with confirmatory visual inspection of the waveforms was used for this proce- dure. Statistical analysis. The Statistica
Breast Cancer Research and Treatment (2005) 94: 53–61 DOI 10.1007/s10549-005-7093-3
Springer 2005
Report
Electrophysiological correlates of information processing in breast-cancer patients treated with adjuvant chemotherapy Baudewijntje P.C. Kreukels1, Sanne B. Schagen1, K. Richard Ridderinkhof3,6, Willem Boogerd2,4, Hans L. Hamburger4,5, and Frits S.A.M. van Dam1,3 1
Department of Psychosocial Research and Epidemiology; 2Department of Medical Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; 3Department of Psychology, University of Amsterdam, The Netherlands; 4Department of Neurology; 5Department of Clinical Neurophysiology, Slotervaart Hospital, Amsterdam, The Netherlands; 6Department of Psychology, Leiden University, The Netherlands
Key words: adjuvant chemotherapy, breast carcinoma, cognitive deficits, cyclophosphamide methotrexate and 5-fluorouracil (CMF), information processing, neurophysiology, neurotoxicity, P3
Summary Cognitive deficits are found in a number of breast-cancer patients who have undergone adjuvant (Cyclophosphamide, Methotrexate, and 5-Fluorouracil (CMF)) chemotherapy, but the underlying mechanisms are still unclear. The objective of this study is to investigate information processing in these patients with concurrent registration of brain activity. Twenty-six breast-cancer patients treated with adjuvant CMF chemotherapy and a control group of 23 stage I breast-cancer patients not treated with chemotherapy were examined. Mean time since treatment for the CMF patients was 5.1 years after the last CMF course, and for the control patients 3.6 years after termination of radiotherapy. An information processing task was administered with concurrent EEG registration. Reaction times and the amplitudes and latencies of an Event Related Potential component (P3) in different task conditions related to input, central, and output processing of information were studied. Significant differences in latency and amplitude of the P3 component were found between the treatment groups with an earlier and reduced P3 in the chemotherapy group. Patients treated with chemotherapy had longer reaction times (although not significantly different) than the control group on all task conditions. Our data provide further evidence for long-term neurocognitive problems in breast-cancer patients treated with adjuvant (CMF) chemotherapy and offer new information regarding abnormalities in brain functioning in these patients.
Introduction Progress in cancer treatment results in prolonged disease-free periods, but may also lead to side effects like long term cognitive problems directly or indirectly linked to the received treatment. In recent years several studies have investigated the effects of chemotherapy on cognitive functioning [1–6]. Neuropsychological studies revealed cognitive deficits in a number of cancer patients treated with systemic chemotherapy in a wide range of functioning including speed of information processing, memory, and attention. In a previous study we found that 28% of the breast-cancer patients treated with Cyclophosphamide, Methotrexate, and 5-Fluorouracil (CMF) chemotherapy showed cognitive deficits as measured approximately 2 years post-treatment in comparison to 12% of the breast-cancer patients not treated with chemotherapy (odds ratio 6.4 [95% confidence interval 1.5–
27.6] p = 0.013) [4]. In addition the patients treated with CMF chemotherapy reported more cognitive problems in daily life, but these complaints were not related to the cognitive deficits found. Methotrexate (MTX), one of the components of the CMF chemotherapy regimen, is known for its neurotoxic effects, however only after high-dose intravenous administration [7,8]. 5-Fluorouracil (5-FU) and Cyclophosphamide are less known for their neurotoxic effects, though 5-FU readily enters the brain [9], and may cause an acute cerebellar syndrome after high-dose administration [8]. The mechanisms underlying the deficits found on neuropsychological tests in those patients treated with chemotherapy are still unclear. Electroencephalography (EEG) and Event Related Potentials (ERPs) by means of monitoring of brain activity during different functional processes might be useful techniques for further investigation.
