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Psychological and immunological characteristics of fatigued women undergoing radiotherapy for early-stage breast cancer.

N. Courtier, T. Gambling, S. Enright, P. Barrett-Lee, J. Abraham, M.D. Mason



Abstract

Purpose


The amelioration of radiotherapy-related fatigue is limited by an equivocal aetiology and uncertainty regarding who is likely to experience significant fatigue. The research objective was to characterise fatigued women undergoing radiotherapy for breast cancer, in order to evaluate whether fatigue was associated with elevated psychological distress and systemic inflammation.

Methods


Participants comprised 100 women, diagnosed with Stage 0 to IIA breast cancer, and prescribed 40Gy in 15 fractions over three weeks. Fatigue was assessed before, during and four weeks after radiotherapy, using the Functional Assessment of Chronic Illness Therapy Fatigue Subscale. Psychological status was self-reported using the Hospital Anxiety and Depression Scale. Sera concentrations of interleukin-6 soluble receptor were established via enzyme-linked immunosorbent assay. The contribution of pre-treatment factors to fatigue analysed using multivariable regression.

Results


38% of participants experienced significant fatigue during radiotherapy, with the remainder little affected. After controlling for baseline fatigue, anxiety before treatment was the strongest unique predictor of subsequent fatigue. During radiotherapy, interleukin-6 soluble receptor (and depression) was significantly elevated in the fatigued group compared to the non-fatigued group (p = 0.01). This association was not mediated by depression.

Conclusions

Inter-related data is consistent with the concept that a lower psychological mood prior to radiotherapy relates to a distinct immunological and behavioural response during radiotherapy. These aetiological insights may inform fatigue treatment pathways, and ensure the targeting of interventions at patients at a high risk of experiencing this disabling symptom of cancer treatment.
Keywords

Fatigue; breast cancer; radiotherapy; psychological mood; inflammation



Introduction

Fatigue is the predominant determinant of health-related quality of life in women with breast cancer prescribed curative radiotherapy [1]. Radiotherapy-related fatigue (RRF) adversely affects physical, cognitive and affective functioning, even years after the completion of treatment [2–4], with profound repercussions for family structure, social-life and finances. Despite patient’s perception of fatigue as the most distressing symptom of radiotherapy [5], an equivocal aetiology renders the symptom largely untreated.

Depression is a known correlate of fatigue in patients with breast cancer [6–8]. Although the two symptoms share a degree of conceptual similarity they can be distinguished. Fatigue is an almost universal symptom of depression, but the latter is not as prevalent as fatigue when determined using diagnostic criteria [9]. According to these criteria, a distinctive feature of RRF is a generalised sensation of weakness, which is associated with an extra-ordinary amount of effort required to complete motor tasks [10]. Depression, but not fatigue, is synonymous with anhedonia [11].

Whether depressed mood antecedes cancer-related fatigue, or vice versa, remains ambiguous. Whilst the presence of fatigue and psychological distress are largely attributable to events surrounding diagnosis and treatment [9] a number of studies have suggested that depressed mood and fatigue either exhibit divergent chronologies and trajectories [12–14] or have independent determinants [10,15].


Studies have advanced the theory that depression and fatigue coexist as components of a treatment-related symptom cluster [16–18], mediated by inflammatory cytokines. Basic evidence for this concept is provided by reports that the therapeutic administration of supraphysiological concentrations of cytokines renders symptom clusters involving fatigue and depression [19,20]. Interleukin-6 (IL-6) is the principal mediator of this acute-phase syndrome. Very few cells express receptors for IL-6. The neuro-behavioural effects of IL-6 ultimately depend on local concentrations of its agonistic soluble receptor (IL-6sR), which when dimerised with IL-6 enables ubiquitous cell signalling from the periphery to the central nervous system, via a process called transsignalling [21,22].
The objective of this research was to examine the characteristics of fatigued women undergoing radiotherapy for breast cancer in order to evaluate whether fatigue in women is associated with elevated psychological distress and systemic inflammation. Translational implications for fatigue attenuation will be discussed.
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Methods and materials

Study design

A cohort study with observations made two weeks before radiotherapy, the end of weeks two and three of radiotherapy and four weeks post-radiotherapy.

