Regular Article

Psychother Psychosom 2007;76:376384 DOI: 10.1159/000107566

Chemotherapy-Induced Nausea, Vomiting, and Fatigue the Role of Individual Differences Related to Sensory Perception and Autonomic Reactivity
R. Zachariae a K. Paulsen a M. Mehlsen a A.B. Jensen b A. Johansson a H. von der Maase b
a

Psychooncology Research Unit, Department of Oncology, Aarhus University Hospital, and Institute of Psychology, University of Aarhus, b Department of Oncology, Aarhus University Hospital, Aarhus, Denmark

Key Words Cancer Chemotherapy Nausea Vomiting Fatigue Autonomic perception Absorption Somatosensory amplification Anxiety Expectation

Abstract Background: In spite of antiemetics, postchemotherapy side effects continue to be common and may affect compliance to cancer treatment. Among the known factors associated with increased symptom severity are: younger age, treatment toxicity, expected severity, and distress, but little is still known about the role of other factors. The aim of our study was to investigate the role of individual differences related to sensory perception for posttreatment side effects. Methods: Hundred and twenty-five women receiving adjuvant chemotherapy for breast cancer completed measures of absorption, autonomic perception, somatosensory amplification, trait anxiety, and expected severity at baseline. Pretreatment distress and posttreatment nausea, vomiting, and fatigue were assessed at the 1st, 4th, 6th and last cycles of chemotherapy. Results: While univariate analyses showed several factors to be associated with side effects, only absorption and pretreatment distress remained independent predictors of nausea and fatigue when controlling for the remaining factors. Posttreatment vomiting was only predicted by expected severity of vomiting. Conclusion: Chemo-

therapy-induced side effects are related to increased autonomic nervous system activity, and absorption has been associated with increased autonomic nervous system reactivity to stress. The results suggest that individuals with high absorption may be at greater risk for developing side effects. Improved precision in identifying patients at risk of experiencing more severe side effects after cancer treatment will increase the ability to target treatments aimed at reducing these side effects. Copyright 2007 S. Karger AG, Basel

Introduction

In spite of the development of antiemetic treatments, postchemotherapy nausea and vomiting continue to be common, significant, and distressing side effects [1, 2], with approximately 60% of cancer patients receiving chemotherapy experiencing nausea and 50% experiencing vomiting [3]. Fatigue is experienced by 8296% of patients undergoing chemotherapy and 65100% of patients undergoing radiotherapy [4]. It has been estimated that failure to control side effects can lead to 2550% of patients delaying or refusing possible life-saving therapy [5]. While the main risk factor for the degree of chemotherapy-induced nausea and vomiting is the emetogenic
Prof. Robert Zachariae Psychooncology Research Unit Jens Christian Skous Vej 4 DK8000 rhus C (Denmark) E-Mail bzach@as.aaa.dk

2007 S. Karger AG, Basel 00333190/07/07660376$23.50/0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/pps

potential of the chemotherapeutic agents used [6], a number of additional risk factors have been identified, including young age, female gender, low alcohol intake, susceptibility to motion sickness, poor previous antiemetic control [2, 3, 6], and possibly genetic factors [7]. Known nonpharmacological risk factors include trait anxiety, distress, and anticipatory fears and expectations about chemotherapy [813]. Factors that may contribute to fatigue are anemia, lack of sleep, anxiety, depression, catastrophizing, and pain [1418]. With the exception of trait anxiety, the possible role of personality factors in the development of chemotherapy-induced side effects has received limited attention, and the known risk factors only explain part of the variation in side effects. One area with potential explanatory power could be personality or trait factors thought to be related to individual differences in sensory perception. It is generally agreed that the autonomic nervous system (ANS) plays a major role in the development and expression of chemotherapy-induced nausea [2], and physical symptoms such as sweating, feeling hot or cold are commonly associated with nausea as preceding or accompanying symptoms. Anxiety may lead to increased autonomic symptom awareness [19], and it has been suggested that patients with medically unexplained symptoms, e.g. multiple chemical sensitivity, are more anxious, focus more on autonomic sensations and have exaggerated perception of normal physiological responses [20, 21]. Only few studies have focused on autonomic perception in cancer patients, but preliminary evidence suggests that cancer patients who attend more to their autonomic reactivity experience more anticipatory as well as postchemotherapy nausea [22, 23]. No studies have focused on associations with other side effects such as fatigue, and individual differences in autonomic perception warrant further investigation. Somatosensory amplification refers to the tendency to experience bodily sensations as intense, noxious, and disturbing [24]. Attention to a symptom is generally thought to amplify it, and anticipatory anxiety could thus be hypothesized to intensify somatosensory amplification of a particular physical symptom. Although somatosensory amplification has primarily been suggested to play a role in illnesses characterized by medically unexplained symptoms [25], it is possible that this factor could also play a role in the interpretation of physical sensations related to side effects of cancer treatments. This has not yet been investigated. The personality trait of absorption [26] is correlated with hypnotizability [27], has been defined as a predispoIndividual Differences and Side Effects

