The current study was performed to determine whether neuropsychologic functioning differs in breast cancer survivors 6 months after the completion of adjuvant treatment compared with women without cancer.
The current study was performed to determine whether neuropsychologic functioning differs in breast cancer survivors 6 months after the completion of adjuvant treatment compared with women without cancer.
Participants were 187 women who were diagnosed with ductal carcinoma in situ or stage I or stage II breast cancer and 187 age-matched and geographically matched women without cancer. Of the survivors, 97 had been treated after surgery with chemotherapy only or chemotherapy plus radiotherapy and 90 had been treated after surgery with radiotherapy only (grading determined according to the American Joint Committee on Cancer grading system).
Small but statistically significant differences in cognitive functioning and cognitive impairment were observed in those survivors who were treated with chemotherapy and their matched controls, as well as in survivors treated with radiotherapy only and their matched controls. No group differences were observed with regard to cognitive symptoms.
Data from the current study suggest that cognitive deficits are subtle and likely the result of the general effects of cancer diagnosis and treatment rather than systemic treatment. Cancer 2009. Published 2009 by the American Cancer Society.
Anecdotal reports of “chemo brain,” or a loss of mental acuity associated with chemotherapy, are well-publicized among breast cancer survivors1, 2 and are a source of significant concern.3 Although self-reported cognitive complaints are not highly correlated with objective neuropsychologic test results,4-6 research indicates that survivors' concerns are merited. Cognitive deficits appear to be pronounced during treatment. Cross-sectional data indicate rates of moderate or severe impairment ranging from 16% to 48% in patients during chemotherapy compared with 4% to 11% in healthy controls.7, 8 Moreover, longitudinal studies indicate that cognitive functioning tends to decline during treatment.6, 9
The extent to which cognitive deficits persist after treatment is less clear. Among breast cancer survivors 3 to 18 months after chemotherapy, Wieneke et al10 determined that 75% scored at least 2 standard deviations (SDs) below population norms on ≥1 tests. Using a longitudinal design, Fan et al11 assessed breast cancer survivors during chemotherapy, 1 year later, and 2 years later compared with noncancer controls. Significantly more survivors displayed moderate to severe cognitive impairment at both follow-up assessment points than controls. Silverman et al12 examined breast cancer survivors 5 to 10 years after treatment using positron emission tomography and found altered frontocortical activation in those who had been treated with chemotherapy compared with those not treated with chemotherapy.
In contrast, results from other studies suggest that the cognitive sequelae of chemotherapy may be transient. Schagen et al13 found that survivors' cognitive functioning improved from 2 years to 4 years after chemotherapy, with survivors performing similarly to controls at 4 years. Jenkins et al14 examined cognitive functioning in breast cancer patients receiving chemotherapy, patients receiving radiotherapy, and noncancer controls before treatment, 6 months after treatment, and 18 months after treatment. They found no differences between the groups over time. Finally, we previously reported no differences in cognitive functioning at 6 months after treatment between survivors treated with chemotherapy and radiotherapy compared with survivors treated with radiotherapy only.15
Building on our previous report,15 we now present comparisons between breast cancer survivors assessed 6 months after the completion of treatment and age-matched and geographically matched female noncancer controls. The current study included a larger set of patients than was included in our previous report and also included nonpatient comparison data that were not reported previously. We hypothesized that survivors treated with chemotherapy would demonstrate lower mean-level cognitive functioning, higher rates of cognitive impairment, and greater cognitive symptoms than their matched controls. To examine whether hypothesized differences were the result of systemic treatment versus the general effects of cancer, we also examined cognitive functioning, cognitive impairment, and cognitive symptoms in breast cancer survivors treated with radiotherapy only compared with their matched controls.
As part of a larger, institutional review board-approved study examining quality of life during and after breast cancer treatment, women diagnosed with ductal carcinoma in situ or stage I or stage II breast cancer were recruited at the H. Lee Moffitt Cancer Center (HLMCC) at the University of South Florida and the Markey Cancer Center (MCC) at the University of Kentucky (grading determined according to the American Joint Committee on Cancer grading system). Additional eligibility criteria were that participants: 1) be at least 18 years of age; 2) have no documented or observable psychiatric or neurologic disorders that would interfere with study participation (eg, dementia or psychosis); 3) be able to speak and read standard English; 4) have no history of cancer other than basal cell skin carcinoma; 6) have been treated surgically with lumpectomy or mastectomy; 7) be scheduled to receive a minimum of 4 cycles of chemotherapy followed by radiotherapy (chemotherapy + radiotherapy group), a minimum of 4 cycles of chemotherapy only (chemotherapy group), or radiotherapy only after surgery (radiotherapy group); 8) have no prior history of treatment with either chemotherapy or radiotherapy; 9) have no other chronic or life-threatening diseases in which fatigue is a prominent symptom (eg, multiple sclerosis); and 10) provide written informed consent.