Participants

The study population comprised women diagnosed with histologically confirmed early-stage carcinoma of the breast, having undergone primary surgery and subsequently referred to Velindre Cancer Centre for adjuvant radiotherapy. All participants were prescribed 4000cGy in 15 fractions over three weeks. Exclusion criteria included thyroid dysfunction; inflammatory diseases; uncontrolled heart, lung or liver disease; a history of significant or untreated depression; prior or concurrent systemic endocrine or cytotoxic therapy; evidence of locally advanced or metastatic disease. A South East Wales Research Ethics Committee approved the study in October 2007.

Measures


Socio-demographic, disease and treatment-related variables were extracted from hospital records.

Fatigue intensity over the previous seven days was measured using the Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F). The format of the scale is a 13-item questionnaire using a Likert-type scale. The items are summed to generate a cumulative score between zero (maximum fatigue) and 52 (no fatigue), in accordance with standardised processing rules [23]. A minimally clinically significant change is defined as three to four points [24].

When the average of scores at week two and three of radiotherapy was ≤ 34 participants were categorised as fatigued, and 35+ as non-fatigued. The cut-off score of 34 was adopted as the most conservative value proposed in previous work [25,26]. An average summary measure is advantageous as it tends to counteract classification bias, response shift and recency, and overcomes the statistical problem of non-independent observations over time [27].

The Hospital Anxiety and Depression Scale (HADS) provided a self-reported measure of anxiety and depression over the previous seven days. This widely validated tool poses 14 questions alternately pertaining to anxiety or depression. Responses to the questions are scored between 0 (none) to 3 (severe), generating a resultant score between 0 and 21 for each symptom. Symptom scores can be categorised as ‘normal’ (0–7), ‘borderline’ (8–10) and ‘probable case’ (11–21) [28].

The validity of longitudinal studies is dependent on the completeness of the data. In an effort to maintain response rates, the researcher scheduled brief meetings with participants on the days questionnaires were due to prompt their return. Whilst participants were informed in broad terms about the study, whenever possible, participants were unaware of specific research questions whilst completing the questionnaires. Conversely, the researcher remained blind to the fatigue status of the participant until all other measurements were complete. These strategies acted as safeguards against bias that can weaken observational study designs.

Aliquots of serum were collected in accordance with standard protocols and immediately stored at -70oC until analysed. Commercially available enzyme-linked immunosorbent assay (ELISA) kits, optimised for use with human serum, determined circulating concentrations of IL-6sR (R&D Systems Quantikine Sandwich ELISA kits, Minneapolis, USA). To minimise known sources of inter-assay variation [29], samples were assayed in batches of the maximum numbers deemed logistically prudent, using kits with common lot numbers.

Sample size and statistical methods

A projected recruitment rate of two per week and a period of 12 months dictated a pragmatic sample size of 100. An a priori power calculation, based on a multiple regression test, was performed using GPower3 software [30]. Assuming a model with five predictors, a moderate effect size of f2 = 0.15 and significance level set at α = 0.05, a sample size of 100 would render power of 84%. If due to missing data, 10 or more subjects were excluded from analysis then statistical power – to correctly reject the null hypothesis that predictors are unrelated to fatigue – would drop below the 80% conventional benchmark for an observational study.

Analyses were conducted using SPSS version 16. All tests were n = 100 unless otherwise stated. Group comparisons were made using the Mann–Whitney test or one-way between groups ANOVA. Bivariate associations were assessed by Spearman’s Rank Order correlations. Based on the correlational analyses, and more importantly theoretical bases, baseline variables were selected for inclusion entry into a multiple regression model by a forced-entry method. Model residuals and scatterplots were examined to check the data fulfilled the test’s underlying assumptions [31].

[wordcount 695]



Results

Between November 2007 and October 2008, 130 eligible women were consecutively approached to participate in the study. Fifteen women were precluded from participation on the basis of a full medical history; most commonly a history of rheumatoid arthritis. A further 15 eligible women declined to participate. Eight did not wish to undergo blood sampling, four declared a resistance to thinking about ‘extra things’, with the remaining three declining to volunteer a reason. The mean (SD) age and median (IQR) pre-treatment FACIT-F score recorded for 12 eligible non-entrants were 57.1 (7.4) and 43 (37–46), respectively.