sition to experience alterations of cognition and emotion over a broad range of situations, and is generally associated with increased suggestibility and imaginative involvement [28]. Absorption has a hereditary component [29] and has been shown to be related to increased reports of distress and somatic symptoms [30, 31], making it a potential risk factor for anxiety disorders [32]. Individuals with high absorption could therefore have more labile or reactive physiological systems, leaving them more reactive in stressful situations [33, 34]. High absorption could thus potentially influence the development of adverse physiological reactions to cancer treatment. This has, however, only been investigated in one previous study, where high absorption, together with increased autonomic perception, was found to be associated with increased risk of developing anticipatory nausea [23]. The role of absorption in the development of fatigue has, to our knowledge, not been investigated. Our aim was therefore to investigate the possible influence of the personality traits of autonomic perception, absorption, and somatosensory amplification on chemotherapy-induced side effects of nausea, vomiting, and fatigue, while controlling for other relevant treatment-related, physical, and psychological variables including emetic potential of treatment, concomitant radiotherapy, age, expected severity of side effects, distress, and trait anxiety.

Methods
Patients Participants were 125 consecutively recruited women receiving adjuvant chemotherapy after surgical treatment for breast cancer (mean age: 48.5 8 8.3 years) at the Department of Oncology, Aarhus University Hospital. Inclusion criteria were women scheduled to receive standard adjuvant chemotherapy for primary breast cancer, age between 18 and 70 years, and ability to read and write Danish. Exclusion criteria were previous cancer, previous chemotherapy, and self-reported ongoing or previous treatment for psychiatric illness. The participants were contacted during their first visit to the Oncology Department, and written informed consent was obtained from all participants before entering the study. The study was approved by the local ethics committee. Treatment The women were treated with either cyclophosphamide, methotrexate and 5-fluorouracil (CMF) (25%) or cyclophosphamide, epirubicin and 5-fluorouracil (CEF) (75%). Approximately half of the women (56%) were scheduled to have a total of 7 cycles of chemotherapy, while the remaining women were scheduled to receive 9 cycles. In addition to chemotherapy, 81% of the women received radiotherapy either as concomitant treatment (46%) or after che-

Psychother Psychosom 2007;76:376384

377

Table 1. Correlations between autonomic perception, somatosensory amplification, absorption, trait anxiety, age, expected nausea,

expected vomiting, expected fatigue, distress, and fatigue measured prior to the 1st cycle of chemotherapy Age Expected Nausea (VAS) 0.07 0.38** 0.05 0.25** Expected vomiting (VAS) 0.09 0.35** 0.19 0.13 Expected fatigue (VAS) 0.12 0.19* 0.07 0.23* Distress (POMS) 0.36** 0.20* 0.17 0.34** Fatigue (EORTC) 0.29** 0.06 0.14 0.17 SSAS TAS TMAS

Autonomic perception (APQ) Somatosensory amplification (SSAS) Absorption (TAS) Trait anxiety (TMAS) * p < 0.05; ** p < 0.01.

0.31** 0.03 0.00 0.02

0.16

0.19* 0.15

0.36** 0.33** 0.20*

motherapy (54%). All women received standard antiemetic treatment with prednisolone, 5-HT3 antagonists, and either methoclopramide or metopimazine. Measures Before the 1st Cycle of Chemotherapy As part of a larger study in which these patients were participating, the women were asked to complete a questionnaire package 1 h prior to the 1st cycle of chemotherapy. Factors thought to be associated with sensory perception were measured with (1) The Tellegen Absorption Scale (TAS) [27, 35], the Somatosensory Amplification Scale (SSAS) [36], and the Anxiety-related subscale of the Autonomic Perception Questionnaire (APQ) [37]. The Bendig short version of the Taylor Manifest Anxiety Scale (TMAS) [38, 39] was included as a trait measure of anxiety. As a measure of general distress, the women were asked to complete the 11-item version of the Profile of Moods State Questionnaire (POMS-11) [40]. The women also completed the Fatigue subscale of the EORTC QLQ-C30 questionnaire [41, 42]. Finally, the women were asked to rate expectation, i.e. the degree to which they expected to experience nausea, vomiting, and fatigue during treatment, on 100-mm Visual Analogue Scales (VAS). Before the 4th, 6th, and Last Cycles of Chemotherapy Before each of the cycles 4, 6, and 7 (or 9), they were asked to complete the POMS-11. Total distress (POMS) scores were calculated for all 4 cycles. After the 1st, 4th, 6th, and Last Cycles of Chemotherapy After each cycle of chemotherapy, the women completed a diary for each of the first 6 days after treatment, recording the number of times they had vomited as well as nausea intensity on a 7point Likert scale. After day 3 and day 6, they were asked to rate the unpleasantness of their vomiting during the past 3 days, likewise on a 7-point Likert scale. Finally, on day 6 after the 4th, 6th and last cycles, they were asked to complete the items of the Fatigue subscale of the EORTC QLQ-C30 questionnaire. Total Nausea Intensity and a Total Vomiting Unpleasantness score was calculated for each of the treatment cycles 1, 4, 6 and 7 (or 9) with total scores ranging from 0 to 100. Finally, the women were asked to rate the perceived efficacy of the antiemetic medication after each cycle on a 7-point Likert scale. A total antiemetic efficacy score (0100) was calculated.