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In a previous study we examined long-term cognitive deficits in breast-cancer patients following adjuvant chemotherapy using electrophysiological data [10]. Asymmetry of the alpha rhythm of 0.5 Hz or more, which is considered indicative of pathology [11], was found in 41% of the breast-cancer patients treated with high-dose CTC-chemotherapy1, compared to 13% of the breast-cancer patients treated with standard-dose FECchemotherapy2 and none of the breast-cancer patients not treated with chemotherapy. No differences with respect to latencies of the event related potential P3 were detected among those groups. However, a significant relation was found between the latency of P3 and the total number of deviant test scores per patient, with longer P3 latencies corresponding to more deviant test results. In order to study the effects of chemotherapy on information processing in more detail we decided to record EEG during performance of a reaction-time task. Whereas overt reaction time (RT) reflects the overall sum of the durations of multiple cognitive processes, eventrelated brain potentials (ERPs), derived from the EEG, give us an indication of the intensity and duration of separate processes. ERPs have been used widely to investigate both individual differences in and pharmacological effects on various cognitive processes (e.g., to study the effects of caffeine, amphetamines, or ageing on information processing [12–14]). Amplitudes of ERP components are related to intensity of activation of neural structures, whereas latencies are related to the timing and duration of the underlying processes [15]. In this paper we will focus on the P3 component, a well studied component of the ERP that is related to high-level attention-dependent cognitive processing [16–18]. Reductions of the P3 component are not uncommon in psychiatric and neurological disorders with cognitive dysfunction like ADHD [19], schizophrenia [20] and dementia [21]. The cognitive task that we administered in the present study was derived from the literature on the Additive Factors Method (AFM), which concerns stages of information processing and the relations among them [22]. The AFM rests on the assumption that information processing proceeds though a series of discrete and serially organized subprocesses or stages. The duration of processing in each stage can be influenced separately by experimental manipulations that target these stages. The efficiency of processing within these stages can be measured in terms of reaction time. The extensive literature of reaction time studies (reviewed by Sanders 1 Four courses of FEC chemotherapy (fluorouracil 500 mg m2 intravenously, epidoxorubicin 120 mg m2 intravenously and cyclophosphamide 500 mg m2 intravenously) and one course of the highdose CTC regimen (cyclophosphamide 6 g m2 intravenously, thiotepa 480 mg m2 intravenously and carboplatin 1.6 g m2 intravenously) with peripheral blood progenitor cell transplantation. 2 Five courses of FEC chemotherapy (fluorouracil 500 mg/m2 intravenously, epidoxorubicin 120 mg/ m2 intravenously and cyclophosphamide 500 mg/m2 intravenously). Patients were randomly assigned to either high-dose treatment (with a fifth course of CTC) or standard-dose treatment (FEC only).
[23,24]) documents that manipulations of stimulus discriminability (SD), stimulus-response compatibility (SRC), and response complexity (RC) selectively influence the duration of stimulus identification (input processing), response selection (central processing), and response preparation processes (output processing), respectively. If our chemotherapy regimen was to affect, for instance, the efficiency of response preparation processes, then the increase in processing time associated with increase in RC should be more pronounced for chemotherapy patients than for controls. Consistent with previous evidence [4], we expect to find a slowing of information processing in the patients treated with CMF chemotherapy as reflected in longer reaction times. If the chemotherapy regimen affects particular stages of information processing, then interaction effects will be observed between treatment group and the experimental manipulations associated with these processing stages. Such interaction effects will reflect a larger increase in reaction time in the difficult compared to easy conditions in the group treated with chemotherapy compared to the control group. Furthermore, because P3 latency appears to be proportional to the duration of stimulus evaluation processes, and is relatively independent of the time required for response selection and execution it may help to locate effects of treatment in either stimulus evaluation or response related processes. Because P3 amplitude is found to be reduced in more difficult tasks [25], we expect to find smaller P3s in difficult compared to easy conditions. Differences between the treatment groups in P3 amplitude might indicate differences in the intensity of activation of neural structures during information processing.