Eligibility was determined by chart review and consultation with the attending physician. Eligible women were recruited and informed consent was obtained during an outpatient clinic visit before the initiation of chemotherapy (the chemotherapy + radiotherapy group and the chemotherapy group) or radiotherapy (radiotherapy group). Approximately 6 months after the completion of radiotherapy (chemotherapy + radiotherapy group and the radiotherapy group) or chemotherapy (chemotherapy group), survivors were scheduled for an outpatient appointment, at which time data relevant to the current report were collected.
Eligibility criteria for noncancer controls were that they must: 1) be women within 5 years of the age of the patient to whom they were being matched; 2) reside in the same ZIP code as the patient to whom they were being matched; 3) have no discernable psychiatric or neurologic disorders that would interfere with study participation; 4) be able to read and speak standard English; 5) report no history of cancer other than basal cell skin carcinoma; 6) report no chronic or life–threatening diseases in which fatigue is a prominent symptom; and 7) provide written informed consent.
Potential control participants were identified using a database maintained by Marketing Systems Group, Inc (Fort Washington, Pa) that draws from all listed telephone households in the US and is estimated to include demographic and contact information for approximately two-thirds of the US population. For each survivor, a list was generated of 25 randomly selected females who resided within the same ZIP code as the survivor and were within 5 years of the survivor's age. An individual was selected at random from each list and a letter of introduction was sent out describing the study. If this individual did not opt out by calling a toll-free telephone number (HLMCC) or did return a postcard expressing interest (MCC), telephone contact was initiated to further determine eligibility. If the individual met all eligibility criteria and agreed to participate, an appointment was set up to obtain written informed consent and conduct the assessment. If the first individual on the list could not be reached, was ineligible, declined, or did not keep the appointment, another individual on the list was randomly selected and approached. This process continued until a matched comparison subject was recruited and completed the assessment that is the focus of this report.
Demographic data were obtained from all participants via a self-report measure. Survivor disease and treatment information was collected via medical chart review.
Cognitive performance was assessed using a battery of neuropsychologic tests that were selected based on a review of published literature at the time of study design.5, 10, 16, 17 Preference was given to tests with demonstrated reliability, validity, and availability of published norms. The battery was designed to assess overall intellectual ability as well as 3 major domains of cognitive functioning: episodic memory, attention, and complex cognition.
The National Adult Reading Test (NART)18 was administered to estimate overall intellectual ability. NART scores were converted to estimated Weschler Adult Intelligence Scale (WAIS)-R full-scale intelligence quotient scores.18
Verbal (California Verbal Learning Test [CVLT])19 and nonverbal (Visual Reproduction subtest of the Weschler Memory Scales-III [WMS-III])20 measures of episodic memory were administered. Scores used in analyses were CVLT immediate recall, long delay free recall, and recognition and WMS-III Visual Reproduction immediate, delayed recall, and delayed recognition.
The Digit Span subtest of the WAIS-III,21 Spatial Span subtest of the WAIS-III,21 Trails A subtest of the Trail Making Test,22 and Ruff 2 & 7 Test23 were administered to assess attention. Scores used in analyses were the number of items completed correctly on Digit Span and Spatial Span, total time to completion on the Trails A subtest, and total speed and total accuracy on the Ruff 2 & 7 Test.
The Digit Symbol subtest of the WAIS-III,21 Trails B subtest of the Trail Making Test,22 and the Controlled Oral Word Association (COWA)24 were administered to assess complex cognition. Scores used in analyses were the number of items completed on the Digit Symbol subtest, total time to completion on the Trails B subtest, and total number of words generated on the COWA.
The Mental Abilities Questionnaire (MAQ)25 is a 48-item, self-report measure that assesses perceptions of cognitive functioning. Using a 5-point Likert scale (with 1 indicating almost never and 5 indicating almost always), respondents rate how often they are able to perform a variety of everyday cognitive tasks compared with other people their age. The MAQ yields a total score and subscale scores for attention, language, verbal memory, visual-spatial memory, and visual-spatial perception. The Cronbach α in the current sample was .93 for the total score and ranged from .72 to .79 for the subscales.