Data Analysis Possible associations between independent variables at baseline and between baseline measures and posttreatment side effects were explored by correlational analyses. Changes in pretreatment distress and posttreatment nausea, vomiting, and fatigue over the course of treatment were analyzed with repeated-measures analyses of variance (ANOVAs). Post-hoc comparisons were controlled for multiple comparisons. The independent associations between the trait factors of autonomic perception, somatosensory amplification, and absorption and the posttreatment side effects were analyzed with multiple, hierarchical, linear regression analyses. All analyses were conducted using the SPPS 13.0 statistical software package. A statistical significance level of 5% (two-tailed) was chosen.

Results

Inclusion and Attrition During the recruitment period, a total of 183 women fulfilling the inclusion criteria were approached. A total of 125 women agreed to participate, yielding an inclusion rate of 68%. Significantly more women receiving CEF (71.5%) than women receiving CMF (53.7%) agreed to participate (Z: 2.56; p ! 0.01). Attrition was 22% with 28 women not having completed the data after the last cycle. Dropouts reported greater expected fatigue (mean: 78.8; SD: 20.1) prior to the 1st cycle than women who completed the study (mean: 62.9; SD: 25.6; t = 2.7; p ! 0.01). No other differences between dropouts and completers reached statistical significance. Correlations at Baseline Correlations between APQ, SSAS, TAS, TMAS scores and age, expected side effects, and fatigue measured prior to the 1st cycle are shown in table 1 together with intercorrelations between APQ, SSAS, TAS, and TMAS scores. While women receiving CMF were significantly
Zachariae /Paulsen /Mehlsen /Jensen / Johansson /von der Maase

378

Psychother Psychosom 2007;76:376384

Table 2. Pretreatment distress (044), intensity of posttreatment nausea (0100), frequency of posttreatment vomiting, percent women reporting vomiting, mean unpleasantness of vomiting (0100), and posttreatment fatigue (0100) at the 1st, 4th, 6th, and last chemotherapy cycles

Cycle 1 Pretreatment distress (POMS) Posttreatment nausea (intensity) Posttreatment vomiting (frequency) Posttreatment vomiting (percent patients reporting) Posttreatment vomiting (unpleasantness) Posttreatment fatigue 11.188.2 16.3819.7 0.782.0 23.2% 6.2814.6 29.2818.71 4 8.287.7 20.0822.3 0.581.4 23.2% 7.5815.1 34.2822.7 6 8.588.9 23.0822.8 1.084.1 24.8% 7.0815.7 50.4827.4 last (7 or 9) 6.787.3 21.4820.8 0.982.7 28.8% 8.0818.4 50.0827.8

Values are expressed as mean8SD. 1 Fatigue was measured before the 1st cycle of chemotherapy.

older (mean age: 57 years) than women treated with CEF (mean age: 46 years; t = 8.3; p ! 0.001), there were no statistically significant differences for any of the other measures at baseline. Pretreatment Distress Mean pretreatment distress scores are shown in table 2. Significant changes over time were found [F(3, 264) = 14.2; p ! 0.001] with distress scores before the 4th, 6th, and last cycles of chemotherapy to be significantly reduced compared with the scores before the first treatment (p ! 0.001). Posttreatment Nausea, Vomiting, and Fatigue Almost all women (92.6%) reported some degree of posttreatment nausea, 51% experienced posttreatment vomiting at least once, and all women experienced some degree of fatigue during treatment. Intensity of posttreatment nausea showed significant changes during the course of chemotherapy [F(3, 3,357) = 3.9; p ! 0.01], with more intense nausea after the 6th (p ! 0.01) and last cycles (p ! 0.02) compared to after the 1st cycle. The women reported significant increases in fatigue during treatment [F(3, 351) = 41.2; p ! 0.001], with increased fatigue found after all subsequent cycles compared to cycle 1 (0.01 1 p 1 0.001). There were no changes over time with respect to frequency of posttreatment vomiting [F(3, 360) = 0.9; p = 0.42] or reported unpleasantness of vomiting [F(3, 264) = 0.5; p = 0.69]. Data are shown in table 2. There were no differences in posttreatment side effects between women who received and women who did not receive radiotherapy between chemotherapy treatments (p = 0.10
Individual Differences and Side Effects