Materials and methods Two groups of breast-cancer patients were included in the current study. The first group with lymph-node positive breast cancer underwent surgery, received locoregional radiotherapy, and six cycles of conventional CMF chemotherapy (cyclophosphamide 100 mg m2 orally on Days 1–14, MTX 40 mg m2 intravenously on Days 1 and 8, and 5-FU 600 mg m2 intravenously on Days 1 and 8). The second group with stage I breast cancer underwent surgery and locoregional radiotherapy only. The patients were recruited from a database of a neuropsychological study performed in the Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute (Amsterdam, the Netherlands). The study was approved by the institutional review board. Medical charts of these patients were examined. Eighty-five patients (46 CMF patients and 39 control patients) fulfilled the following inclusion criteria: (1) no presence of metastatic disease or relapse; (2) no history of neurological or psychiatric signs that might lead to deviant test results; (3) no use of medication that might lead to deviant test
Neurophysiological evaluation of chemotherapy results; (4) no alcohol or drug abuse; (5) sufficient command of the Dutch language. Patients were interviewed by phone regarding cognitive problems experienced in daily life. This semi-structured interview about problems in memory, concentration, thinking, and language [4,5] was administered in 75 of the 85 patients. Thirty patients (35.3%: 17 patients treated with CMF and 13 control patients) declined from participating in the neurophysiological study. Reasons for withholding participation were: too busy, lack of interest, participation in other studies, and uncomfortable with EEG examination. Additionally two patients could not be traced and four patients cancelled their appointment. Non-participants did not differ from participants in age and education. Non-participants that answered the cognitive complaints interview did not differ from participants in self-reported cognitive problems. The final study population consisted of 26 patients treated with CMF chemotherapy and 23 patients not treated with chemotherapy with a mean time since treatment of 4.4 years. Written informed consent was obtained from all participants according to institutional guidelines. Demographic and clinical characteristics of these patients are presented in Table 1. There were no statistically significant differences between these two groups with regard to age and eduTable 1. Patient demographic and clinical characteristics Characteristic
Chemotherapy-group (n = 26)a
Control-group (n = 23)b
Age (years) c
Mean (SD)
51.5 (5.6)
53.2 (8.5)
Range
35–61
28–66
Time since treatment (years) Mean (SD)
5.1 (0.6)
3.6 (0.7)
Range
4.16–6.21
2.57–5.10
Educationd Low
4 (15.4%)
6 (26.1%)
Middle
11 (42.3%)
9 (39.1%)
High
11 (42.3%)
8 (34.8%)
Menopausal statuse
a
Pre-menopausal
1 (3.8%)
4 (17.4%)
Peri-menopausal
1 (3.8%)
2 (8.7%)
Post-menopausal
24 (92.3%)
17 (73.9%)
Tamoxifen Current user
6 (23.1%)
2 (8.7%)
Past user
7 (26.9%)
0 (0%)
Never user
13 (50%)
21 (91.3%)
Chemotherapy group: breast-cancer patients treated with CMFchemotherapy, see text for description of CMF chemotherapy regimen. b Control group: stage I breast-cancer patients not treated with chemotherapy. c SD = standard deviation. d Low = primary school; middle = secondary school; and high = university and graduate school. e Pre-menopausal = menstruating regularly during past 12 months; perimenopausal = menstruated during the past 12 months, but experiencing changes in the menstrual cycle length and menstrual irregularity; post-menopausal = amenorrhea for at least 12 months.
