Oncology Outpatients with Worse Anxiety AND Sleep Disturbance Profiles Are at Increased Risk for a Higher Symptom Burden and Poorer Quality of Life

Patients and Settings

This study is part of a larger, longitudinal study of the symptom experience of oncology outpatients receiving chemotherapy²³ that was guided by the Theory of Symptom Management.²⁴ Briefly, patients were ≥18 years of age; had a diagnosis of breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding four weeks; were scheduled to receive at least two additional cycles of chemotherapy; were able to read, write, and understand English; and provided written informed consent. Patients were recruited from two comprehensive Cancer Centers, one Veteran's Affairs hospital, and four community-based oncology programs.

Study Procedures

The study was approved by the Institutional Review Board at each of the study sites. Of the 2234 patients approached, 1343 (60.1%) consented to participate. The major reason for refusal was being too overwhelmed with their cancer treatments. These patients completed questionnaires, a total of six times over two chemotherapy cycles (i.e., prior to chemotherapy administration, approximately 1 week after chemotherapy administration, and approximately 2 weeks after chemotherapy administration). A total of 1331 patients who had complete data on both the anxiety and sleep disturbance measures were included in this analysis.

Instruments

Data Analysis

LPA was used to identify subgroups of patients with distinct anxiety AND sleep disturbance profiles. Using Mplus version 8.4,⁴⁰ this LPA was done with the combined set of variables over time (i.e., using the STAI-S AND GSDS total scores obtained during the six assessments in a single LPA). This approach provides a profile description of these two symptoms with parallel profiles over time.

In order to incorporate expected correlations among the repeated measures of the same variable and cross-correlations of the series of the two variables (i.e., STAI-S and GSDS total scores), we included covariance parameters among measures at the same occasion and those that were one or two occasions apart. Covariances of each variable with the other at the same assessments were included in the model and autoregressive covariances were estimated with a lag of two with the same measures and with a lag of one for each variable’s series with the other variable. We limited the covariance structure to a lag of two to accommodate the expected reduction in the correlations that would be introduced by two chemotherapy cycles within each set of three measurement occasions and to reduce model complexity.⁴¹

Estimation was carried out with full information maximum likelihood with standard errors and a chi-square test that are robust to non-normality and non-independence of observations (“estimator=MLR”). Model fit was evaluated to identify the solution that best characterized the observed latent class structure with the Bayesian Information Criterion,⁴² Vuong-Lo-Mendell-Rubin likelihood ratio test (VLRM), entropy, and latent class percentages that were large enough to be reliable.⁴³ Missing data were accommodated for with the use of the Expectation-Maximization (EM) algorithm.⁴⁴

Data were analyzed using SPSS version 27 (IBM Corporation, Armonk, NY). Differences among the anxiety AND sleep disturbance classes in demographic, clinical, and symptom characteristics, and QOL outcomes at enrollment were evaluated using parametric and nonparametric tests. Bonferroni corrected p-value of <0.017 was considered statistically significant for the pairwise contrasts (i.e., 0.05/3 possible pairwise contrasts).

Latent profile analysis

A three-class solution was selected because the BIC for that solution was lower than the BIC for the 2-class solution. In addition, the VLMR was significant for the 3-class solution, indicating that three classes fit the data better than two classes. Although the BIC was smaller for the 4-class than for the 3-class solution, the VLMR was not significant for the 4-class solution, indicating that too many classes were extracted (Table 1).

Based on clinically meaningful cutoff scores,^{29, 33} as shown in Figure 1, the state anxiety AND sleep disturbance latent classes were classified as “no anxiety and low sleep disturbance” (59.7%, No ANX+Low SD); “moderate anxiety and high sleep disturbance” (32.5%, Mod ANX+High SD); and “high anxiety and very high sleep disturbance” (7.8%, High ANX+Very High SD). For the No ANX+Low SD and the Mod ANX+High SD classes, state anxiety and sleep disturbance scores increased slightly at the second and fifth assessments (i.e., following the administration of chemotherapy). For the High ANX+Very High SD class, state anxiety and sleep disturbance scores increased at the second assessment and remained relatively stable over time.

Differences in demographic and clinical characteristics

Compared to the No ANX+Low SD class, the other two classes were significantly younger; more likely to self-report being of Hispanic or Mixed ethnicity; less likely to be married or partnered; had a lower annual household income; were more likely to report childcare responsibilities; and more likely to receive an antiemetic regimen that contained a neurokin-1 (NK-1) receptor antagonist and two other antiemetics (Table 2). Compared to the No ANX+Low SD class, the Mod ANX+High SD class was more likely to be female; more likely to live alone; less likely to be employed; more likely to report elder care responsibilities; and had a higher MAX2 score.