0.96), and radiotherapy was therefore excluded from subsequent analyses. Correlations between Baseline Measures and Posttreatment Side Effects Univariate correlations between posttreatment side effects and the independent variables and potential risk factors are shown in table 3. A number of significant correlations were found between nausea and fatigue and potential risk factors. Vomiting, on the other hand, was associated only with age and expected vomiting. When comparing correlations between baseline measures and early (day 13) or delayed (day 46) side effects, no pattern emerged (data not shown). When controlling for trait anxiety (TMAS) with partial correlations, the significant correlations found between the trait measures of APQ and SSAS and nausea and fatigue ceased to be statistically significant. Controlling for TMAS did not appear to influence correlations between side effects and absorption (data not shown). Significant correlations (p ! 0.01) were found between all three expectation measures and distress scores prior to the 1st and the 4th cycle with coefficients ranging from 0.23 to 0.38 (data not shown). Multiple Linear Regressions Multiple, hierarchical, linear regression analyses were conducted with posttreatment side effects as dependent variables, and APQ, SSAS, TAS entered simultaneously at the first step, and TMAS, pretreatment distress (POMS), age, toxicity of chemotherapy, and expected severity of the dependent variable in question entered at the second
Psychother Psychosom 2007;76:376384

379

Table 3. Correlations between posttreatment nausea, vomiting, and fatigue and age, expected side effects, pretreatment distress, au-

tonomic perception, somatosensory amplification, absorption, and trait anxiety measured at baseline Cycle Nausea 1 4 6 7 or 9 1 4 6 7 or 9 APQ1 0.05 0.14 0.17 0.10 0.16 0.05 0.02 0.06 0.14 0.01 1 4 6 7 or 9 0.02 0.12 0.08 0.17 0.13 1 4 6 7 or 9 0.29** 0.13 0.23* 0.20* 0.28** SSAS 0.14 0.17 0.13 0.19* 0.21* 0.15 0.07 0.01 0.11 0.01 0.17 0.09 0.06 0.00 0.14 0.06 0.13 0.21* 0.15 0.19** TAS 0.00 0.12 0.20* 0.10 0.13 0.09 0.08 0.12 0.02 0.08 0.14 0.00 0.03 0.09 0.05 0.14 0.21* 0.22* 0.20* 0.26** TMAS 0.16 0.05 0.18 0.21* 0.18* 0.03 0.10 0.01 0.04 0.01 0.02 0.06 0.02 0.04 0.01 0.17 0.13 0.31** 0.29** 0.31** POMS1 0.27** 0.32** 0.26** 0.28** 0.39** 0.03 0.01 0.04 0.11 0.16 0.01 0.18 0.16 0.31** 0.28** 0.53** 0.57** 0.51** 0.37** 0.60** Age 0.04 0.03 0.22* 0.10 0.9 0.00 0.07 0.08 0.16 0.13 0.02 0.16 0.22* 0.21* 0.24* 0.06 0.09 0.06 0.16 0.13 Expected nausea 0.17 0.20* 0.22* 0.19* 0.24** 0.22 0.02 0.01 0.04 0.05 0.09 0.02 0.06 0.03 0.03 0.21* 0.22* 0.19* 0.20* 0.27** Expected vomiting 0.15 0.23* 0.22* 0.22* 0.27** 0.27** 0.08 0.20* 0.12 0.29* 0.13 0.09 0.18 0.18 0.26* 0.15 0.17 0.17 0.16 0.21** Expected fatigue 0.04 0.01 0.04 0.03 0.02 0.12 0.02 0.05 0.04 0.02 0.11 0.15 0.02 0.06 0.03 0.22* 0.24* 0.12 0.25** 0.27**

Total nausea Vomiting (frequency)

Total vomiting (frequency) Vomiting (unpleasantness)

Total vomiting (unpleasantness) Fatigue

Total fatigue

* p < 0.05; ** p < 0.01. 1 Correlations with POMS measured prior to the relevant cycle of chemotherapy.