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cation level. Patients in the chemotherapy group were off treatment approximately 2 years longer than patients not treated with chemotherapy. Fifty percent of the patients in the chemotherapy group were current or past users of tamoxifen, compared to 8.7% of the patients in the control group. Electrophysiological recording Patients were examined at the Department of Clinical Neurophysiology of the Slotervaart Hospital (Amsterdam, the Netherlands). The electroencephalogram (EEG) was recorded with a 32-channel tin-electrodes Quickcap (Neuroscan) referenced to the left mastoid. For this study we used only Pz to mastoid for further calculations. Eye movements were recorded from bipolar tin electrode pairs placed above and below the left eye, and left and right of the outer canthi of both eyes. AFz served as a ground electrode. Impedances were kept below 5 kW. Subjects were seated in a semi-dark sound-proof room in a comfortable chair with response boxes attached to the armrests on both sides and in front of a 17 inch monitor located 80 cm from the subject. The EEG signals were amplified by a SynAmps amplifier (Neuroscan). Signals were recorded for a 2048 ms period starting 200 ms before stimulus presentation, digitized at 250 Hz, and bandpass filtered between 0.15 and 40 Hz. Information processing task (AFM task) The subject’s task is to determine the direction of a double arrowhead and to select and execute the designated response. Stimulus Discriminability was manipulated by presenting the arrowheads either in a clearly discernable shape, or in a shape that requires more thorough perceptual processing to identify its direction. Stimulus-Response Compatibility was manipulated by requiring subjects to issue either spatially compatible or incompatible reactions (in different trial blocks), with the hand at the same side or opposite to the direction indicated by the arrowheads, respectively. Response Complexity was manipulated by requiring subjects to respond with either the index finger alone (simple response) or a sequence of the index, ring, and middle finger (complex response). Patients had to respond as quick and accurate as possible with left or right hand responses to the double arrowheads presented on the monitor. In each condition a similar number of trials was presented. Stimuli were delivered by Experimental Response Time System (ERTS) in four different task blocks. The stimuli were presented within a framework of 2.8 cm (width) by 2.1 cm (height) in the center of the screen. This framework served as an on-screen fixation area. The target stimulus consisting of the two arrowheads was presented for 1000 ms. The inter-stimulus interval (ISI) was varied between 2718 and 3219 ms. Reaction time was measured from the onset of the stimulus to the onset of the button press of the index
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finger. Responses were scored as correct when all required button presses were executed in the correct order within 1500 ms. First, subjects received on-screen instructions and practiced each block (32 trials). Prior to each block subjects were informed on-screen whether they had to respond in a compatible or incompatible way and with a simple or complex response. Experimental blocks consisted of 200 trials each with a short break after every 25 trials. Block order was varied across subjects. The task took approximately 50 minutes to complete. Psychological distress Hopkins Symptom Checklist-25 was used to determine the rate of depression and anxiety [26–28]. Patients had to indicate on a four-point Likert scale from 1 (not at all) to 4 (very much) how much they were troubled by a problem in the past week. The Profile of Mood States (POMS) is a questionnaire for the measurement of moods [29]. The shortened version consists of 32 items measuring 5 dimensions (depression, anger, fatigue, vigor and tension). The POMS is frequently used in physiological studies and pharmacological studies to study and control for changes in mood during the experimentation session and is also used in neurocognitive outcome studies in cancer patients [2,30]. The POMS was administered at the beginning and at the end of the experimentation session. Fatigue Fatigue was assessed with the Multidimensional Fatigue Inventory (MFI-20) [31,32]. The MFI-20 consists of 20 items on 5 subscales (general fatigue, physical fatigue, mental fatigue, reduction in activity and reduction in motivation). General procedure First all questionnaires were completed and then electrodes were applied. Subsequently an auditory discrimination task with concurrent EEG registration was administered and standard EEG in eyes open and eyes closed conditions was registered. These data will be reported separately. Thereafter the AFM task was administered. Each patient went through this order of data collection. The experimentation session lasted 2½ h including electrode positioning and removal. Off-line electrophysiological data processing and analysis EEG data were low-pass filtered at 16 Hz with 96 dB/ oct (zero phase shift). Three minutes of EEG and EOG was recorded while patients fixated on a cross in the center of the screen to detect spontaneous eye blinks. This file was used to compute an average blink for each
patient individually. The resulting file was used in the linear derivation procedure in Neuroscan to correct for blinks. EEG epochs that contained extensive horizontal eye movements or contained voltages in excess of plus or minus 100 lV and epochs that coincided with incorrect behavioral responses, were excluded. EEG epochs for each condition and each participant were then averaged and aligned to a baseline (i.e., the average amplitude during the 200 ms preceding stimulus presentation was subtracted from each signal). To assure reliable ERP-analysis, average waveforms consisting of less than 20 epochs that could be evaluated (due to prior exclusion) were excluded from subsequent analysis. Averaged waveforms were subsequently smoothed with an unweighted moving average of 84 ms. The P3 component peak latencies were quantified by scanning for the most positive peak within a specified time window (280–600 ms) at the Pz channel. An automatic peak-picking program with confirmatory visual inspection of the waveforms was used for this procedure.