Fatigue group characteristics

The median FACIT-F fatigue scores for the whole cohort decreased from 44 at baseline, to 41 at week two, reaching a nadir of 37 at week three, with a subsequent improvement to 42 at four-week follow-up.

When the cohort was divided based on the criteria for a fatigue case, 38% of participants were categorised as fatigued, with the remaining 62% classified as non-fatigued. The median FACIT-F response for the two groups is shown in Figure 1. The grouped participant characteristics are presented below in Table 1.

Figure 1 Median longitudinal Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F), for fatigued and non-fatigued groups of breast radiotherapy patients

(Error bars = inter-quartile range; percentages = the proportion of the cohort classified in each group)


Table 1 Pre-radiotherapy sample characteristics for fatigued and non-fatigued groups of the n = 100 sample of breast radiotherapy patients

Characteristic



Fatigued group

(n = 38)


Non-fatigued group

(n = 62)


Age (years)

55.9 (9.3)

59.0 (8.5)

BMI (Kg/m2)

29.2 (4.8)

27.6 (4.6)

Work status

Retired/Housewife

Continued to work during RT

Postponed work during RT

24 (63.2%)

2 (5.3%)

12 (31.6%)


34 (54.8%)

6 (9.7%)

22 (35.5%)



Menopausal status

Post-menopausal

Peri-menopausal

Pre-menopausal

25 (65%)


7 (18.4%)

6 (15.8%)


48 (77.4%)

9 (14.5%)

5 (8.1%)


HRT history

Never

Previous

25 (65.8%)

13(24.2%)

45 (72.6%)

17 (27.4%)


Smoking history

Never

Past

Current

16 (42.1%)

14 (36.8%)

8 (21.1%)


34 (54.8%)

18 (29%)

10 (16.1%)



Pack-yearsa

12.6 (16.4)

6.2 (9.7)

Histological diagnosis

Ductal carcinoma in-situ

Invasive ductal carcinoma

Invasive lobular carcinoma

Other

6 (15.8%)

18 (47.4%)

5 (13.2%)

9 (23.7%)

7 (11.3%)

43 (69.4%)

7 (11.3%)

5 (8.1%)


Tumour sizea (mm)

17 (10.1)

18.4 (10.4)

Histopathological grade

Grade 1

Grade 2

Grade 3

14 (36.8%)

17 (44.7%)

7 (18.4%)


17 (27.4%)

34 (54.8%)

11 (17.7%)



TNM stage

0

I

IIA

7 (18.4%)

25 (65.8%)

6 (15.8%)


6 (9.7%)


45 (72.6%)

11 (17.7%)



Laterality

Right

Left

20 (52.6%)

18 (47.4%)

32 (51.6%)

30 (48.4%)


Time from surgery to RT (days)

61.5 (12.2)

61.0 (16.7)

Normally distributed continuous variables are means (standard deviation)

a Non-normally distributed continuous variables are medians (inter-quartile range)

Categorical variables are numbers (and percentages) of patients in that group

(BMI = body mass index; HRT = hormone replacement therapy; RT = radiotherapy)
Figure 1 obscures the fact that 27(%) of subjects recorded decreased fatigue at week three as compared to baseline. The majority (22) of these ‘improvers’, were in the non-fatigued group, exhibiting a modest improvement of up to five scale points. Conversely, 26% of participants remained categorised as fatigued at follow-up.

Psychological mood

HADS depression data classified 92 (%) as normal, 4 (%) as borderline and only a further 4 (%) at the lower bounds of the probable case range. By week three these proportions were 79%, 14% and 7%, respectively. The corresponding figures for anxiety were 75%, 12% and 13% at baseline, and 73%, 14% and 13% at week three.

Median (IQR) HADS scores for the cohort were relatively stable from baseline to week three, being 5 (3–7) to 4 (2–7), and 2 (1–5) to 3 (1–6) for anxiety and depression respectively. The relationships between fatigue group and psychological mood are illustrated in Figures 2 and 3.