step. The results are shown in table 4. When controlling for the remaining factors, only absorption (TAS) and pretreatment distress (POMS) emerged as independent predictors of nausea and fatigue, and only expected severity of vomiting was significantly associated with frequency and unpleasantness of vomiting. The final models accounted for 18% of the variation in total nausea, 16% for total frequency of vomiting, 20% for total unpleasantness of vomiting, and 54% for total fatigue. Comparing Women with High and Low Absorption Mean scores of nausea, fatigue, and distress at the 1st, 4th, 6th and last cycles of treatment of women with high (above the median = 15) and low absorption scores (scores at the median and below) were compared with repeatedmeasures ANOVAs. A significant interaction between time and absorption was found for nausea [F(3, 342) =
380
Psychother Psychosom 2007;76:376384

2.8; p ! 0.05], with subsequent comparisons showing that women with high absorption reported more posttreatment nausea after the 6th cycle than women with low absorption (p ! 0.05). A significant between-subjects effect of absorption was found for fatigue [F(1, 112) = 7.4; p ! 0.01], but no interaction between time and absorption. While mean pretreatment distress scores of women with high absorption were higher than the scores of women with low absorption at all time points, the differences did not reach statistical significance. In addition, a t test for independent samples showed that women with high absorption scored significantly (p ! 0.05) lower on perceived efficacy of antiemetic medication (mean = 36.1; SD = 22.4) than women with low absorption (45.5; 21.5), while there were no differences in expected nausea (means: 41.7 vs. 42.0).

Zachariae /Paulsen /Mehlsen /Jensen / Johansson /von der Maase

Table 4. Results ( -coefficients) of the second and last step of multiple linear, hierarchical regression analyses with posttreatment side effects as dependent variables, and APQ, SSAS, TAS entered at the first step, and TMAS, Distress (POMS), age, toxicity, and expected severity of side effects entered at the second step

Cycle Nausea 1 4 6 7 or 9 1 4 6 7 or 9

APQ 0.08 0.00 0.02 0.09 0.04 0.04 0.04 0.08 0.01 0.09

SSAS 0.03 0.02 0.03 0.04 0.04 0.11 0.05 0.05 0.13 0.07 0.09 0.08 0.15 0.14 0.04 0.12 0.04 0.14 0.02 0.01

TAS 0.13 0.13 0.24* 0.07 0.15 0.08 0.13 0.09 0.05 0.04 0.15 0.04 0.02 0.06 0.02 0.20* 0.23* 0.26** 0.27* 0.32**

TMAS 0.02 0.15 0.03 0.09 0.07 0.03 0.19 0.01 0.16 0.12 0.11 0.22(*) 0.05 0.10 0.11 0.14 0.08 0.03 0.19(*) 0.00

POMS1 0.15 0.31* 0.16 0.30* 0.36** 0.08 0.03 0.00 0.20 0.11 0.09 0.13 0.08 0.33* 0.27(*) 0.59** 0.58** 0.49** 0.22* 0.60**

Age 0.12 0.10 0.07 0.06 0.04 0.01 0.03 0.04 0.08 0.06 0.02 0.04 0.09 0.18 0.09 0.01 0.11 0.03 0.25(*) 0.10

Toxicity2 0.21 0.02 0.09 0.05 0.05 0.18 0.09 0.09 0.04 0.14 0.03 0.12 0.13 0.03 0.08 0.04 0.10 0.16 0.10 0.02

Expected severity3 0.11 0.12 0.08 0.02 0.10 0.34** 0.12 0.24* 0.22(*)

R2

Total nausea Vomiting (frequency)

0.18

Total vomiting (frequency) Vomiting (unpleasantness) 1 4 6 7 or 9

0.16 0.30** 0.16 0.11 0.25* 0.24* 0.24(*) 0.14 0.10 0.06 0.13 0.11 0.20

0.15 0.12 0.06 0.10 0.03

Total vomiting (unpleasantness) Fatigue 1 4 6 7 or 9

Total fatigue

0.01 0.14 0.02 0.10 0.08

0.54

(*) p < 0.10; * p < 0.05; ** p < 0.01. 1 POMS measured prior to the relevant treatment cycle. 2 CMF = 1; CEF = 2. 3 Expected severity of relevant dependent variable.

