Fatigue is a highly prevalent symptom for patients during chemotherapy (CTX).1 Although work by our team demonstrated that morning fatigue is distinct from evening fatigue,2–6 research on morning fatigue is limited. Newer analytic techniques, such as latent profile analysis (LPA), can facilitate the identification of patients at a higher risk for more severe symptoms.
Techniques such as LPA group individuals into classes with similar outwardly unobservable characteristics.7 Only 3 studies were identified that used this approach to identify groups of patients with distinct fatigue profiles.3,8,9 In the 2 studies that evaluated average fatigue scores in patients with breast cancer before surgery and after CTX or radiation therapy,8,9 2 latent classes (ie, higher and lower fatigue) were identified. It is difficult to compare findings across these studies because the measures of fatigue and timing of assessments differed. Neither study examined diurnal variations in fatigue severity.
In the third study,3 we identified 3 distinct morning fatigue profiles (ie, low, high, and very high). Compared with those in the low class, patients in the very high class were more likely to be younger and female and to have a higher body mass index (BMI) and less likely to be married/partnered or to exercise regularly. In addition, they had a lower annual income, a lower functional status, and a worse comorbidity profile. To develop targeted interventions for patients who are at risk for higher levels of morning fatigue, additional studies are needed to refine these profiles. Therefore, the purposes of this study, using a larger sample (n = 1332), were to evaluate for subgroups of patients with distinct morning fatigue profiles; evaluate how these subgroups differed on demographic, clinical, and symptom characteristics; and confirm our previous morning fatigue LPA findings.3
Patients and Settings
Methods for this study were published previously.3,4,10 In brief, patients were diagnosed with breast, gastrointestinal, gynecological, or lung cancer; had received CTX within the preceding month; were scheduled for 2 additional CTX cycles; were adults (≥18 years old); could read, write, and understand English; and gave written informed consent. Patients were recruited from 7 outpatient settings.
Information was obtained on various demographic characteristics. The Alcohol Use Disorders Identification Test was used to assess alcohol consumption. Scores of 8 or higher are defined as hazardous use, and scores of 16 of 40 or higher are defined as use of alcohol that is likely to be harmful to health. The Alcohol Use Disorders Identification Test has well-established validity and reliability in the general population.11 In our study, its Cronbach's α was .63.
Functional status was evaluated using the Karnofsky Performance Status (KPS) scale.12 For the Self-Administered Comorbidity Questionnaire (SCQ), patients indicated whether they had 13 common medical conditions, whether they received treatment of any of them, and whether each condition limited their activities. The total SCQ score ranges from 0 to 39. The SCQ has well-established validity and reliability in inpatient populations.13
Fatigue was evaluated using the Lee Fatigue Scale (LFS). Each of the 18 items was rated on a 0 to 10 numeric rating scale. Total fatigue and energy scores were calculated as the mean of the 13 fatigue items and the 5 energy items, respectively. Higher scores indicate greater fatigue severity and higher levels of energy. Using a separate LFS, patients rated each item based on how they felt within 30 minutes of awakening (ie, morning fatigue, morning energy) and before going to bed (ie, evening fatigue, evening energy). The LFS has established cutoff scores for clinically meaningful levels of fatigue (ie, ≥3.2 for morning fatigue, ≥5.6 for evening fatigue) and energy (ie, ≤6.2 for morning energy, ≤3.5 for evening energy). The LFS has well-established validity and reliability in the general population.14 In our study, the Cronbach's αs were .96 for morning fatigue, .93 for evening fatigue, .95 for morning energy, and .93 for evening energy.
Trait and state anxiety were measured using Spielberger State-Trait Anxiety Inventories (STAI-S and STAI-T). Total scores range from 20 to 80. Cutoff scores of 31.8 or higher and 32.2 or higher indicate high levels of trait and state anxiety, respectively. The STAI-T and STAI-S have well-established validity and reliability in the general population.15 In our study, the Cronbach's αs for the STAI-T and STAI-S were .92 and .96, respectively.
Depressive symptoms were evaluated using the Center for Epidemiological Studies-Depression (CES-D) scale. The total CES-D score ranges from 0 to 60. Scores of 16 or higher indicate the need for individuals to seek clinical evaluation for major depression. The CES-D scale has well-established validity and reliability in the general population.16 In our study, its Cronbach's α was .89.
Sleep disturbance was evaluated using the General Sleep Disturbance Scale (GSDS), which assesses the quality of sleep in the past week. Each item was rated on a 0 (never) to 7 (everyday) numeric rating scale. A total GSDS score of 43 or higher indicates a significant level of sleep disturbance.17 The GSDS has well-established validity and reliability in the general population.17 In our study, its Cronbach's α was .83.