The Fatigue Symptom Inventory (FSI)26 is a 14-item measure that assesses the frequency and severity of fatigue and its perceived disruptiveness. Analyses were conducted using an average of ratings of the degree to which fatigue interfered (with 0 indicating no interference and 10 indicating extreme interference) with daily activities, relations with others, enjoyment of life, and mood. Previous research has demonstrated the reliability and validity of the FSI in women diagnosed with breast cancer.26, 27
The 20-item Center for Epidemiological Studies of Depression Scale (CES-D)28 identifies current symptoms of depression. It assess 6 components of depressed mood: guilt or worthlessness, feelings of helplessness and hopelessness, psychomotor retardation, loss of appetite, and sleep disturbance. Previous research has demonstrated the reliability and validity of the CESD in individuals with cancer.29, 30
Raw test scores on neuropsychologic tests were converted to standardized scores based on published normative data to facilitate comparisons between tests. CVLT, Trail Making Test, and Ruff 2 & 7 Test raw scores were converted to age-corrected and education-corrected z scores.19, 22 COWA raw scores were also converted to age-corrected and education-corrected z scores.24 WMS-III and WAIS-III subtest raw scores were converted to age-corrected z scores.20, 21
Because of the small number of survivors treated with chemotherapy only (n = 14), the chemotherapy only and chemotherapy + radiotherapy groups were combined in all analyses. Differences with regard to age, race, education, annual household income, and overall intellectual ability (ie, NART scores) were examined between survivors and matched controls using the dependent–sample Student t test and McNemar test. Variables that differed significantly between groups (P < .05) were entered as covariates in later analyses.
To examine mean-level differences in cognitive functioning and cognitive symptoms between survivors and controls, linear mixed models were used. To examine differences in rates of cognitive impairment, participants were categorized as impaired or unimpaired on individual tests and overall. In accordance with previous research,31 impairment on individual tests was defined as −1.5 SD below the normative mean; overall impairment was defined as ≥2 impaired tests. Generalized estimating equations were used to determine significant differences in rates of impairment between survivors and controls. The study was designed to yield a power of at least .80 to detect an effect size of .30 at an α of .05.
The clinical characteristics of the survivors are presented in Table 1 and sociodemographic comparisons between survivors and controls are presented in Table 2. Compared with controls, survivors treated with chemotherapy were significantly younger. Survivors treated with radiotherapy only were younger and more likely to have higher estimated overall intellectual ability. These 2 variables were included as covariates in all later analyses.
|Characteristic||No. of Patients|
|Chemotherapy plus radiotherapy||83|
|Doxorubicin and cyclophosphamide||52|
|Doxorubicin, cyclophosphamide, and docetaxel||13|
|Doxorubicin, cyclophosphamide, and paclitaxel||14|
|Cyclophosphamide, methotrexate, and 5-flourouracil||11|
|Doxorubicin and docetaxel||2|
|Cyclophosphamide, epirubicin, and 5-flourouracil||2|
|Cyclophosphamide, epirubicin, 5-flourouracil, and paclitaxel||2|
|No hormonal therapy||57|
|Tamoxifen and anastrozole||2|
|Tamoxifen and megestrol||1|
|Age, y: Mean (SD)||50 (9)||53 (8)||11.31*||58 (9)||59 (9)||4.78*|
|Race/ethnicity: White||84 (88%)||90 (93%)||1.47||86 (96%)||85 (94%)||.14|
|Annual household income: ≥$40k||68 (73%)||74 (78%)||.33||59 (73%)||65 (74%)||.15|
|Education: Some college or less||47 (48%)||44 (45%)||.18||54 (60%)||48 (53%)||.90|
|NART: Mean (SD)||112 (7)||110 (8)||1.27||112 (7)||109 (7)||2.13†|
