Cancer treatments and their side effects are associated with aggravation of insomnia: Results of a longitudinal study
We wish to acknowledge the important contribution of Julie Villa, Aude Caplette-Gingras, Marie-Solange Bernatchez, Valérie Tremblay, Lucie Casault, Caroline Desautels, Geneviéve Dumont, Dave Flanagan, Nathalie Gagnon, Catherine Gonthier, Geneviève Laurent, Marie-Eve Le May, Julie Maheux, Marie-Esther Paradis, Sylvie Perron, Julie Roy, Sophie Ruel, Elaine Thériault, Claudia Trudel-Fitzgerald, and Maude Villeneuve who were involved in the recruitment and assessment of the participants or the data entry and the study coordination, as well as the participants who volunteered their time for this study.
Abstract
BACKGROUND
Insomnia affects between 30% to 60% of patients with cancer but to the authors' knowledge little is known regarding factors associated with its development. It has been postulated that adjuvant cancer treatments and their side effects could trigger sleep disturbances in this population but empirical evidence is lacking. The goal of the current study was to assess, separately in patients with breast and prostate cancer, the effect of adjuvant treatments on the evolution of insomnia symptoms and the mediating role of somatic symptoms.
METHODS
As part of a population-based epidemiological study, patients with breast cancer (465 patients) and prostate cancer (263 patients) completed at baseline (perioperative period) and 2 months, 6 months, 10 months, 14 months, and 18 months later the Insomnia Severity Index (ISI) and a questionnaire assessing various somatic symptoms.
RESULTS
In patients with breast cancer, radiotherapy (overall effect) and chemotherapy (at 2 months), but not hormone therapy, were associated with increased insomnia severity, whereas androgen deprivation therapy was related to increased insomnia in patients with prostate cancer. In patients with breast cancer, the effect of chemotherapy and radiotherapy on insomnia was found to be significantly mediated by a variety of somatic symptoms, whereas night sweats had a particularly marked mediating role for hormone therapy, both in patients with breast and prostate cancer.
CONCLUSIONS
The findings of the current study indicate that cancer treatments and their side effects contribute to the aggravation of insomnia symptoms. Side effects of cancer treatments should be monitored more closely and managed as effectively as possible to prevent the occurrence or aggravation of insomnia. Cancer 2015;121:1703–1711. © 2015 American Cancer Society.
INTRODUCTION
Insomnia is a common problem in patients with cancer. Although insomnia is highly prevalent before any treatment is administered,1 longitudinal data suggest that there are factors occurring during the cancer care trajectory that trigger its development. A recent population-based epidemiological study revealed that insomnia affected up to 59% of patients during the perioperative period.2 However, 14.4% of patients had a first incidence and 19.5% had a recurrence of insomnia symptoms during the course of the study, for a total incidence rate of 31.8%.3
Although causes of insomnia comorbid with cancer are most likely multifaceted,4, 5 it has been postulated that adjuvant treatments play a significant role.6, 7 To the best of our knowledge, only a few longitudinal studies to date have focused on this issue. Although lack of an association has also been noted,8 receiving chemotherapy has been found to predict an increase in sleep disturbance during the cancer care trajectory.1, 9 Two studies of patients with breast cancer found that radiotherapy was associated with a temporary augmentation of sleep difficulties10, 11 and one study revealed that intensity-modulated radiotherapy for the treatment of nasopharyngeal cancer was associated with an increased rate of clinically significant sleep impairments.12 In patients with prostate cancer, the introduction of androgen deprivation therapy was found to be related to increased insomnia symptoms.13 Hence, it would appear that all 3 of these adjuvant treatments can increase the risk of insomnia, although studies disentangling their respective effects are lacking.
There are several plausible mechanisms through which cancer treatments could lead to sleep disturbances. Although other mechanisms are possible (eg, anticipatory anxiety, behavioral changes such as day napping that impair circadian rhythms, or chemotherapy-induced inflammation),4, 14-16 adjuvant treatments can also induce sleep disturbances through some of their negative side effects. Nocturnal hot flashes (due to chemotherapy and hormone therapy17), urinary incontinence (eg, due to radiotherapy to the urogenital area), and gastrointestinal symptoms (eg, chemotherapy-induced nausea) as well as pain (eg, associated with the use of aromatase inhibitors in both men and women16) are all very likely to negatively affect sleep quality.6, 7, 18 However, to our knowledge, very little research data are available to help delineate their role in precipitating insomnia comorbid with cancer.