Changes in cognitive function were evaluated using the Attentional Function Index (AFI). Higher total mean AFI scores indicate greater capacity to direct attention. Total scores are grouped into 3 categories of attentional function (ie, <5.0, low function; 5.0-7.5, moderate function; and >7.5, high function). The AFI has well-established reliability and validity in oncology patients.18 In our study, its Cronbach's α was .93.
The Brief Pain Inventory was used to assess the occurrence of pain.19 Patients who indicated that they had pain were asked whether their pain was or was not related to their cancer treatment.
The Committees on Human Research at the University of California, San Francisco, and at each of the study sites approved the study. Patients were approached in the infusion unit by a research staff member to discuss participation in the study. Written informed consent was obtained from all patients. Depending on their CTX cycle length, patients completed the various questionnaires in their homes, a total of 6 times over 2 cycles of CTX (ie, before CTX administration, approximately 1 week after CTX administration, approximately 2 weeks after CTX administration).
SPSS version 23 (Armonk, New York) was used to calculate descriptive statistics for the sample characteristics. Latent profile analysis was used to identify subgroups of patients with distinct morning fatigue profiles. Estimation was carried out with full information maximum likelihood with standard errors and a χ2 test that are robust to nonnormality and nonindependence of observations. The Akaike Information Criteria, Bayesian Information Criterion, and entropy values were used to determine the best fitting model. Vuong-Lo-Mendell-Rubin likelihood ratio test was used to compare the models. With the Vuong-Lo-Mendell-Rubin likelihood ratio test, a significant P value suggests that 1 estimated model fits the data better than another model with only fewer groups.20 The LPA was conducted using Mplus version 7.2 (Muthen & Muthen, Los Angeles, California) with 1000 to 2400 random starts.
Differences in demographic and clinical characteristics among the latent classes were evaluated using parametric and nonparametric tests with Bonferroni-corrected post hoc contrasts. A P < .05 was considered statistically significant.
Latent Class Analysis
On the basis of the fit indices, a 4-class solution was selected (Table 1). Morning fatigue classes were labeled as very low, low, high, and very high based on the morning LFS cutoff score of 3.2 or higher. The trajectories of morning fatigue differed among the latent classes (Figure). For the very low (19.6%) and very high (10.6%) classes, morning fatigue scores remained relatively stable across the 6 assessments. For the low (30.2%) and high (39.6%) classes, morning fatigue scores exhibited a distinct increase at the second and fifth assessments.
Demographic and Clinical Characteristics
For most of the demographic and clinical characteristics, no differences were found among the latent classes (Table 2). Compared with those in the very low and low classes, patients in the very high class were more likely to be younger and not married/partnered, live alone, and have lower incomes, a higher number of comorbidities, a higher SCQ score, and a higher BMI and were less likely to exercise regularly. Compared with those in the very low class, patients in the very high class were more likely to be female. Compared with those in the low class, a higher percentage of patients in the very high class were more likely to be unemployed. Compared with those in the very low class, patients in the high class were more likely to be diagnosed with breast cancer. Across the 4 classes, as morning fatigue severity increased, KPS scores decreased (ie, very low > low > high > very high for KPS scores) and the occurrence of depression increased (ie, very low < low < high < very high). Patients in the very high class were more likely to report anemia than patients in the low and very low classes.
Symptom Characteristics at Enrollment
For the trait anxiety, state anxiety, depression, sleep disturbance, morning fatigue, and evening fatigue scores, significant differences were found among the latent classes (ie, very low < low < high < very high; Table 3). Attentional function scores were significantly different among the 4 classes (ie, very low > low > high > very high). For morning energy, patients in the very low class had higher scores than those in the other 3 classes and patients in the low class had higher scores than those in the high and very high classes. For evening energy, compared with patients in the other 3 classes, patients in the very high class had lower scores. Compared with those in the very low and low classes, a higher percentage of patients in the high and very high classes reported both cancer and noncancer pain.
This study extends our previous work on the identification of distinct morning fatigue profiles in oncology patients. Whereas, in our previous study,3 3 morning fatigue profiles were identified, in this study, with the addition of 750 patients, 4 profiles were found. In this study, a very low class was identified using the clinically meaningful cutoff score for morning fatigue. Compared with the low class in the previous study who had a mean enrollment LFS score of 1.3,3 the LFS score for the very low class in this study was 0.9. This clinically meaningful difference (d = 0.77) in LFS scores21 supported the identification of a fourth latent class and the refinement of the morning fatigue phenotype. In the high and very high classes, which included 50.2% of our sample, morning fatigue scores were higher than the LFS clinically meaningful cutoff score (ie, ≥3.2) across all 6 assessments. The high prevalence of morning fatigue suggests that clinicians need to assess for diurnal variations in fatigue severity.
