Higher Levels of Stress Are Associated with a Significant Symptom Burden in Oncology Outpatients Receiving Chemotherapy

INTRODUCTION

A cancer diagnosis, its related treatments, and the uncertainty of the disease course are stressful experiences for most patients.^1,2 While the types and the duration of stressors, as well as their impact, vary greatly,³ a significant amount of variability in individuals’ cognitive, emotional, and neurobiological responses to stress.⁴ A growing, albeit limited, body of preclinical and clinical evidence, summarized below, suggests that these inter-individual differences in oncology patients’ responses to stress may contribute to the occurrence and severity of common physical symptoms (i.e., fatigue, sleep disturbance, deficits in energy levels, cognitive impairment) associated with the receipt of chemotherapy (CTX).

Fatigue occurs in up to 90% of patients undergoing CTX.⁵ In the general population, fatigue is an adaptive response to acute stress that assists an individual to conserve energy and maintain homeostasis. However, in situations of chronic stress or cumulative exposure to stressful life events, the sympathetic nervous system (SNS), parasympathetic nervous system (PNS), and hypothalamic-pituitary-adrenal (HPA) axis experience an increased allostatic load which results in increases in fatigue severity.⁶ In terms of oncology patients, as suggested in a recent review,² stress-induced increases in inflammatory responses may be one of the underlying mechanisms for fatigue. However, only one study was identified that evaluated for associations between fatigue severity and stress in oncology patients receiving CTX. In this study, that used latent profile analysis (LPA) to identify subgroups of patients with distinct morning and evening fatigue profiles,⁷ higher levels of general and disease-specific stress were reported by patients in the highest morning and evening fatigue subgroups.

Sleep disturbance is reported by 30% to 88% of oncology patients and has a significant impact on patients’ mood, functional status, and quality of life.^8,9 As noted in two recent reviews,^10,11 findings from several animal and human studies suggest that stress can have an impact on the sleep-wake cycle in a variety of ways depending primarily on the types of stressors experienced, the duration of exposure (i.e., acute versus chronic stress), and inter-individual responses to stress. However, research on the association between sleep disturbance and stress in oncology patients in extremely limited. In the only study identified,¹² that evaluated twenty-nine newly diagnosed patients with breast cancer and co-occurring insomnia, while no measure of stress was used, patients with insomnia prior to their cancer diagnosis reported high cognitive arousal scores (i.e., a proxy measure of stress) prior to bedtime.

Cancer-related cognitive impairment (CRCI) can occur in up to 75% of patients receiving CTX.¹³ In an excellent review,¹⁴ Datta and Arnsten described the influences of chronic stress on the functioning of the prefrontal cortex (PFC). Findings across studies of the general population suggest that this area of the brain, that controls behaviors, thoughts, and emotions, when exposed to chronic stress exhibits changes in connectivity and neuronal atrophy. It is interesting to note that in a recent magnetic resonance imaging (MRI) study of forty patients with breast cancer,¹⁵ CRCI was associated with changes in functional connectivity in the PFC. In addition, findings from a systematic review suggest that psychosocial factors, including increased stress, are associated with CRCI.¹⁶ Finally, in a study of patients undergoing CTX,¹⁷ higher levels of general and disease specific stress were associated with worst cognitive dysfunction.

Given the high levels of stress that oncology patients experience; the growing preclinical evidence, as well as evidence from the general population, on the associations between stress and common physical symptoms; and the paucity of research on these associations in oncology patients, in this study we extend our work on stress in oncology patients. This current analysis study is an extension of our previous report that identified distinct stress profiles in a large sample of oncology patients undergoing CTX (n=957).¹⁸ In brief, we used LPA to identify subgroups of patients based on their concurrent evaluations of global (i.e. Perceived Stress Scale¹⁹) and cancer-specific stress (i.e., Impact of Event Scale-Revised²⁰), lifetime stress exposure (i.e., Life Stressor Checklist-Revised²¹), and resilience (i.e., Connor-Davidson Resilience Scale²²). Three subgroups of patients with distinct stress profiles were identified (Table 1). The first group, labeled “Stressed” (39.3%) reported the highest levels of global and cancer specific stress, the lowest resilience scores, and the most life stress. The second group, labeled “Normative” (54.3%), was characterized by intermediate levels of global stress and resilience, lower levels of cancer-related stress, and the lowest amount of cumulative life stress. The third group, labeled “Resilient” (5.7%) had the lowest global stress scores, levels of cancer-specific stress that were comparable to the “normative” group, the highest resilience scores, and intermediate levels of cumulative life stress. The purpose of this study was to evaluate for differences in the severity of fatigue, lack of energy, sleep disturbance, and cognitive function, among these three stress groups. We hypothesized that compared to patients in the other two groups, patients in the “stressed” group would have the highest physical symptom severity scores.

METHODS

RESULTS

DISCUSSION

This study is the first to evaluate for differences in fatigue, energy levels, sleep disturbance, and cognitive function in subgroups of patients with distinct stress profiles. Details on the differences among these subgroups in terms of their specific stress profiles, as well as demographic and clinical characteristics are described in our previous publication,¹⁸ which allows us to focus this discussion our findings related to differences among the subgroups in the severity of common physical symptoms associated with cancer and CTX administration.