As shown in Table 3, when compared with controls, survivors treated with chemotherapy performed significantly worse on tests assessing episodic memory (WMS-III Visual Reproduction delayed recall) and complex cognition (Digit Symbol subtest and COWA). Effect sizes (ds) were small (ds = .19-.24) by Cohen's criteria.32 Survivors treated with radiotherapy only performed significantly worse on tests measuring attention (Trails A) and complex cognition (Trails B). These effect sizes were also small (ds = .29-.31).32
|Patients||Controls||F(1, 188)||Patients||Controls||F(1, 174)|
|CVLT immediate recall||−.05 (.11)||.06 (.11)||.09||.02 (.10)||−.03 (.10)||.08|
|CVLT long delay free recall||−.31 (.15)||−.32 (.13)||.05||−.24 (.13)||−.38 (.13)||.12|
|CVLT recognition||−.26 (.14)||−.11 (.12)||.31||−.08 (.11)||−.17 (.11)||.05|
|WMS-III Visual Reproduction immediate recall||.15 (.11)||.01 (.09)||.30||−.11 (.11)||−.06 (.11)||1.98|
|WMS-III Visual Reproduction delayed recall||−.04 (.10)||.15 (.11)||3.85†||−.13 (.10)||.01 (.10)||2.46|
|WMS-III Visual Reproduction recognition||−.01 (.11)||.07 (.09)||.76||.09 (.11)||−.15 (.11)||.92|
|WAIS-III Digit Span||.01 (.10)||.02 (.10)||.40||.08 (.11)||−.11 (.11)||.25|
|WAIS-III Spatial Span||.07 (.09)||.04 (.10)||.01||−.00 (.11)||−.12 (.11)||.01|
|Trails A||.04 (.11)||.04 (.09)||.01||−.19 (.11)||.10 (.11)||4.51†|
|2 & 7 Test speed||.06 (.11)||.12 (.10)||.35||−.15 (.10)||−.04 (.10)||1.57|
|2 & 7 Test accuracy||−.02 (.10)||.15 (.10)||2.64||−.08 (.11)||−.06 (.11)||.62|
|WAIS-III Digit Symbol||−.08 (.10)||.16 (.10)||4.43†||−.11 (.11)||.03 (.11)||2.65|
|Trails B||−.05 (.11)||.09 (.10)||2.12||−.17 (.12)||.13 (.12)||6.78‡|
|COWA total||−.14 (.09)||.08 (.11)||3.98†||−.00 (.10)||.07 (.10)||1.23|
Post hoc analyses were conducted to explore potential contributing factors to cognitive differences between survivors and controls. Two additional sets of mixed model analyses were conducted as described earlier, but with the inclusion of depressive symptoms and fatigue as additional covariates. These analyses yielded the same pattern of statistically significant cognitive differences between survivors and controls as shown in Table 3. Regression analyses were then conducted to compare mean-level cognitive differences between: 1) survivors treated with chemotherapy and tamoxifen and survivors treated with chemotherapy but not tamoxifen and 2) survivors treated with radiotherapy and tamoxifen and survivors treated with radiotherapy but not tamoxifen. No significant differences were observed (P >.05).
Rates of impairment are shown in Table 4. Survivors treated with chemotherapy were more likely than controls to be categorized as impaired in episodic memory (CVLT recognition). Survivors treated with radiotherapy only were more likely than controls to be categorized as impaired in attention (Trails A).
|CVLT immediate recall||12 (12%)||7 (7%)||1.07||6 (7%)||5 (6%)||.19|
|CVLT long delay free recall||21 (22%)||15 (15%)||.65||16 (18%)||15 (17%)||.41|
|CVLT recognition||16 (16%)||5 (5%)||1.99*||10 (11%)||7 (8%)||.98|
|WMS-III Visual Reproduction immediate recall||8 (8%)||4 (4%)||1.36||10 (11%)||9 (10%)||.67|
|WMS-III Visual Reproduction delayed recall||8 (8%)||8 (8%)||.30||7 (8%)||7 (8%)||−.10|
|WMS-III Visual Reproduction recognition||10 (10%)||7 (7%)||.74||6 (7%)||6 (7%)||.44|
|WAIS-III Digit Span||5 (5%)||3 (3%)||.47||4 (4%)||4 (4%)||.65|
|WAIS-III Spatial Span||5 (5%)||7 (7%)||−.41||8 (9%)||9 (10%)||−.03|
|Trails A||8 (8%)||7 (7%)||.53||13 (14%)||4 (4%)||2.16*|
|2 & 7 Test speed||7 (7%)||6 (6%)||.13||5 (6%)||6 (7%)||−.32|
|2 & 7 Test accuracy||11 (11%)||8 (8%)||.79||10 (11%)||8 (9%)||.76|
|WAIS-III Digit Symbol||9 (9%)||4 (4%)||1.49||8 (9%)||5 (6%)||.81|
|Trails B||8 (8%)||7 (7%)||.38||11 (12%)||5 (6%)||1.95|
|COWA total||8 (8%)||3 (3%)||1.76||4 (4%)||1 (1%)||1.14|
|Overall impairment||33 (34%)||22 (23%)||1.71||27 (30%)||21 (23%)||1.67|
No significant differences were found between survivors and controls with regard to total cognitive symptoms or subscales of attention, language, verbal memory, visual-spatial memory, and visual-spatial perception (P ≥ .18).