Statistical analysis The Statistical Package for Social Sciences (SPSS) 11.0 software was used for all statistical analyses. To ensure that the behavioral data, self-reported complaints, and questionnaire data are comparable to the electrophysiological data, patients that had less than 20 EEG epochs per condition that could be evaluated (due to false responses or artifacts) were also excluded from all other analyses. Differences in patient and clinical characteristics between groups were analyzed by chi-square tests and univariate analysis of variance (ANOVA). Questionnaire scores were recoded using standard scoring rules. Differences in questionnaire scores between groups were analyzed by means of independentsamples t-tests. Scores on the five subscales of the POMS before and after the examination were entered in an ANOVA for repeated measures. Group differences in reported cognitive complaints from the semi-structured interview were analyzed by chi square tests. Mean reaction times, performance accuracy, P3 amplitudes and latencies for the within-subject factors SD, SRC and RC, and the between-subject factor Treatment were entered in an ANOVA for repeated measurements. The correlations between performance and ERP measures, socio-demographic variables, anxiety/depression, and subjective measures of cognitive functioning were examined using Spearman rank order correlations. For all analyses (2-sided), a p-value less than 0.05 was required for significance.
Neurophysiological evaluation of chemotherapy
57
Table 2. Mean reaction times (in ms), P3 latencies (in ms) and P3 amplitudes (in lV) (standard deviations) for correct responses on all trials as a function of Stimulus Discriminability (SD) and Stimulus Response Compatibility (SRC) by treatment group Reaction times in ms
P3 latencies in ms
P3 amplitudes in lV
Chemotherapy
Controls
Chemotherapy
Controls
Chemotherapy
Controls
(n = 25)
(n = 23)
(n = 25)
(n = 23)
(n = 25)
(n = 23)
SRC easy
SD easy
480 (75)
458 (44)
396 (45)
453 (45)
10.8 (3.1)
13.3 (3.5)
SRC hard
SD hard SD easy
528 (78) 536 (107)
503 (53) 499 (55)
409 (45) 409 (61)
470 (53) 477 (73)
9.0 (2.6) 8.8 (2.7)
11.8 (3.2) 11.6 (4.2)
SD hard
585 (113)
541 (67)
424 (56)
479 (64)
8.4 (2.8)
10.4 (4.1)
ms = milliseconds; lV = microvolts; SD easy = strong arrows, SD hard = weak arrows; SRC easy = compatible responses, SRC hard = incompatible responses.
Results
Event Related Potentials
Behavioral data
Figures 1 and 2 depict the ERPs on the Pz channel in each of the experimental conditions and for both patient groups. It can be seen that the ERPs are dominated by a prominent positive (downward) deflection that peaks
The mean percentage of errors in the complex response condition was 22.6% compared to 3.6% in the simple response condition. Performance accuracy did not differ significantly between the two treatment groups. Mean percentage of errors over all trials was 14.3% for the chemotherapy group and 11.9% for the control group (F(1,47)=0.401; p = 0.530). Poor performance in complex response trials resulted in the exclusion of six patients of the chemotherapy group and five patients of the surgery group. To examine the effects in the complete sample, it was therefore decided to execute the analyses on simple response trials alone (with the factor RC excluded). One CMF patient was excluded from analyses due to a large number of errors in simple trials as well. The results of these analyses are reported in Tables 2 and 3. In all conditions patients treated with chemotherapy responded slower than patients not treated with chemotherapy (see Table 2). However, the difference in reaction time between treatment groups did not reach statistical significance (see Table 3). ANOVA on reaction time further revealed the expected main effects for the two experimental factors SD and SRC, but no interaction effects (see Table 3).
Figure 1. Stimulus Discriminability (SD). Stimulus locked grand averages recorded from Pz during correct responses. Patients treated with CMF-chemotherapy (n = 25; solid lines) and patients not treated with chemotherapy (n = 23; dashed lines). SD easy: thick lines; SD hard: thin lines.