The goals of this secondary analysis of a previous epidemiological study by Savard et al2, 3 were to assess, separately in individuals with breast and prostate cancer, 1) the effect of adjuvant treatments on the evolution of insomnia symptoms and 2) to what extent somatic symptoms mediated the relationship between adjuvant treatments and insomnia symptoms. It was hypothesized that all adjuvant treatments would be associated with increased insomnia through the mediating effect of somatic symptoms.
MATERIALS AND METHODS
Participants
Recruitment
Inclusion criteria for the main study were: 1) a first diagnosis of nonmetastatic cancer (a few patients with American Joint Committee on Cancer (AJCC) TNM staging system stage IV prostate cancer were included but they had no distant metastases); 2) patients were scheduled to undergo curative surgery; 3) patients were aged 18 to 80 years; and 4) patients were able to read and understand French. Exclusion criteria were: 1) the administration of neoadjuvant cancer treatment; 2) upcoming surgery was part of brachytherapy for prostate cancer; 3) presence of severe cognitive impairments (eg, Alzheimer disease) or severe psychiatric disorder (eg, psychosis); 4) presence of a sleep disorder other than insomnia (eg, sleep apnea); and 5) presence of severe visual, hearing, or language defects.
Participants were recruited at the CHU de Québec from January 2005 to May 2007. Patients meeting the initial inclusion criteria were approached by a research assistant on the day of their preoperative visit and eligible patients were invited to provide their written consent. The study was approved by the ethics review board of the study institution. Of the 3196 patients approached at the clinics, 1519 were excluded and 715 refused to participate in the study, thus giving a participation rate for the larger study of 57.4% (962 patients; for a detailed flowchart see the study by Savard et al3). For the purpose of the current analysis, only the 2 larger subgroups of patients could be included (ie, patients with breast cancer [465 patients] and prostate cancer [263 patients]) (Table 1).
| Breast Cancer n = 465 | Prostate Cancer n = 263 | |||
|---|---|---|---|---|
| Variable | Mean (SD) | No. (%) | Mean (SD) | No. (%) |
| Age, y | 54.9 (9.6) | 61.7 (6.4) | ||
| Sex (female) | 465 (100) | 0 (0.0) | ||
| Marital status | ||||
| Married/cohabitating | 286 (62.0) | 205 (78.5) | ||
| Single | 54 (11.7) | 13 (5.0) | ||
| Separated/divorced/widowed | 121 (26.3) | 43 (16.5) | ||
| Education | ||||
| Primary diploma or less | 24 (5.2) | 25 (9.7) | ||
| High school diploma | 192 (41.7) | 90 (35.0) | ||
| College degree | 120 (26.1) | 65 (25.3) | ||
| University degree | 124 (27.0) | 77 (30.0) | ||
| Annual family income (in Canadian dollars) | ||||
| <$20,000 | 72 (18.7) | 24 (10.4) | ||
| $20,001-$40,000 | 114 (29.6) | 75 (32.5) | ||
| $40,001-$60,000 | 73 (19.0) | 59 (25.5) | ||
| $60,001-$80,000 | 61 (15.8) | 33 (14.3) | ||
| ≥$80,001 | 65 (16.9) | 40 (17.3) | ||
| Current occupation | ||||
| Working (full/part time) | 201 (43.6) | 96 (36.9) | ||
| Family work | 32 (6.9) | 1 (0.4) | ||
| Sick leave | 79 (17.1) | 18 (6.9) | ||
| Retired | 138 (29.9) | 142 (54.6) | ||
| Unemployed | 11 (2.4) | 3 (1.2) | ||
| Time since initial diagnosis, mo | 1.6 (0.9) | 3.9 (2.7) | ||
| AJCC Cancer stage of disease | ||||
| 0 | 44 (9.5) | 0 (0.0) | ||
| I | 198 (42.6) | 2 (0.8) | ||
| II | 148 (31.8) | 160 (60.8) | ||
| III | 57 (12.3) | 83 (31.6) | ||
| IVa | 0 (0.0) | 18 (6.8) | ||
| Unspecified | 18 (3.9) | 0 (0.0) | ||
| Cancer treatments received during the studyb | ||||
| Radiotherapy | 367 (85.6) | 10 (4.2) | ||
| Chemotherapy | 232 (54.1) | 2 (0.8) | ||
| Hormone therapy | 309 (72.0) | 25 (10.4) | ||