Discussion

Our univariate analyses generally confirmed previously reported associations between younger age, distress, expectation and increased severity of side effects [2, 3, 6, 810, 13]. The results also revealed associations between side effects and trait anxiety, autonomic perception, somatosensory amplification, and absorption. However, when controlling for the remaining factors in multivariate analyses, of the trait measures investigated, only high scores on absorption remained a significant predictor of nausea and fatigue. No aspect of vomiting was predicted by any of the trait measures investigated. Since absorption has been suggested to be a potential risk factor for both anxiety disorders [32] and somatic symptoms [30, 31], and since trait anxiety has been shown
Individual Differences and Side Effects

to be associated with the severity of side effects [43], we specifically explored the possible influence of trait anxiety on the associations between side effects and the three remaining trait measures. The associations found between side effects and sensory amplification and autonomic perception ceased to be significant when controlling for trait anxiety. It has been suggested that somatosensory amplification may more likely be a measure of negative emotionality and general distress than a measure of somatic sensitivity as such [44], and our results seem to support this hypothesis. This could also be the case for autonomic perception. Absorption, on the other hand, continued to be associated with nausea (after the 6th cycle) and fatigue after controlling for trait anxiety as well as for other variables thought to influence reports of posttreatment side effects. The mechanisms mediating
Psychother Psychosom 2007;76:376384

381

the association between absorption and side effects are, however, still unknown. Nausea is generally accompanied by changes in ANS activity, and many of the clinical symptoms reported by patients in chemotherapy are indeed manifestations of ANS activity [2]. There have also been reports of a relationship between autonomic dysfunction and chemotherapy-induced nausea and vomiting [45]. Absorption has been found to be moderately, but consistently, associated with hypnotizability [27], and we have previously found both absorption and hypnotizability to be associated with increased physiological reactivity [33, 34, 46, 47]. We therefore find it possible that high absorption is associated with increased ANS reactivity following chemotherapy. Absorption has also been shown to be related to increased reports of distress [30, 31], and pretreatment distress in the form of anxiety and depression has generally been shown to be a significant predictor of reported symptoms, including nausea and vomiting [8, 12, 4850], and fatigue [51, 52] in cancer patients. It is therefore possible that associations between absorption and side effects are explained by higher levels of distress in high-absorption women. However, although women high in absorption generally exhibited higher distress scores at all time points, this was not statistically significant. Likewise, absorption continued to be a significant independent predictor of both fatigue and nausea (after the 6th cycle), after controlling for pretreatment distress. This suggests that the suggested increased physiological reactivity of women high in absorption is relatively independent of differences in distress. High-absorption women showed a dramatic increase in nausea, compared to lowabsorption women, peaking after the 6th cycle, while the moderately increased report of fatigue in high-absorption women compared to low-absorption women was consistent over time, suggesting that the association between absorption and fatigue is of a more general nature, and not specifically related to chemotherapy-induced ANS activity. Some limitations of our design due to our wish not to burden the women with too many questionnaires should be noted. Both oncologists and general practitioners frequently prescribe antidepressant medications, benzodiazepines, and other psychotropic drugs that may have antiemetic effects or interact with the efficacy of antiemetic medication. Other factors, e.g. physical activity, may also play a role. We only included assessments before and after 4 chemotherapy cycles, and we were therefore unable to control for side effects after the cycle immediately prior to each of the cycles included. Finally, while we measured
382
Psychother Psychosom 2007;76:376384

general pretreatment distress, we did not include specific state measures of depression and anxiety. These limitations could be a potential source of bias.

Conclusion

The results confirmed our hypotheses that severity of posttreatment nausea and fatigue may be influenced by individual differences in absorption, independently of other known risk factors. It is possible that individuals high in absorption are more labile or have more reactive physiological systems, leaving them more physiologically reactive to stressful situations such as cancer and cancer treatment. Although clearly preliminary, our results could suggest that factors associated with individual differences in psychophysiological reactivity may play a moderating role in the development of side effects, and studies using a psychophysiological perspective are needed.

Acknowledgements
The authors wish to thank the women who participated in the study and the staff at the Department of Oncology, Aarhus University Hospital, for their assistance during the data collection phase. The study was supported by The Danish Cancer Society, grant 9915003.