Modifiable Risk Factors
One of our goals was to identify modifiable characteristics associated with more severe morning fatigue. On the basis of our previous3 and current LPAs and hierarchical linear modeling (HLM) analyses,4 the phenotypic characteristics associated with higher morning fatigue scores and membership in the very high morning fatigue classes are summarized in Table 4. The remainder of the discussion describes these phenotypic characteristics within the context of the literature on morning fatigue.
Consistent with our previous studies,3,4 younger age and being female were associated with higher levels of morning fatigue. Across other studies, younger patients reported higher average fatigue severity scores.22 “Response shifts,”23 age-related changes in inflammatory responses,24 and different treatment regimens25 may explain this association. It is difficult to determine whether gender is an independent predictor of higher levels of morning fatigue because this association may be confounded by the high percentage of patients with female cancers enrolled in our study.
In contrast to our HLM findings,4 in this LPA, living alone, marital/partnership status, income level, and employment status were associated with a worse morning fatigue profile. Consistent with previous findings,26 patients in the very high class were less likely to be employed than patients in the low class and more likely to have higher incomes than patients in the other 3 classes. Higher incomes may mitigate the financial burden of cancer treatment and its negative impact on patients' symptom burden.27 Consistent with previous findings,26 patients in the very high morning fatigue class were more likely not to be married/partnered and to be living alone. Although these demographic characteristics are not easily modified, knowledge of these risk factors can be used to guide appropriate referrals.
Consistent with our previous findings,3,4 lack of regular exercise was associated with membership in the very high morning fatigue class. Although exercise is the only effective intervention to decrease fatigue,28 no studies have evaluated the efficacy of exercise for morning fatigue. An emerging area of research is an evaluation of the association between an individual's chronobiology and his/her physical activity preferences.29 Of note, when CTX was administered based on chronotype (classified as a “morning” or “evening” person), treatment efficacy increased and symptoms decreased.30 Future studies should evaluate for associations between patients' chronotype, preferences for exercise, and fatigue severity.
For both our HLM analysis4 and the current LPA, a higher BMI was associated with membership in the very high morning fatigue class. Patients in the very high class had an average BMI of 27.6 that is in the “overweight” range. Higher BMIs are associated with inflammation and may contribute to the inflammatory processes associated with morning fatigue.24 As a modifiable risk factor, clinicians need to recommend weight loss and exercise programs to oncology patients to decrease fatigue and improve overall health status.
Consistent with our previous studies,3,4 as well as other reports that evaluated average fatigue,31,32 lower functional status was associated with higher levels of morning fatigue. Compared with the very low class, the differences in KPS scores for the other 3 classes were not only statistically significant but also clinically meaningful (ie, d = 0.3 [vs. low], d = 0.8 [vs. high], and d = 1.0 [vs. very high]). Fatigue and physical function may be related through shared risk factors and/or common underlying mechanisms. Additional research is needed to elucidate these relationships.
Consistent with our previous LPA,3 compared with those in the very low and low classes, patients in the very high class had a higher comorbidity burden. Although associations were found between a higher comorbidity burden and increased fatigue,33 whether or not each chronic condition contributes incrementally or synergistically to increases in fatigue severity warrants investigation in future studies.
In contrast to our previous work in oncology patients receiving CTX,3,4,10 specific comorbidities, hemoglobin, and hematocrit levels were associated with membership in the higher morning fatigue classes. Compared with those in the very low and low classes, patients in the very high class were more likely to self-report a diagnosis of anemia or blood disease. Whereas the hemoglobin and hematocrit levels were similar among the 3 highest fatigue classes, significantly lower values were found between the low and high classes compared with the very low class. Failure to identify a significant difference for the very high class may be related to the relatively small sample size for this class. In patients undergoing CTX, anemia is defined as a hemoglobin level of less than 12 g/dL in both men and women.34 Although, across the 4 classes, the average hemoglobin levels were less than 12 g/dL, the differences among the classes are not clinically meaningfully. Because findings regarding the association between anemia and fatigue severity are inconsistent,35 future studies of the molecular mechanisms of fatigue may provide insights into these associations.
Patients with breast cancer were more likely to be in the low and high classes than in the very low class. In contrast, compared with the other 3 classes, patients with gastrointestinal cancer were more likely to be in the very low class. However, the number and types of previous cancer treatments and CTX cycle length were not associated with latent class membership. The associations among cancer diagnoses, treatment regimens, and fatigue severity warrant additional investigation.