Figure 2 Median longitudinal Hospital Anxiety and Depression Scale (HADS) anxiety scores for fatigued and non-fatigued groups of the n = 100 sample of breast radiotherapy patients

(Error bars = inter-quartile range)



Figure 3 Median longitudinal Hospital Anxiety and Depression Scale (HADS) depression scores for fatigued and non-fatigued groups of the n = 100 sample of breast radiotherapy patients

(Error bars = inter-quartile range)

IL-6sR concentrations

Heterogeneity was evident in both the baseline sera IL-6sR concentrations and longitudinal changes from baseline. IL-6sR concentration increased for 68% of participants, and decreased for the remaining 32% during radiotherapy. Median data is presented for the two fatigue groups in Figure 4.



Figure 4 Median longitudinal sera interleukin-6 soluble receptor (IL-6sR) concentrations for fatigued and non-fatigued groups

((Error bars = inter-quartile range; IL-6sR = interleukin-6 soluble receptor; ng/dL = nanogram per decilitre)

Mann–Whitney U tests revealed statistically significant differences in the group IL-6sR concentrations at weeks two (U = 854, z = -2.30, p = 0.02) and three (U = 837, z = -2.42, p = 0.01), but not pre or post-treatment. Associated effect sizes were moderate, r ≈ 0.3. As twelve women declined to return for a blood test after treatment, the four week follow-up IL-6sR data was n = 88.

Inter-relationships between variables

As a prelude to multivariable analysis, bivariate (Spearman’s Rank correlation) analyses were conducted for all time points. The strongest statistical correlation with baseline FACIT-F score was a negative correlation with depression, ρ = -.71, p < 0.001. The relationship between anxiety and fatigue was approximately half the strength, ρ = -.35, p < 0.001. Older age was significantly associated with lower anxiety, ρ = -.27, p = 0.004, but not with depression level, ρ = -.009, p = 0.9.

Statistically significant correlations were also revealed between baseline IL-6sR concentration and both fatigue, ρ = -.30, p = 0.003, and depression ρ = .29, p = 0.003.

To determine if the correlation between baseline fatigue and IL-6sR was influenced by associations between the latter and depression, an exploratory Pearson’s partial correlation analyses was undertaken. Histograms and scatter plots suggested assumptions of normality, linearity and homoscedasticity were reasonably met. The zero-order correlation, r = -.32, p = 0.002, was rendered statistically non-significant, r = -.07, p = 0.5, when controlling for depression. In contrast, the zero-order correlation between IL-6sR and fatigue at week three, r = -.31, p = 0.005, was unchanged when controlling for depression level.

The apparent influence of depression on the relationship between baseline fatigue and IL-6sR concentration instigated an exploratory one-way between-groups ANOVA. Low, medium and high depression groups were formed by dividing the cohort into ordinal thirds. A statistically significant difference was evident in IL-6sR concentration for the three groups: F (2, 97) = 4.5, p = 0.01, η2 = 0.9 (moderate effect size). Post-hoc Tukey HSD comparisons indicated that the mean (SD) concentration for the high depression group, M = 46.3 ng/mL (11.6), was significantly different from the low group, M = 37.9 ng/mL (11.5), but the moderate group, M = 41.2 ng/mL (9.2) did not differ significantly from the other two. An equivalent analysis was conducted for baseline anxiety: no significant difference was found between any groups: F (2, 97) = 2.1, p = 0.1.



A standard multiple regression analysis determined the relative contribution of baseline risk factors to fatigue during radiotherapy. The dependent variable was the mean of the fatigue scores at week two and three. Two models were computed: model 1 with, and model 2 without, baseline fatigue. The results are summarised in Table 2.