Zachariae /Paulsen /Mehlsen /Jensen / Johansson /von der Maase

References
1 Osoba D, Zee B, Warr D, Latreille J, Kaizer L, Pater J: Effect of postchemotherapy nausea and vomiting on health-related quality of life. The Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group. Support Care Cancer 1997;5:307313. 2 Morrow GR, Roscoe JA, Hickok JT, Andrews PR, Matteson S: Nausea and emesis: evidence for a biobehavioral perspective. Support Care Cancer 2002;10:96105. 3 Morrow GR, Roscoe JA, Hickok: Nausea and vomiting; in Holland JC (ed): Psycho-Oncology, ed 2. New York, Oxford University Press, 1998, pp 476484. 4 Iop A, Manfredi AM, Bonura S: Fatigue in cancer patients receiving chemotherapy: an analysis of published studies. Ann Oncol 2004;15:712720. 5 Schnell FM: Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist 2003; 8:187198. 6 Jordan K, Kasper C, Schmoll HJ: Chemotherapy-induced nausea and vomiting: current and new standards in the antiemetic prophylaxis and treatment. Eur J Cancer 2005;41:199205. 7 Kaiser R, Sezer O, Papies A, Bauer S, Schelenz C, Tremblay PB, Possinger K, Roots I, Brockmoller J: Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 2002;20: 28052811. 8 Andrykowski MA, Gregg ME: The role of psychological variables in post-chemotherapy nausea: anxiety and expectation. Psychosom Med 1992;54:4858. 9 Jacobsen PB, Bovbjerg DH, Redd WH: Anticipatory anxiety in women receiving chemotherapy for breast cancer. Health Psychol 1993;12:469475. 10 Passik SD, Kirsh KL, Rosenfeld B, McDonald MV, Theobald DE: The changeable nature of patients fears regarding chemotherapy: implications for palliative care. J Pain Symptom Manage 2001;21:113120. 11 Rabin C, Ward S, Leventhal H, Schmitz M: Explaining retrospective reports of symptoms in patients undergoing chemotherapy: anxiety, initial symptom experience, and posttreatment symptoms. Health Psychol 2001;20:9198. 12 Molassiotis A, Yam BM, Yung H, Chan FY, Mok TS: Pretreatment factors predicting the development of postchemotherapy nausea and vomiting in Chinese breast cancer patients. Support Care Cancer 2002; 10: 139 145. 13 Roscoe JA, Bushunow P, Morrow GR, Hickok JT, Kuebler PJ, Jacobs A, Banerjee TK: Patient expectation is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer 2004;101:27012708. 14 Bower JE, Ganz PA, Desmond KA, Rowland JH, Meyerowitz BE, Belin TR: Fatigue in breast cancer survivors: occurrence, correlates, and impact on quality of life. J Clin Oncol 2000;18:743753. 15 Yan H, Sellick K: Symptoms, psychological distress, social support, and quality of life of Chinese patients newly diagnosed with gastrointestinal cancer. Cancer Nurs 2004; 27: 389399. 16 Jacobsen PB, Andrykowski MA, Thors CL: Relationship of catastrophizing to fatigue among women receiving treatment for breast cancer. J Consult Clin Psychol 2004;72:355 361. 17 Greenberg DB: Fatigue; in Holland JC (ed): Psycho-Oncology, ed 2. New York, Oxford University Press, 1998, pp 485493. 18 Cella D: Factors influencing quality of life in cancer patients: anemia and fatigue. Seminars Oncol 1998;25(suppl 7):4346. 19 Shields SA: Reports of bodily change in anxiety, sadness, and anger. Motiv Emot 1984;8: 121. 20 Bailer J, Rist F, Witthft M, Paul C, Bayerl C: Symptom patterns, and perceptual and cognitive styles in subjects with multiple chemical sensitivity (MCS). J Environm Psychol 2004;24:517525. 21 Houtveen JH, Rietveld S, de Geus EJC: Exaggerated perception of normal physiological responses to stress and hypercapnia in young women with numerous functional somatic symptoms. J Psychosom Res 2003; 55: 481 490. 22 Sjden PO, Olafsdottir M, Steinholtz L: Correlates of anxiety, taste and odor experiences in chemotherapy cancer patients. Scan J Behav Ther 1987;16:5967. 23 Challis GB, Stam HJ: A longitudinal study of the development of anticipatory nausea and vomiting in cancer chemotherapy patients: the role of absorption and autonomic perception. Health Psychol 1992; 11:181189. 24 Barsky AJ: Amplification, somatization, and the somatoform disorders. Psychosomatics 1992;33:2834. 25 Nakao M, Barsky AJ, Kumano H, Kuboki T: Relationship between somatosensory amplification and alexithymia in a Japanese psychosomatic clinic. Psychosomatics 2002; 43: 5560. 26 Tellegen A, Atkinson G: Openness to absorbing and self-altering experiences (absorption), a trait related to hypnotic susceptibility. J Abn Psychol 1974; 83:268277. 27 Zachariae R, Jorgensen MM, Christensen S: Hypnotizability and absorption in a Danish sample: testing the influence of context. Int J Clin Exp Hypn 2000;48:306314. 28 Roche SM, McKonkey KM: Absorption: nature, assessment, and correlates. J Pers Soc Psychol 1990; 59:91101. 29 Tellegen A, Lykken DT, Bouchard TJ, Wilcox KJ, Segal NL, Rich S: Personality similarity in twins reared apart and together. J Pers Soc Psychol 1988; 54:10311039. 30 Gick M, McLeod C, Hulihan D: Absorption, social desirability, and symptoms in a behavioral medicine population. J Nerv Ment Dis 1997;185:454458. 31 Vassend O: Dimensions of negative affectivity, self-reported somatic symptoms, and health-related behaviors. Soc Sci Med 1989; 28:2936. 32 Lillienfeld SO: The relation of anxiety sensitivity to higher and lower order personality dimensions: implications for the etiology of panic attacks. J Abnorm Psychol 1997; 106: 539544. 33 Ehrnrooth E, Zacharia R, Svendsen G, Jorgensen MM, Yishay M, Sorensen BS, Hjelm Poulsen J, von der Maase H: Increased thymidylate synthase mRNA concentration in blood leukocytes following an experimental stressor. Psychother Psychosom 2002;71:97 103. 34 Zachariae R, Jorgensen MM, Bjerring P, Svendsen G: Autonomic and psychological responses to an acute psychological stressor and relaxation: the influence of hypnotizability and absorption. Int J Clin Exp Hypn 2000;48:388403. 35 Tellegen A, Atkinson G: Openness to absorbing and self-altering experiences (absorption), a trait related to hypnotic susceptibility. J Abnorm Psychol 1974; 83:268277. 36 Barsky AJ, Wyshak G, Klerman GL: The somatosensory amplification scale and its relationship to hypochondriasis. J Psychiatr Res 1990;24:323334. 37 Shields SA, Simon A: Is awareness of bodily change in emotion related to awareness of other bodily processes? J Pers Assess 1991;57: 96109. 38 Taylor JA: A personality scale of manifest anxiety. J Abnorm Soc Psychol 1953;48:285 290. 39 Bendig AW: The development of a short form of the Manifest Anxiety Scale. J Consult Psychol 1956;20:384. 40 Cella DF, Jacobsen PB, Orav EJ, Holland JC, Silberfarb PM, Rafla S: A brief POMS measure of distress for cancer patients. J Chron Dis 1987;40:939942.