Table 3. Main effects and interaction effects SD, SRC and treatment on reaction times, P3 latencies and P3 amplitudes (n = 48) Reaction
P3 latencies
times F(1,46) p SD SRC
P3 amplitudes
F(1,46) p
F(1,46) p
193.439 0.000 16.046 0.000 39.613 0.000 32.839 0.000 12.055 0.001 17.044 0.000
Treatment
2.345 0.133 16.229 0.000
SD*SRC
0.001 0.976
1.166 0.286
9.039 0.004 5.181 0.028
SD*treatment SRC*treatment
0.582 0.449 1.133 0.293
0.602 0.442 0.069 0.793
0.405 0.528 0.193 0.663
SD*SRC*treatment
0.517 0.476
1.876 0.177
2.947 0.093
SD: Stimulus Discriminability; SRC: Stimulus Response Compatibility.
Figure 2. Stimulus Response Compatibility (SRC). Stimulus locked grand averages recorded from Pz during correct responses. Patients treated with CMF-chemotherapy (n = 25; solid lines) and patients not treated with chemotherapy (n = 23; dashed lines). SRC easy: thick lines; SRC hard: thin lines.
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Table 4. Reported cognitive problems in daily life Chemotherapy
Controls
(n = 25)
(n = 23)
Memory
60.0%
43.5%
0.252
Concentration
52.0%
34.8%
0.230
Thinking
16.0%
13.0%
0.772
Language
28.0%
21.7%
0.617
p-value*
* Pearson Chi-Square
around 400–450 ms post-stimulus. Consistent with the literature, this component is identified as the P3. The graphs show that the P3 peaks somewhat later and with smaller amplitude for difficult compared to easy task conditions. For patients treated with chemotherapy, the P3 appears to have earlier and smaller peaks than for control patients. P3 peak latency ANOVA confirmed that P3 latencies (presented in Table 2) were significantly shorter for chemotherapy patients than for surgery patients (see Table 3). Main effects were found also for the experimental factors SD and SRC, with more difficult conditions associated with later peak latencies. No interaction effects were observed. P3 peak amplitude P3 amplitudes (presented in Table 2) were significantly lower for chemotherapy patients than for surgery patients (see Table 3). The experimental factors SD and SRC each produced main effects, with more difficult conditions associated with smaller peaks. A two-way interaction was observed for SD*SRC. The difficult SD condition generated a smaller decrease of the P3 amplitude in incompatible trials compared to compatible trails than the easy SD condition. Subjective data Table 4 shows the percentage of patients who reported having cognitive problems in one of the four domains (memory, concentration, thinking, and language). There were no statistically significant differences between the two treatment groups in reported cognitive complaints. However, on all domains patients treated with CMF chemotherapy reported more cognitive problems experienced in daily life than patients not treated with chemotherapy. No differences between the chemotherapy and surgery group were found in reported psychological distress. Patients were comparable with regard to their scores on the depression and anxiety subscales of the Hopkins Symptom Checklist (Mean HSCL25-total for patients treated with chemotherapy: 11.9 and for patients not treated with chemotherapy: 14.1). Mood as reflected on the subscales of the POMS did not differ between the treatment groups before and after the
experimentation session. The subscales and total score of the Multidimensional Fatigue Inventory did not indicate significant differences between the treatment groups (Mean MFI total for patients treated with chemotherapy (n = 25): 45.1 and for patients not treated with chemotherapy (n = 23): 44.3). All scores (HSCL, POMS and MFI) were within the normal range as compared to age-related healthy norm groups. Relations between behavioral, neurophysiological, and self-reported measures There was a significant relationship between P3 latency and reaction time in the control patients (Spearman’s q = 0.557; p = 0.006). However, the correlation between these two variables was not significant in the CMF group (Spearman’s q =0.274; p = 0.184). In all patients reaction times correlated negatively with mean P3 amplitude over simple trials (Spearman’s q = )0.396; p = 0.005). Self-reported cognitive complaints did not correlate with any of the behavioral or neurophysiological measures, but did correlate with fatigue, depression, and anxiety.