Table 2 Hierarchical multiple regression to determine the contribution of baseline factors to fatigue during radiotherapy treatment

Baseline variable

β

Sig

% ∆ R2

Model 1










Fatigue

.46

.0002

9.0

Anxiety

-.29

.002

6.0

Depression

-.73

.6

0.2

IL-6sR concentration

.071

.4

0.5

Model 1 adjusted R2 = .47







15.7%













Model 2










Anxiety

-.29

.004

6.0

Depression

-.43

.00004

12.0

IL-6sR concentration

.048

.6

0.2

Model 2 adjusted R2 = .37







18.2%

(% ∆ R2 parameter is based on part-correlation squared statistics, which indicate the percentage of the variance in the dependent variable uniquely explained by each variable after the removal of any shared variance.)
[wordcount 846]
Discussion

Fatigue


The cohort reported a modest, but clinically significant, increase of seven points in median fatigue at the end of radiotherapy compared to baseline. Based on the adopted fatigue cut-off point, 38% of participants were categorised as fatigued, with the remainder categorised as non-fatigued. Categorisation demonstrates that the non-fatigued group remain virtually unaffected from baseline levels of fatigue; which are comparable to normative population data for age-matched females [32]. Participants who were not fatigued before treatment tend to remain so. In comparison, the fatigued subgroup was significantly more fatigued before radiotherapy and fatigue intensifies throughout treatment. The group difference in median scores was 13 at baseline, 23 at week three before closing to 16 four weeks later. The trend for recovery after treatment is reassuring. However, considerable variance in post-treatment trajectory was evident, with 26 (%) still categorised as fatigued at four weeks follow-up, and 10 subjects reporting a clinically significant deterioration of four points or more.

To our knowledge this data is the first time the acute fatigue response has been reported for the current NICE recommended UK breast radiotherapy fractionation schedule. Whilst fatigue may be attenuated when compared to longer international schedules [12,26], both the prevalence and the course of fatigue are broadly in accordance with the closest comparator [26], which reported that 43% experience significant fatigue. This slightly higher proportion was derived using a less stringent FACIT-F cut-off of < 37. Notwithstanding minor methodological discrepancies, the consistent findings and careful exclusion of confounding co-morbidities suggest a reasonable estimate of the proportion of ductal carcinoma in-situ and patients with early breast cancer suffering significant RRF is 40%.

Psychological mood

The HADS data for the aggregated cohort remain relatively static over time. The relationships between anxiety and depression are more comprehensible at the fatigue group level. The divergence of fatigue and depression evident in previous reports is then removed and the course of the two symptoms is congruent. It is notable that participants were highly unlikely to be clinically depressed: a finding that replicates the 3.1% of ‘probable depression’ cases in the much larger UK START trials [33].

Anxiety scores for the fatigued group were higher at baseline than for the non-fatigued group – median scores being eight and four respectively. By week three of treatment, both groups had recorded a decrease of one point – presumably due to familiarisation with the realities of treatment. The parallel longitudinal course for the two fatigue groups indicates that anxiety primarily affects baseline fatigue level, and the increase in subsequent fatigue reported by the fatigued group is not attributable to changes in anxiety during treatment.

Baseline depression was the factor that contributed most to fatigue level before radiotherapy, after controlling for other factors. When considering the contribution of baseline variables to on-treatment fatigue, the inclusion of baseline fatigue increases the proportion of fatigue explained from 37% to 47%. It is also becomes clear that considerable overlap exists in variance explained between fatigue and depression. The proportion of on-treatment fatigue that depression uniquely explains decreases from 12% to a negligible 0.2%. Anxiety is actually the most important explanatory variable as it makes the largest unique contribution.

It is worthwhile cautioning that multiple regression is based on correlation and no definitive claims should be made about causation. However, supporting evidence for causation can be evaluated by considering both the strength and temporality of relationships, and theoretical underlying mechanisms. Fatigue is ultimately a centrally driven phenomenon. Research at the interface of psycho-neuro-immunology has coalesced around the concept that stressors modulate bi-directional communication between a peripheral immunogenic event (eg. radiotherapy) and the central nervous system [34–36].

Psychological stress may plausibly precipitate/potentiate RRF via a cytokine-mediated dysfunction of the neuro-endocrine system. A review of the biological effects of psychological interventions in breast cancer patients identified psychological stress-related dysregulation of cortisol as the principal mediator of relevant biological processes [37]. It has been demonstrated that fatigued breast cancer survivors have a suppressed cortisol response to acute psychological stress [38,39]. As cortisol is a potent hormonal suppressor of the inflammatory response it is not surprising that supressed cortisol activity is associated with augmented IL-6 activity in patients with breast cancer [40].