| Other (eg, trastuzumab) | 37 (8.6) | 0 (0.0) | ||
| Type of chemotherapyc | ||||
| AC | 85 (36.6) | |||
| FEC plus docetaxel | 36 (15.5) | |||
| FEC | 35 (15.1) | |||
| AC plus paclitaxel plus gemcitabine | 14 (6.0) | |||
| AC plus docetaxel | 13 (5.6) | |||
| AC plus paclitaxel | 9 (3.9) | |||
| Other/not specified | 40 (17.2) | 2 (100.0) | ||
| Type of hormone therapyc, d | ||||
| Anastrozole | 148 (47.9) | 0 (0.0) | ||
| Tamoxifen | 146 (47.2) | 4 (16.0) | ||
| Letrozole | 28 (9.1) | 0 (0.0) | ||
| Exemestane | 9 (2.9) | 0 (0.0) | ||
| Bicalutamide | 0 (0.0) | 19 (76.0) | ||
| Goserelin | 3 (1.0) | 16 (64.0) | ||
| Leuprolide | 0 (0.0) | 3 (12.0) | ||
| Insomnia Severity Index | ||||
| Baseline | 10.3 (5.9) | 305 (66.2)e | 6.4 (5.6) | 96 (36.9) e |
| 2 mo | 9.7 (5.6) | 264 (62.6) | 7.0 (5.2) | 89 (38.7) |
| 6 mo | 8.5 (5.8) | 203 (51.0) | 5.9 (5.3) | 66 (29.0) |
| 10 mo | 7.7 (5.4) | 166 (43.1) | 5.4 (4.9) | 57 (26.4) |
| 14 mo | 7.3 (5.4) | 149 (40.6) | 5.8 (5.1) | 64 (30.9) |
| 18 mo | 7.0 (5.1) | 137 (38.8) | 5.3 (4.5) | 52 (25.2) |
- Abbreviations: AC, cyclophosphamide and doxorubicin; AJCC, American Joint Committee on Cancer; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; SD, standard deviation.
- a Patients with stage IV cancer did not have distant metastases.
- b Some patients did not receive any adjuvant treatment whereas others received >1 treatment during the study.
- c The percentages computed over the number of users.
- d Patients could have received >1 treatment.
- e The percentage of patients displaying a clinical level of insomnia (Insomnia Severity Index ≥8).
Study Design
This study used a prospective longitudinal design comprising 6 time points: baseline (perioperative phase; T1) and 2 months (T2), 6 months (T3), 10 months (T4), 14 months (T5), and 18 months (T6). Overall, 72.7% of the patients with breast cancer (338 patients) and 69.6% of patients with prostate cancer (183 patients) completed all 6 assessments (Mean (M) = 5.2).
Measures
Demographics, health behaviors, and cancer characteristics
Demographics, medical comorbidity, medication use, and health behaviors (smoking status, alcohol and caffeine use, and physical activity) were collected using a questionnaire. Cancer-related data (eg, cancer site and stage and adjuvant treatments received) were obtained from the patient's medical record.
Insomnia Severity Index
The Insomnia Severity Index (ISI)19 is a 7-item questionnaire evaluating insomnia severity (eg, difficulties falling asleep). Each item is rated using a 5-point Likert scale ranging from 0 (not at all) to 4 (very much), for a total score ranging from 0 to 28. The French-Canadian version of the ISI was validated in the context of cancer.20 A cutoff score of 8 was found to indicate the presence of clinical levels of insomnia.20
Physical Symptoms Questionnaire
The Physical Symptoms Questionnaire is adapted from the Memorial Symptom Assessment Scale21 and assesses 18 somatic symptoms commonly associated with cancer and its treatment. Only the frequency scores (from 0 indicating never to 4 indicating almost constantly) were analyzed. Symptoms had to meet the following criteria to be investigated as possible mediators: 1) be reported by ≥20% of the sample; 2) have a mean frequency >2 on the scale of 0 to 4; 3) ≥1 cancer treatment was found to be significantly associated with the symptom; and 4) the symptom exhibited at least a small association (beta >.10)22 with ISI scores. Seven symptoms were retained as possible mediators: headache (breast cancer), dyspnea (both), nausea (breast cancer), digestive problems (breast cancer), night sweats (both), pain (both), and 2 items related to urination (frequent and involuntary; r = 0.48), which were combined together (both).