Individual Differences and Side Effects

Psychother Psychosom 2007;76:376384

383

41 Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85:365376. 42 Groenvold M, Klee MC, Sprangers MA, Aaronson NK: Validation of the EORTC QLQC30 quality of life questionnaire through combined qualitative and quantitative assessment of patient-observer agreement. J Clin Epidemiol 1997;50:441450. 43 Fujii M, Ohno Y, Tokumaru Y, Imanishi Y, Kanke M, Tomita T, Kanzaki J: Manifest Anxiety Scale for evaluation of effects of granisetron in chemotherapy with CDDP and 5FU for head and neck cancer. Support Care Cancer 2001;9:366371.

44 Aronson KR, Barrett LF, Quigley KS: Feeling your body or feeling badly: evidence for the limited validity of the Somatosensory Amplification Scale as an index of somatic sensitivity. J Psychosom Res 2001;51:387394. 45 Bellg AJ, Morrow GR, Barry M, Angel C, DuBeshter B: Autonomic measures associated with chemotherapy-related nausea: techniques and issues. Cancer Invest 1995; 13:313323. 46 Zachariae R, Jorgensen MM, Christensen S, Bjerring P: Effects of relaxation on the delayed-type hypersensitivity (DTH) reaction to diphenylcyclopropenone (DCP). Allergy 1997;52:760764. 47 Jorgensen MM, Zachariae R: Autonomic reactivity to cognitive and emotional stress of low, medium, and high hypnotizable healthy subjects: testing predictions from the high risk model of threat perception. Int J Clin Exp Hypn 2002;50:248275. 48 Carey MP, Burish TG: Etiology and treatment of the psychological side effects associated with cancer chemotherapy: a critical review and discussion. Psychol Bull 1988; 104: 307335.

49 Blasco T, Pallares C, Alonso C, Lopez Lopez JJ: The role of anxiety and adaptation to illness in the intensity of postchemotherapy nausea in cancer patients. Span J Psychol 2000;3:4752. 50 Lee EH, Yae CB, Boog PH, Hong CK: Relationships of mood disturbance and social support to symptom experience in Korean women with breast cancer. J Pain Symptom Manage 2004;27:425433. 51 Stone P, Richards M, AHern R, Hardy J: A study to investigate the prevalence, severity and correlates of fatigue among patients with cancer in comparison with a control group of volunteers without cancer. Ann Oncol 2000; 11:561567. 52 Tavio M, Milan I, Tirelli U: Cancer-related fatigue (review). Int J Oncol 2002; 21: 1093 1099.

384

Psychother Psychosom 2007;76:376384

Zachariae /Paulsen /Mehlsen /Jensen / Johansson /von der Maase

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.