A secondary pathway that may enable anxiety to gain control of fatigue responses is via poor health behaviours associated with stress, such as increased smoking, alcohol and fat consumption, and reduced exercise [37,41].

IL-6sR


A normal serum range quoted for healthy populations is 15.2 to 45.0 ng/mL, with a mean of 25.5 ng/mL [42]. No comparative results for IL-6sR concentration during radiotherapy could be identified. Data for breast cancer survivors between one and five years post-radiotherapy are available [45]: mean plasma concentrations of 30.6 ng/mL and 40.1 ng/mL, were reported for non-fatigued and fatigued participants, respectively. The current study recorded mean sera concentrations that were comparable to the latter at baseline and approximately 20% higher at week three.

Variance in IL-6sR samples made it difficult to discern if a partial elevation during radiotherapy was a substantive finding. Certainly, statistically significant differences between fatigue groups were only evident during treatment. Further analyses suggested that IL-6sR concentration was more directly associated with fatigue during radiotherapy, in contrast to a relationship mediated by depression before radiotherapy. IL-6sR was related to depression score, but not anxiety, in the absence of irradiation.

Together, the data suggest that women with high levels of perceived stress – in response to diagnosis, surgery, life factors etc. – who undergo radiotherapy, may be most at risk for neuro-behavioural problems such as fatigue. This hypothesis is consistent with both psychological theory [7] and empirical data suggesting psychological distress can sensitise the immunological and behavioural response to subsequent inflammatory events [36,37,41].

Study limitations

A strength of the current study is the homogeneity of the sample. However, the study findings should strictly only be generalised to comparable patient groups. Whilst relevant comorbidities were excluded, no attempt was made to control the use of medication that may be a confounder of inflammation and/or fatigue.

This study cannot determine whether the participants whose fatigue levels did not improve post treatment continued on a downward trajectory. Evidence does exist to suggest that fatigue levels during the acute phase are a strong risk factor for experiencing chronic fatigue [2,4]

The degree to which peripheral cytokine concentrations reflect local concentrations is also at issue. Furthermore, cytokine release is known to be affected by circadian, diurnal and menstrual rhythms, none of which were controlled for. The time of day and fasting effects appear to have no material effect on short-term variability of IL-6sR [42].

Implications for theory and practice

The divergent course of fatigue groups suggests that baseline factors are determinants of fatigue that radiotherapy consequentially exacerbates. Screening of predictors of fatigue before treatment would enable the majority of patients to be reassured that fatigue is likely to be mild and transitory. For a significant minority of women, we hypothesise that the anxiety response affects fatigue before treatment and sensitises for subsequent behavioural symptoms. Levels of anxiety and fatigue that indicate a need for enhanced support are thus sustained throughout treatment.

The current study has not yet provided definitive evidence of a mediating role of inflammation. However, a psychological distress response antecedes the neuro-immunological effects, possibly via hypothalamic-pituitary-adrenal axis modulation. The implication is that interventions to address fatigue should focus on distress reduction, which should be instigated prior to radiotherapy. Efforts should focus on providing coping techniques rather than fundamental change of relatively stable personality traits [7]. The active components of psychological interventions have been previously elucidated [44], although much uncertainty remains regarding the optimal format and delivery.

Even the most active intervention will show insufficient promise when tested in the majority of women who report negligible fatigue (and anxiety and depression) both before and during radiotherapy. Instead, help should be targeted at women at a high risk of experiencing fatigue. This study, and others [33], indicate that younger women find the prospect of daily confrontation with their disease particularly distressing. Deprivation and social support are contextual factors that are likely to modulate anxiety responses [45].

Further experimental research should extend from the acute into the chronic period to discern if changes in fatigue are sustained. The measurement of waking cortisol concentrations in future work could provide useful mechanistic evidence of intervening variables. Structural equation modelling would then be an appropriate method to test a proposed ‘causative’ model. The targeted treatment of fatigue is vital to maximise the quality of life after curative radiotherapy.

[wordcount 1406]

TOTAL = 3307



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