Procedure
At each time point, participants were given a battery of self-report scales including the ISI and the Physical Symptoms Questionnaire that they had to complete within the next week and mail back. More details on the procedure are available elsewhere.2
Statistical Analyses
Descriptive and inferential statistics were conducted using SAS statistical software (version 9.3; SAS Institute Inc, Cary, NC).23 The alpha level was fixed at 5% (2-tailed) for all inferential tests. All participants with at least 1 available time point on the main outcome (ISI) were included in the analyses (728 participants) and no data imputation was performed because the chosen statistical models are robust to missing data. Several variables were investigated for a possible inclusion in statistical models as covariates (eg, demographics, cancer site and stage, medications, comorbidity, and health behaviors) but none of them was retained because none had at least a minimal correlation with the dependent variable (ISI) (correlation coefficient [r] = ±0.30) (a medium effect size [r ≥0.30] rather than statistical significance was deemed to be a more appropriate criterion because of the large sample in the current study, which was likely to yield numerous significant but fortuitous associations).24 In both groups, patients did not receive any adjuvant treatment at baseline, and therefore these data could not be used as dependent variables. In patients with breast cancer, T5 and T6 could not be used either because none of the patients received radiotherapy at those times, thus leaving T2 to T4 for these analyses. Because <10 of the patients with prostate cancer received radiotherapy and chemotherapy at any time point of the study, only the use of hormone therapy was analyzed (from T3 to T6) (Fig. 1).
Percentage of patients with (a) breast cancer and (b) prostate cancer exposed to each treatment since the last assessment at each time point are shown.
Three binary independent variables, specifying whether each participant was exposed to chemotherapy, radiotherapy, and hormone therapy at each time point, were created. Linear mixed models using a factorial design (group [chemotherapy, radiotherapy, and hormone therapy] × time) were performed to test the significance of temporal changes, while adjusting means for missing data and taking into account individual baseline (random effect). Main treatment and time effects and treatment × time interactions were systematically tested and interactions were decomposed using simple effects. The best-fitting covariance matrix for each model was selected based on the Bayesian information criterion. Empirical “sandwich” estimators of standard errors for fixed effects were used.
Longitudinal mediation analyses were computed using an autoregressive mediation model,25 which permitted the examination of both concurrent (associations of variables all assessed at the same time point) and longitudinal (effect of each treatment at 1 time point on the mediator and insomnia severity assessed at the subsequent time point) mediation. For longitudinal relations, only lag-1 associations (between consecutive time points) were investigated, mainly because we were interested in investigating the proximal factors triggering an aggravation of insomnia. Paths tested are illustrated in Figure 2.
Summary of the relationships tested with the longitudinal autoregressive mediational model of the lagged (P) and current (C) contributions of chemotherapy (C), radiotherapy (R), and hormone therapy (H) to the Insomnia Severity Index, mediated by the frequency of a physical symptom, is shown. The first letters of the abbreviations in circles designate the time point (P indicates previous assessment and C indicates current assessment), whereas the second letters designate the variable (C indicates chemotherapy; R, radiotherapy; H, hormone therapy; S, symptom; and I, insomnia). For example, PC indicates “previous chemotherapy.” The mediation was tested by estimating 2 paths: treatment to mediator (alpha relation) and mediator to insomnia (beta relation). Indirect alpha relations between treatments and the mediator were tested for previous treatments (PC, PR, and PH→CS) and current treatments (CC, CR, and CH→CS). Indirect beta relations between the mediator and insomnia were tested for the previous mediator (PS→CI) and the current mediator (CS→CI). Direct relations between treatments and insomnia, controlling for the mediator effect, were tested for previous treatments (PC, PR, and PH→CI) and current treatments (CC, CR, and CH→CI). Autoregressive relations to control for temporal dependency were tested for both the mediator (PS→CS) and insomnia (PI→CI).
Three linear mixed models were performed for each mediator (symptom) to estimate: 1) the total relationship (treatment→insomnia); 2) the alpha relationship (treatment→mediator); and 3) the beta (mediator→insomnia) and direct (treatment→insomnia, controlling for the mediator) relationship. The overall mediation effect was estimated as the product of the alpha and beta regression coefficients and its standard error was computed according to the procedure of MacKinnon et al (Z-prime formula).26 The ratio of the mediation effect (alpha-beta product) on its standard error yielded a Z-prime statistic, which was compared against the appendix in MacKinnon et al26 (ie, null hypothesis indicates no mediating effect; N = 500) to determine the significance of the mediating effect. The percentage of the total effect explained by the mediated (indirect) effect was computed as the ratio of the mediation standard coefficient on the standard coefficient for the total treatment effect. A mediation was considered a total mediation when only the mediation (indirect) effect was statistically significant, whereas a partial mediation was determined when both mediation and directs effects were significant.