Compared to the No ANX+Low SD class, the High ANX+Very High SD class was less likely to exercise on a regular basis and more likely to self-report diagnoses of ulcer or stomach disease, kidney disease, and anemia or blood disease. In addition, significant differences were found among the three classes in KPS scores (i.e., No ANX+Low SD > Mod ANX+High SD > High ANX+Very High SD), as well as total number of comorbid conditions, SCQ scores, and self-reported diagnoses of depression and back pain that followed the same pattern (i.e., No ANX+Low SD < Mod ANX+High SD < High ANX+Very High SD; Table 2).

Differences in sleep disturbance subscale scores

For the sleep quality, sleep onset latency, early awakenings, excessive daytime sleepiness subscale scores as well as for the total GSDS score, significant differences among the three latent classes followed the same pattern (i.e., No ANX+Low SD < Mod ANX+High SD < High ANX+Very High SD; Table 3). Compared to the No ANX+Low SD class, patients in the other two classes reported higher scores for sleep quantity (i.e., fewer hours of sleep), mid-sleep awakenings, and use of medications for sleep.

Differences in common symptoms

As shown in Table 4, for depressive symptoms, trait and state anxiety, morning and evening fatigue, and pain interference scores, differences among the latent classes followed the same pattern (i.e., No ANX+Low SD < Mod ANX+High SD < High ANX+Very High SD). In terms of morning and evening energy and cognitive function scores, differences among the latent classes followed the same pattern (i.e., No ANX+Low SD > Mod ANX+High SD > High ANX+Very High SD). Compared to the No ANX+Low SD class, a higher percentage of patients in the other two classes reported the occurrence of both cancer and non-cancer pain and higher worst pain intensity scores.

Differences in QOL

As shown in Figure 2, for the SF-12’s role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, and MCS scores, differences among the classes followed the same pattern (i.e., No ANX+Low SD > Mod ANX+High SD > High ANX+Very High SD). For the physical functioning and PCS scores, compared to the No ANX+Low SD class, patients in the other two classes reported lower scores.

For the QOL-PV’s physical well-being, psychological well-being, social well-being, and spiritual well-being subscale scores as well as for the total QOL scores, differences among the classes followed the same pattern (i.e., No ANX+Low SD > Mod ANX+High SD > High ANX+Very High SD; Figure 3).

Sleep disturbance characteristics

As shown in Table 3, all of our patients had a total GSDS score that was above the clinically meaningful cutoff (i.e., ≥43.0) across all six assessments. In terms of its clinical context, the scores for our two highest classes are comparable to those reported by permanent shift workers (i.e., 60.5)³¹ and mothers of newborn infants (i.e., 55.5).⁵⁵ In addition, the total GSDS scores for these two highest classes are higher than patients undergoing radiation therapy (i.e., 44.3 (breast cancer),⁵⁶ 34.5 (prostate cancer)⁵⁶) or cancer surgery (i.e., 48.1 (breast cancer),⁵⁷ 56.2 (lung cancer)⁵⁸). It is possible that differences among the patients with types of cancers and/or treatments may be related to the presence of a sleep disturbance prior to study enrollment; the timing of the sleep disturbance assessments; or the use of sleep medications. In addition, it is possible that different cancer treatments may have differential effects on the magnitude of inflammatory processes and associated symptom burden.

All three latent classes reported insufficient quantity of sleep and problems with sleep maintenance (i.e., mid-sleep awakenings, early awakenings). However, patients in the two highest classes also reported poorer quality of sleep, difficulty initiating sleep (i.e., sleep onset latency) and excessive daytime sleepiness for more than 4 days per week which suggests problems with both initiation and maintenance of sleep. These findings are consistent with a review that reported that even with low levels of anxiety, sleep disturbance was a common problem in oncology patients.⁵⁹ Given that sleep disturbance tends to persist for long periods of time,⁶⁰ clinicians need to conduct routine assessments of sleep disturbance and educate patients to use appropriate sleep management interventions (e.g., scheduled bed and wake times).

Demographic and clinical characteristics

Table 5 summarizes the risk factors associated with the two highest anxiety and sleep disturbance profiles. Compared to the No ANX+Low SD class, several common risk factors were associated with membership in the other two classes, namely: younger age, more likely to self-report being of Hispanic or Mixed ethnicity, less likely to be married or partnered, more likely to have lower annual household income, and more likely to have child care responsibilities. In terms of age, while in some studies no association was found between age and anxiety⁵ and age and sleep disturbance,²² others found that younger oncology patients reported higher levels of anxiety⁶¹ and sleep disturbance.⁶² Given that younger patients tend to develop more aggressive types of cancers that warrant more aggressive treatments,^{63, 64} they may have higher levels of anxiety and sleep disturbance because of concerns about changes in their physical appearance, fertility), and survival.⁶¹ In addition, a cancer diagnosis at a younger age can be more stressful because these patients may be trying to establish themselves professionally or be raising young children, which would have a significant impact on their physical and mental health.⁶⁵

Several lines of evidence support our profile associations with marital status, child care responsibilities and income. For example, in one study,⁶⁶ support during chemotherapy, particularly in relationship to child care, was provided by the patient’s intimate partner. The lack of adequate support at home with activities of daily living, not only places increased demands on the patient, but may contribute to a lower socioeconomic status because of loss of work productivity during the treatment.^67-69 Increased stress, lack of support, and financial hardship associated with inability to work may exacerbate anxiety and sleep disturbance.^{20, 68, 70} Additional research that incorporates measures of social support, as well as other social determinants of health, is needed to confirm our findings and determine more definitive associations.