Discussion In this study we examined the effects of CMF chemotherapy on information processing with the use of both behavioral and neurophysiological measures. Reaction time data of the information processing task revealed main effects of the task factors SD and SRC; more difficult conditions generated longer reaction times than easy conditions. This indicates that the experimental manipulations succeeded, thereby supporting internal validity of the task based on the AFM. A general slowing tendency (of 32 ms on average) appeared to be present in patients treated with chemotherapy reflected by longer reaction times on all task conditions in these patients compared to controls, although this tendency was not statistically significant. We found that the P3 component of the ERP peaked significantly earlier (by some 60 ms) for chemotherapy patients than for control patients, suggesting that the duration of stimulus evaluation processes is shorter in the chemotherapy group than in the control group. A decrease in P3 latency, in the face of unaltered reaction time or even slowing of reaction time is not reported often in the literature. One possible explanation is in terms of rushed stimulus evaluation and subsequent compensation. Stimulus evaluation processes may be completed at insufficient depth, requiring more deliberate response-related processes (reminiscent of doublechecking) to compensate for the superficial levels of stimulus evaluation. Halliday et al. [12] reported similar findings and proposed a similar explanation for the effects of yohimbine, a noradrenergic drug. Yohimbine administration resulted in decreased P3 latencies without affecting reaction time.
Neurophysiological evaluation of chemotherapy P3 amplitude was affected by each of the experimental factors, with smaller P3s for difficult compared to easy conditions. This is in agreement with the finding that the amplitude of the P3 is reduced in more difficult conditions [25]. Furthermore we observed an overall significant reduction in amplitude of the P3 component in the chemotherapy group compared to the control group. Several theories have been proposed regarding the functional significance of the P3 component. A wellknown theory is the context-updating hypothesis [16,33]. According to this hypothesis, the P3 can be seen as a manifestation of activity occurring whenever one’s model of the environment is revised. The amplitude of the P3 is proportional to the change in the model and to the extent that the stimuli provide the subject with information that can help in optimizing task performance [16,17]. The P3 amplitude reduction in the chemotherapy group might indicate a loss in available information needed for optimizing task performance in this group. In contrast with P3 latency, which reflects timing of mental processes, P3 amplitude has been considered to be more closely related to the intensity of processing [18]. The resource-allocation theory hypothesizes that the amplitude of the P3 is related to the allocation of processing resources [25]. A reduction in P3 amplitude as was observed in our CMF group might thus indicate that these patients have more problems with energetic aspects of information processing. The LC-P3 hypothesis states that phasic activity of the Locus Coeruleus and the norepinephrine system is critical in generating the P3 [34,35]. The decrease in P3 amplitude in the chemotherapy group possibly might reflect changes in these systems. Potential physiological bases for P3 amplitude reduction are less tissue in or near the hippocampus or the left temporal lobe, different orientation of the neurons that generate the P3, fewer neurons firing, or fewer neurons firing synchronously [36]. The complex response condition of the AFM task proved to be too difficult for some patients independent of treatment. Even after extensive practice a considerable number of patients (CMF patients and controls) did not succeed to apply the complex response pattern. Furthermore, a response was scored as correct only when the complete pattern was executed within 1500 ms. Some patients did succeed in applying the response pattern, but were simply too slow. In future experiments attention has to be directed to this complex response and a condition ought to be developed that is challenging, but performable. For exploratory purposes we also performed analyses (not reported in the results section) in which only the patients that were able to apply the complex response pattern were included. In this limited sample we observed a more pronounced increase in reaction time in the incompatible condition compared to the compatible condition in the chemotherapy group in contrast to the control group. As SRC is associated with response selection [23,24], this suggests that central processes might be affected by CMF chemotherapy. However, this