The current study assessed reports of “chemo brain,” or loss of mental acuity after chemotherapy, in breast cancer survivors 6 months after the completion of adjuvant treatment. We hypothesized that survivors treated with chemotherapy would display worse cognitive functioning relative to age-matched and geographically matched women without cancer. Findings indicated that survivors treated with chemotherapy displayed poorer episodic memory and attention than controls, although effect sizes (ds) were small. Survivors treated with chemotherapy also displayed significantly greater impairment in the domain of episodic memory. To examine whether differences in cognitive functioning were due specifically to chemotherapy as opposed to the general effects of cancer, the current study also compared a group of survivors who were treated with radiotherapy only with age-matched and geographically matched controls. Survivors treated with radiotherapy only demonstrated poorer attention and complex cognition, although effect sizes were small. Survivors treated with radiotherapy only also demonstrated higher rates of impairment in the domain of attention. There were no differences noted between survivors and controls with regard to reports of cognitive symptoms.
Taken together, these findings suggest that the cognitive deficits noted in breast cancer survivors are relatively subtle and are the result of the general effects of cancer rather than systemic treatment per se. Follow-up analyses were conducted to examine whether fatigue or depressive symptoms accounted for observed cognitive differences between survivors and controls. The same pattern of cognitive differences emerged when fatigue and depressive symptoms were statistically controlled, suggesting that differences were not attributable to these factors. This finding is consistent with previous literature suggesting that neither fatigue nor depression are significantly associated with objective cognitive functioning.10, 11, 13, 16 Further research is needed to determine mechanisms that play a role in post-treatment cognitive functioning, such as cancer-related distress or worry about recurrence.
Post hoc analyses also were conducted to explore whether hormonal therapy contributed to cognitive differences between survivors and controls. Survivors treated with tamoxifen did not demonstrate significant differences in cognitive functioning compared with survivors treated without tamoxifen. Previous research is mixed regarding the effects of hormonal therapy on post-treatment cognitive functioning. Some studies have reported that hormonal therapy increases the risk of cognitive deficits,33, 34 whereas other studies have reported no effects of hormonal therapy.5, 11, 14 Nevertheless, the findings of the current study regarding tamoxifen should be interpreted with caution. Because of small numbers of survivors in some cells, the tamoxifen analyses were likely underpowered. In addition, survivors were not randomly assigned to treatment in the current study, and thus may be systematically different in ways that were not statistically controlled. Because hormonal treatment is typically initiated after the completion of adjuvant treatment, some survivors may not have been receiving hormonal treatment long enough for an effect to be observed. Future research should examine the role of hormonal therapy in the development of cognitive deficits after breast cancer treatment.
Several strengths characterize the current study. Women were recruited before the initiation of adjuvant treatment as part of a longitudinal study examining quality of life. This may have reduced the potential recruitment bias of studies designed specifically to assess post-treatment cognitive functioning.35 With 187 pairs of survivors and matched controls, the current report is to our knowledge 1 of the largest studies published to date examining cognitive functioning in cancer survivors. Noncancer controls were matched with survivors with regard to age and geographic residence and were recruited using a large database. This is a significant advantage over survivor-nominated controls, whose performance may be biased by their relationship to the survivor. Moreover, the inclusion of survivors treated with radiotherapy only and matched controls permits examination of the specific effects of chemotherapy compared with the general effects of cancer on cognitive functioning. However, the current study was not without limitations. Survivors were not evaluated before the initiation of adjuvant treatment, and therefore it is unclear whether the current findings reflect an improvement, deterioration, or no change from baseline. Well-powered longitudinal studies are needed to clarify cognitive changes over time in breast cancer survivors compared with women without cancer.
In summary, data from the current study suggest that, on average, women treated for breast cancer display subtle cognitive deficits when compared with women without cancer. Areas of specific deficits were noted regardless of treatment type, suggesting that mechanisms other than chemotherapy may affect cognitive functioning. Future research is needed to identify these mechanisms. In addition, rates of impairment in the current study indicate that there appear to be a subset of survivors for whom cognitive deficits are pronounced. Additional efforts to evaluate and remediate these deficits are needed.
We wish to thank the women who participated in this research.
Supported by a grant from the National Cancer Institute (R01 CA82822).