In terms of clinical characteristics, compared to the No ANX+Low SD class, membership in the other two classes was associated with a higher overall comorbidity burden, lower functional status, self-reported diagnoses of depression and back pain, and receiving an antiemetic regimen containing a neurokin-1 (NK-1) receptor antagonist in combination with other two antiemetics. Our findings are consistent with previous studies of oncology patients that found that a higher comorbidity burden and a poorer functional status increase the likelihood of anxiety^71-73 and sleep disturbance.⁷⁴ Given the bi-directional relationships between depression, anxiety, and sleep disturbance,^{5, 75} it is not surprising that patients with higher levels of anxiety and sleep disturbance self-reported a diagnosis of depression, because several factors (e.g., genetic, social, environmental)^75-77 and common inflammatory and neurobiological pathways⁷⁵ may be involved in the development of all three symptoms during chemotherapy. In addition, while not evaluated in patients undergoing chemotherapy specifically, back pain was found to be prevalent in oncology patients and was associated with anxiety and sleep disturbance experienced during various cancer treatments (e.g., chemotherapy, surgery).⁷⁸ Since higher comorbidity burden and lower functional status are associated with higher levels of anxiety and sleep disturbance during chemotherapy, clinicians need to remain vigilant and conduct routine assessments, particularly in patients with higher number of comorbidities.

Common symptoms

In terms of the differences in the severity of common symptoms, significant differences were found among the latent classes, in a stepwise fashion, in depressive symptoms, trait and state anxiety, morning and evening fatigue, as well as decrements in morning and evening energy and cognitive function, suggesting additive or synergistic effects (Table 4). Of note, while all three classes had morning energy scores below the clinically meaningful cutoff score (i.e., ≤6.2), for the two higher symptom profiles, all of the other symptom scores were above the clinically meaningful cutoff. Emerging evidence suggests that some of these symptoms occur in clusters during chemotherapy⁷ because they may share common biological mechanisms.^{79, 80} Additional research is warranted to evaluate the causal relationships among the most common symptoms associated with cancer and its treatments and the co-occurrence of anxiety AND sleep disturbance.

Consistent with prior reports that found that patients with higher levels of pain were more likely to experience anxiety^{81, 82} and sleep disturbance,⁸³ compared with the 22.9% of patients No ANX+Low SD class, 39.6% and 50.5% of the patients in the Mod ANX+High SD and High ANX+Very High SD classes, respectively, reported both cancer and non-cancer pain. In addition, the patients in these highest two classes had moderate to severe pain and pain interference. These findings are not surprising given that pain is one of the most prevalent and burdensome symptoms reported by oncology patients^{84, 85} and is often undertreated.^{83, 86} For example, in one study,⁸⁶ uncontrolled cancer pain was found to be a risk factor for higher levels of state anxiety. In another study that examined the relationship between anxiety and pain,⁸¹ patients with pain were 4.44 more likely to report anxiety than patients without pain. A similar pattern is noted for sleep disturbance. In a study that evaluated factors that affect sleep in cancer patients,⁸⁷ undertreatment of pain was found to be an important risk factor of poor sleep quality, daytime tiredness, and problems with initiation and maintenance of sleep. Given that information on the specific causes of pain were not obtained in this study, additional research is warranted on the effects of acute and chronic pain on the co-occurrence of anxiety and sleep disturbance.

QOL outcomes

Consistent with prior studies that reported associations between anxiety and sleep disturbance as single symptoms decrements in QOL in both oncology patients^{88, 89} and general populations,^{90, 91} for all of the general and disease-specific QOL domains, as the anxiety and sleep disturbance profiles worsened, all aspects of QOL were impacted. Of note, for both the PCS and MCS scores, patients with the two worst profiles, reported scores of less than 50, which is lower than the normative score for the general population.³⁹ Furthermore, compared with the No ANX+Low SD class, all of the differences across the various domains of QOL in the High ANX+Very High SD class represent not only statistically significant but clinically meaningful differences (d = 0.52–2.74). Our findings can be partially explained by the fact that patients undergoing chemotherapy often experience multiple co-occurring symptoms that affect all aspects of their daily life.