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analysis revealed interaction effects between the task factors. These interaction effects complicate inferences based on the Additive Factor Method. Nevertheless, the possible effect of the CMF regimen on central information processing provides an interesting hypothesis for future research. Moreover, even in this limited sample a significantly earlier and reduced P3 was found in the CMF patients. We think that of the components of the CMF-regimen, MTX is the most likely candidate for involvement in longterm cognitive deficits. In an earlier study we found that in contrast to patients treated with CMF chemotherapy, patients treated with FEC chemotherapy did not show a significantly elevated risk when compared with breastcancer patients not treated with chemotherapy (OR = 2.4; 95% CI, 0.5–11.5; p = 0.287)[5]. The difference in cognitive functioning between CMF and FEC patients might suggest that MTX plays a significant role in the occurrence of cognitive problems [37]. Neurotoxicity is reported as a complication of intrathecal MTX administration either alone or in combination with cranial irradiation and of high-dose intravenous MTX given as single treatment [38]. Dosages of MTX in the CMF regimen are however much lower and not known to penetrate the Blood Brain Barrier [39]. A subgroup of the patients treated with chemotherapy also received tamoxifen. Vasomotor symptoms, like hot flashes, are commonly observed in women treated with tamoxifen and are thought to represent the anti-estrogen effect of this drug acting at the level of the hypothalamus [40]. So tamoxifen probably crosses the Blood Brain Barrier. It is therefore possible that the observed differences might be due, in part, to tamoxifen. We performed a separate analysis in the CMF patients comparing the current, past and never users of tamoxifen and did not find any significant differences between these three groups. However, current tamoxifen users appeared to have a reduced P3 compared to the other two groups. As the sample sizes of these subgroups were very small, we have to be careful making assumptions with regard to the possible impact of tamoxifen on P3 amplitude. Previous studies with regard to cognitive functioning in breast-cancer patients treated with tamoxifen point to different directions. Some studies suggest a negative effect of tamoxifen on cognitive functioning [40–42], whereas others report no differences between patients treated with chemotherapy with or without tamoxifen [1,4], or even propose a neuroprotective or repair role for tamoxifen [43]. The influence of tamoxifen on the central nervous system and its effects on cognitive ability remain controversial and merit further study. It is widely accepted that Event Related Potentials result from intracortical currents induced by postsynaptic potentials, which are triggered by the release of neurotransmitters. It has been postulated that neurotoxicity of MTX, might arise from changes in the synthesis of neurotransmitters [38]. Methotrexate induces an inhibition of the enzyme dihydrofolate reductase. This enzyme is essential for the synthesis of
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purines and thymidylate, and plays a role in the synthesis of the neurotransmitters serotonin and dopamine [37]. In our CMF group, the P3, that is supposed to be linked to activity in the norepinephrine system, is decreased. Our results with regard to P3 latency correspond to a study examining the effects of yohimbine, a noradrenergic drug [12]. Further study into changes in neurotransmitter systems in patients treated with CMF chemotherapy is therefore recommended. A limitation of this study is its cross-sectional nature and its case-control design. A longitudinal design with pre- and post-treatment neurophysiological examination in the same subjects is recommended for future research. In the last decades many breast-cancer patients have been treated with CMF chemotherapy. Although nowadays CMF-chemotherapy is largely replaced by other chemotherapy regimens as standard-adjuvant treatment in breast-cancer patients, CMF is still administered, for example as primary chemotherapy [44]. Furthermore, the separate components of the regimen, i.e. cyclophosphamide, MTX, 5-FU, are administered in various combinations with other substances in cancer treatment. Therefore the possible neurotoxicity of one or more or the combination of these cytostatic drugs remains an important research topic. In addition, we like to emphasize that the mean time since treatment for the CMF patients was 5.1 years with a range of 4.2–6.2 years. Earlier studies suggested that cognitive deficits following chemotherapy might be transient [45], but our results do not support this and are more in line with a study that showed cognitive deficits in survivors, on average, approximately 10 years after chemotherapy [1]. The current study showed electrophysiological differences between breast-cancer patients treated with CMF chemotherapy and breast-cancer patients not treated with chemotherapy and provides us with further evidence for adverse changes in brain functioning after treatment with CMF chemotherapy.
Acknowledgements Supported by the Josephine Nefkens Fund and the University of Amsterdam. The authors gratefully acknowledge Dr E. Rutgers and Prof Dr S. Rodenhuis for their help recruiting patients, Mr M. Muller for his helpful comments, Mr M. Spaan and Mr B. Molenkamp for their technical support, and Dr F Smulders for the original version of the AFM task.
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[email protected] 