This study is the first to demonstrate that, for every symptom except energy and pain, statistically significant differences were found among the 4 latent classes in the most common symptoms experienced by oncology patients. Of note, for the high and very high fatigue classes, except for depression, all of the symptom severity scores were higher than the clinically meaningful cutoff scores. For depression, patients in the high class had CES-D scores that indicate subsyndromal depression16 and patients in the very high class had scores that warrant evaluation for clinically significant depression.
Although morning fatigue is considered a diagnostic criterion for depression, limited evidence exists to support a causal association or interdependence between these 2 symptoms. In 1 study,36 higher levels of average fatigue were associated with increased evening cortisol levels and increased overall cortisol secretion but not with morning cortisol levels, independent of depression. Evaluation of distinct underlying mechanisms may provide insights into the co-occurrence of these 2 symptoms.
Consistent with our HLM analysis4 and our other studies of fatigue,37,38 higher levels of anxiety and sleep disturbance were associated with higher levels of morning fatigue. The co-occurrence of these symptoms during CTX is well documented.39 One possible explanation for the co-occurrence of these symptoms is that they are associated with alterations in circadian rhythms.40 On the basis this evidence, clinicians can recommend individualized sleep promotion plans to regulate circadian rhythms and improve sleep disturbance.41
An assessment of attentional function evaluates patients' executive function, not physical fatigue.18 In our patients, higher levels of morning fatigue were associated with lower levels of attentional function. Compared with the very low class, the differences in AFI scores of patients in the other 3 classes were not only statistically significant but also clinically meaningful (ie, d = 0.6 [vs. low], d = 1.0 [vs. high], and d = 2.0 [vs. very high]. This finding is consistent with previous studies that found that increases in physical fatigue were associated with decrements in cognitive function.42,43 Inflammatory processes triggered by CTX44 and/or dysregulation in cortisol rhythm or the hypothalamic-pituitary-adrenal axis36 are hypothesized mechanisms for these 2 co-occurring symptoms. However, research is needed to understand the bidirectional associations between decrements in attentional function and morning fatigue.
In terms of energy, only the high and very high classes had clinically meaningful decrements in evening energy levels, with the very low and low classes' evening energy levels at or lower than the clinical cutoff score. In contrast, morning energy levels were well less than the cutoff score for all 4 latent classes. Often considered the opposite of fatigue, energy is defined as a person's potential to perform physical and mental activities.45 In contrast, fatigue is a distressing and persistent sense of physical tiredness not related to physical activity.1 Direct comparisons of our findings are not possible because no studies have evaluated morning and evening energy levels and morning fatigue in oncology patients during CTX. However, we found that decrements in morning and evening energy were associated with worse functional status and higher levels of sleep disturbance46,47 and had distinct molecular mechanisms.48 Future studies need to evaluate for associations among these 3 common co-occurring symptoms and their common and distinct molecular mechanisms.
Although not found in our HLM analysis,4 in this LPA, having cancer or noncancer pain was associated with membership in the high and very high morning fatigue classes. No studies have examined the association between pain and morning fatigue in oncology patients. Although the exact causes of pain in our patients are not known, pain, fatigue, and sleep disturbance are common co-occurring symptoms during CTX.49,50 Pain disrupts patients' sleep, decreases their ability to engage in physical activity, and increases fatigue. Pharmacologic treatments of pain may increase the severity of fatigue and sleep disturbance.
Limitations and Conclusions
Several limitations warrant consideration. Because patients were recruited at various time points during their CTX, risk profiles for morning fatigue from the initiation of CTX through its completion were not evaluated. Although patients did not report the exact time that they completed the morning fatigue questionnaire, their ratings of morning fatigue were lower than evening fatigue. This finding supports the ecologic validity of the diurnal measurements. The findings related to exercise and pain need to be interpreted with caution given the limited amount of information collected on these 2 characteristics. However, this large representative sample of oncology patients with diverse diagnoses, the assessments of morning fatigue over 2 cycles of CTX, and the statistical approaches used to identify the latent classes are major strengths of this study.
Implications for Practice
This study increases our understanding of modifiable risk factors associated with distinct morning fatigue profiles. Patients in the high and very high morning fatigue classes experienced high symptom and comorbidity burdens and significant decrements in functional status. Using this information, clinicians can identify patients who are at an increased risk for higher levels of morning fatigue and prescribe interventions to improve this devastating symptom. Additional research is warranted to evaluate for differences among these morning fatigue profiles based on a variety of psychosocial characteristics (eg, resilience, coping) and genomic markers.
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