 (.33) | 29.3 (.40) | 6.16 | .003 | Non-Cancer > Chemo & Local-therapy* | |
| LN - Total raw score | 9.1 (2.1) | 8.7 (2.0) | 11.0 (2.0) | 10.58 | .000 | Non-Cancer > Chemo & Local-therapy |
| 9.0 (.40) | 8.8 (.41) | 10.9 (.47) | 6.46 | .003 | Non-Cancer > Chemo & Local-therapy* | |
| Trail A - Time (s) | 37.8 (8.9) | 39.4 (12.2) | 29.3 (8.7) | 8.75 | .000 | Non-Cancer < Chemo & Local-therapy |
| 39.2 (1.97) | 37.4 2(1.9) | 30.3 (2.3) | 4.67 | .013 | Non-Cancer < Chemo & Local-therapy* | |
| Rey-O - Total copy score | 33.3 (2.0) | 29.2 (2.9) | 32.0 (2.9) | 18.68 | .000 | Local-therapy < Chemo & Non-Cancer |
| 33.1 (.46) | 29.5 (.45) | 32.9 (.5) | 17.09 | .000 | Local-therapy < Chemo & Non-Cancer* | |
| BVRT - Total error score | 5.3 (2.2) | 6.8 (2.3) | 4.4 (2.8) | 5.92 | .004 | Local-therapy > Non-Cancer |
| 5.3 (.46) | 6.76 (.51) | 4.0 (.56) | 6.75 | .002 | Local-therapy > Chemo & Non-Cancer* | |
| RAVLT - Total recall | 48.6 (8.3) | 41.8 (9.8) | 49.4 (8.7) | 6.42 | .003 | Local-therapy < Chemo & Non-Cancer |
| 48.1(1.7) | 42.6 (1.67) | 48.1 (2.0) | 3.08 | .052 | Local-therapy < Chemo & Non-Cancer* | |
| WCST -Categories | 2.9 (1.6) | 2.8 (1.5) | 5.0 (1.9) | 14.46 | .000 | Non-Cancer > Chemo & Local-therapy |
| 2.9 (.31) | 2.9 (.35) | 5.5 (.35) | 20.09 | .000 | Non-Cancer > Chemo & Local-therapy* |
Results of each analysis of covariance for the respective neuropsychological measure; the adjusted means were obtained and reported.
For performances on the RAVLT, an ANCOVA [F(2, 86) = 3.081, p = .052] revealed a change in the main effects when compared with results of the ANOVA [F(2, 86) = 6.42, p = .003]. However, post-hoc analysis revealed similar findings, such that the local-therapy group underperformed in comparison to the chemotherapy (p = .029) and normal control (p = .044) groups. Results of the ANCOVA post-hoc analyses are presented in Table 2.
Overall, results from the univariate ANCOVAs suggested that even after controlling for age, education, and medical cormorbidity, the BCS group scored lower on the MMSE, Letter-Number Sequencing, Trail Making A, and WCST. In addition, when cancer survivors were compared based on whether they received chemotherapy or not, the local-therapy group scored lower than the chemotherapy-exposed and non-cancer group on the RAVLT and BVRT.
Discussion
The aim of this study was to evaluate the effects of chemotherapy on cognition in long-term survivors of breast cancer. We further assessed for differential effects among various treatment modalities by comparing chemotherapy-exposed to non-chemotherapy-exposed survivors (i.e., local-therapy). We hypothesized that a history of cancer would be associated with greater cognitive deficits when compared to a matched sample of healthy, community-dwelling older adults, and that chemotherapy survivors would endorse greater cognitive deficits when compared to local therapy survivors.
Our findings confirm those of previous studies examining the effects of cancer on cognitive outcomes. Specifically, we observed evidence of lower general mental status (MMSE), reduced performance in working memory function (Letter Number Sequencing), and weaker executive functioning (Wisconsin Card Sorting Task). The NC group outperformed both cancer treatment groups in the aforementioned measures. These findings are consistent with past studies, suggesting that patients exposed to chemotherapy showed a decline in cognitive performance compared with healthy comparison subjects (e.g., [1, 7, 11, 12]).