Consistent with our a priori hypothesis, patients in the Stressed class had the highest symptom severity scores for all four symptoms and all of these scores were above the clinically meaningful cutoffs for the various instruments. In contrast, while the stress and resilience scores differed between the Normative and Resilient classes, for most of the symptoms, no between group differences in symptom severity scores were found. This finding may be related to the relatively high symptom burden experienced by all three classes or the relatively small number of patients in the Resilient class. An additional consideration may be that the correlations between the various symptom scores differed among the latent classes. As shown in Supplemental Table 3, the correlations between the various symptoms were in the small to moderate range and did not differ among the latent classes.

While numerous studies have investigated risk factors for CRCI,^47–50 the majority evaluated for associations with only demographic, clinical, and treatment characteristics. In this study, we provide additional evidence that a subgroup of oncology patients with high levels of general and disease-specific stress, as well as cumulative life stress had the worse decrements in cognitive function. While the total scores and the interpersonal effectiveness subscale scores of the AFI differentiated among the three classes, both the Stressed and Normative classes had total AFI scores that suggest moderate decrements in cognitive function. As a subjective measure, the AFI evaluates patients’ perceptions of their effectiveness in carrying out basic activities of daily living that require focused attention; their perceived difficulties in directing attention on daily tasks, as well as their perceptions of their ability to interact in a deliberate manner that depends on selective attention.³¹ While controversy exists on whether subjective and/or objective measures should be used to evaluate CRCI, in a recent functional MRI study, that evaluated patients with breast cancer undergoing CTX,⁵¹ decreases in AFI scores paralleled disruptions in resting-state blood oxygen level dependent (BOLD) functional connectivity in parietal and frontal brain regions. To confirm the previous observations that chronic stress effects the functioning of the PFC,¹⁴ future studies of CRCI should include both subjective and objective measures of cognitive function as well as multidimensional measures of stress.

While all three latent classes reported total sleep disturbance scores above the clinically meaningful cutoff, patients in the Stressed class had scores that represent an extremely high level of sleep disturbance that is comparable to scores reported by shift workers (i.e., 60.5)³³ and parents of newborn infants (55.5).³⁸ In terms of the GSDS subscale scores, the high levels of mid-sleep and early awakenings suggest that all three classes have problems with sleep maintenance. Of note, for patients in the Stressed class, all of the GSDS subscale scores were above the clinically meaningful cutoff of >3 days per week. In particular, their score of 3.6 (+2.3) on the sleep onset latency subscale suggests that these patients have problems with both sleep initiation and maintenance. Our findings are consistent with the preclinical and human studies of the negative impact of stress on sleep.^10,11

Previous research from our group demonstrated that morning and evening fatigue are distinct but related symptoms.^23,52,53 Based on the scores reported by our Stressed class, high levels of general and disease specific stress, as well as cumulative life stress are associated with clinically meaningful levels of both morning and evening fatigue. While lack of energy and fatigue are used interchangeably in the symptom literature, a growing body of evidence suggests that energy and fatigue are distinct but related symptoms.^54–56 While no studies have evaluated for associations between decrements in energy levels and stress, our Stressed class reported clinically meaningful decrements in both morning and evening energy levels and the other two classes reported morning energy levels that were well below the clinically meaningful cutoff of ≤6.2. These findings may be related to the relatively high levels of sleep disturbance in all three classes and warrant confirmation in future studies.

Consistent with our a priori hypothesis, patients in the Stressed class reported the highest level of symptom burden. Of note, the patients in this subgroup (i.e., 40% of the sample) reported clinically meaningful levels of all four of these co-occurring symptom. This extremely high risk group was younger, more likely to be female, had a lower socioeconomic status, was not married or partnered, was more likely to live alone, had a poorer functional status, and a worse comorbidity profile (see Supplementary Table 2).¹⁸ These high risk patients warrant ongoing assessments of both stress and symptom burden.

While this study has several limitations, it provides directions for future research. While the sample was heterogeneous in terms of cancer types and CTX regimens, it was fairly homogenous in terms of gender, educational level, and ethnicity. In addition, this study focused on associations between stress and physical symptoms in oncology patients, future studies need to examine the relationships between stress profiles and anxiety and depressive symptoms. Given that the stress measures were done only once, changes in the severity of stress and symptoms could not be evaluated. Future longitudinal studies, that use analytic techniques like parallel process growth modeling,⁵⁷ will be able to discern the causal relationships between stress and symptom burden. While recent investigations in symptoms science are focused on an evaluation of multiple co-occurring symptoms and symptom clusters in oncology patients and patients with other chronic conditions,^58,59 as noted in the introduction to this paper, the limited amount of research has focused on an examination of the relationships between stress and single symptoms. Given the findings from this study, careful consideration should be given to an evaluation of not only general, disease-specific, and cumulative life stress but multiple co-occurring symptoms in patients with cancer and other chronic conditions. These types of studies that include both subjective and objective measures, as well as biomarkers will increase our knowledge of the fundamental mechanisms that underlie the relationships between stress and symptoms.

Supplementary Material