Interestingly, cancer survivors who had not been exposed to chemotherapy scored lower than the other survivors and NCs on measures of verbal learning (RAVLT), visual perception (Rey figure), as well as visual attention and short-term retention (BVRT). Participants from the local-therapy group were significantly older than both the chemotherapy and non-cancer group, yet these difference persisted after controlling for age differences. Given that the tests involved included verbal learning and short-term retention, one might surmise that these individuals displayed cognitive changes in a pattern that is consistent with age-related cognitive changes, but perhaps at a slightly more accelerated pace due to the effects of surviving the cancer and local-therapy. That is, an accelerated normal aging process secondary to a vulnerable brain given a history of cancer and therapy is plausible.
It is not clear why the chemotherapy group did not show the verbal learning changes that were evident in the local-therapy cancer group. This was inconsistent with our expectation that chemotherapy would incur an additional vulnerability to the other deleterious effects of experiencing a cancer diagnosis and treatment. Unfortunately, the survivorship literature about the persistent effects of chemotherapy has been variable and, for example, the long-term effects of chemotherapy on cognition with survivors who received high-dose treatment, standard treatment, and no chemotherapy treatment (i.e., surgery and radiation therapy only) approximately five years post-treatment revealed no group differences [34]. In contrast, Ahles et al. [1] found that survivors treated with systemic chemotherapy scored significantly lower on tests of verbal memory and psychomotor functioning compared with those treated with local therapy only more than five years post-diagnosis.
For our present findings, subtle differences in general health, disease severity, or selection factors that were not discernable by our selection procedures (e.g., differences in the type of cancer treatment selection despite similar cancer staging), are likely factors that may play a role in survivorship differences that are undetectable. Additionally, the nature of combination chemotherapy treatment does not allow us to identify the individual effects of each specific chemotherapy regimens (i.e., cyclophosphamide versus anthracycline). However, variations in chemotherapy treatment have not been implicated to display differences in cognitive effects. In a study examining the long-term cognitive effects of adjuvant chemotherapy in older women diagnosed with breast cancer (n = 6,932), Raji et al. [35] found no significant association between types of chemotherapy agents (e.g., Anthracycline, CMF, Taxane, and others) and risk of dementia diagnoses.
There are some limitations to this study. A larger sample may have helped us better distinguish the neuropsychological patterns between subjects exposed to surgical treatment compared to chemotherapy treatment. Furthermore, group differences were not observed for mood in our sample but further exploration of other factors such as anxiety may have also helped distinguish the groups, although it is important to note that being ten years since diagnosis without recurrence, our participants were past the typical phase of cancer-related stress that is observed at the time of acute diagnosis and initial treatment. Despite being past the initial phase of treatment-related stress, it is possible that other psychosocial stressors may have been playing a role in the cognitive outcomes of this sample that we failed to detect in this sample. It is also possible that endocrine therapy and early menopause has the potential to affect the variance in cognition particularly in the chemotherapy-exposed group. However, in this group the mean duration since the initial diagnosis of cancer was 16.8 years (SD = 2.8; range 13.8–22.5 years). Consequently time elapsed between menopause and/or endocrine therapy (e.g., tamoxifen) and our assessment would have been for a substantial duration, as tamoxifen is utilized only for the first five years after cancer diagnosis. Approximately half our sample received tamoxifen and half did not and we did not find that its presence affected the neuropsychological measures in our study. Finally, limitations of cross-sectional study design have been discussed by the International Cognition and Cancer Task Force [36]. Specifically, interpretations of results may be limited due to group differences among comparison groups (e.g., patients exposed to chemotherapy to those exposed to surgical removal and local radiation). Therefore, differences in neuropsychological outcomes may not necessarily reflect changes caused by chemotherapy.
These preliminary analyses of the effects of chemotherapy on long-term survivorship in breast cancer can provide a foundation for future studies. Specifically, these data may serve as a baseline as our study progresses to include longitudinal neuropsychological evaluations. As the number of long-term survivors continue to increase, efforts to better understand the implications of systemic interventions of cancer is necessary.
Acknowledgments
Preparation of this manuscript was supported by the National Institute of Health grant NCI R01CA122934; National Institute on Aging Career Development Award to Natalie L. Denburg (K01 AG022033); and by an Agency for Healthcare Research and Quality (AHRQ) Centers for Education and Research on Therapeutics cooperative agreement #5 U18HSO16094.
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