RESULTS
Objective 1: Effect of Adjuvant Treatments on the Evolution of Insomnia Severity
Breast cancer
In participants with breast cancer, the results of a normal linear mixed model conducted on ISI scores revealed a significant time effect (F(2,760) = 9.77; P<.001) and a significant and unique radiotherapy effect (F(1,345) = 3.84; P = .05), but no significant main effect for chemotherapy (F(1,190) = 0.79; P = .38) or hormone therapy (F(1,175) = 0.06; P = .80) after controlling for the effect of the other 2 treatments. However, simple effects demonstrated that women receiving chemotherapy had significantly greater ISI scores at T2 than those not receiving this treatment (M of 10.6 vs 9.1; F(1,760) = 5.29 [P = .02]) (Fig. 3a), which corresponds to their peak exposure to chemotherapy (Fig. 1a). Overall, the exposure to radiotherapy was associated with significantly higher ISI scores throughout the study (M of 9.0 vs 8.4) (Fig. 3b). No treatment × time interaction was found to be statistically significant (P = .23 for chemotherapy, P = .87 for radiotherapy, and P = .66 for hormone therapy).
Adjusted Insomnia Severity Index (ISI) scores are shown for participants exposed or not to each cancer treatment since the time of the last assessment. Only time points with at least 10 participants exposed are shown: (a) chemotherapy in breast cancer, (b) radiotherapy in breast cancer, (c) hormone therapy in breast cancer, and (d) hormone therapy in prostate cancer.
Prostate cancer
The mixed model analysis conducted among participants with prostate cancer revealed a significant main effect for hormone therapy (F(1,9) = 5.01; P = .05) but no significant time effect (F(1,610) = 0.62; P = .60) or interaction (F(1,610) = 0.83; P = .48). Overall, participants reported significantly higher ISI scores throughout the study when exposed to hormone therapy (M of 7.3 vs 5.4) (Fig. 3d). In addition, simple effects revealed that patients receiving hormone therapy had significantly greater ISI scores at T4 (P = .03), T5 (P = .04), and T6 (P = .03), which corresponds to the peak exposure to hormone therapy in that group (Fig. 1b).
Objective 2: Mediating Effect of Somatic Symptoms in the Relationship Between Adjuvant Treatments and Insomnia
Table 2 presents the results of mediation effects calculated by the product method for both subgroups of participants. All significant relationships indicated worse insomnia symptoms in association with cancer treatments and somatic symptoms. With the exception of one effect for radiotherapy, all effects indicated a total mediation.
| Breast Cancer (n = 465) | Prostate Cancer (n = 263) | |||||||
|---|---|---|---|---|---|---|---|---|
| Chemotherapy | Radiotherapy | Hormone Therapy | Hormone Therapy | |||||
| Concurrent | Longitudinal | Concurrent | Longitudinal | Concurrent | Longitudinal | Concurrent | Longitudinal | |
| Symptoms | Z′ (%) | Z′ (%) | Z′ (%) | Z′ (%) | Z′ (%) | Z′ (%) | Z′ (%) | Z′ (%) |
| Headache | NS | 1.39a (73.0) T | NS | 0.95b (35.9) T | 0.90b (15.4) T | NS | - | - |
| Dyspnea | 0.96b (13.5) T | NS | 1.64a (19.8) P | NS | NS | NS | 1.35a (18.0) T | NS |
| Nausea | 2.45a (34.7) T | 1.08b (14.3) T | NS | 0.92b (3.9) T | NS | NS | - | - |
| Digestive | 1.72a (14.4) T | 1.56a (20.2) T | NS | NS | 1.44a (21.8) T | 1.09a (36.7) T | - | - |
| Urination | 3.09a (39.1) T | NS | NS | NS | NS | NS | 1.55a (16.6) T | NS |
| Night sweats | 2.05a (30.0) T | NS | 1.12a (14.9) T | NS | 3.56a (100) T | NS | 1.83a (48.6) T | 0.85b (45.8) T |
| Pain | NS | NS | NS | NS | NS | NS | 1.25a (13.8) T | NS |
- Abbreviations: %, percentage of the total relation accounted for by the mediation effect; NS, not significant; P, partial mediation; T, total mediation; Z′, Z-prime statistic for the alpha × beta mediation test.
- a P < .01.
- b P < .05.
Breast cancer
Concurrent mediation effects were more frequent (10 significant effects from 21 tests) than lagged ones (6 significant effects from 21 tests). More specifically, the concurrent effect of chemotherapy on insomnia symptoms was significantly mediated by urinary symptoms (39.1% of the total effect explained by the mediation effect), nausea (34.7% of the total effect), night sweats (30.0% of the total effect), digestive symptoms (14.4% of the total effect), and dyspnea (13.5% of the total effect). The lagged (longitudinal) effect of chemotherapy on insomnia was significantly mediated by headache (73.0% of the total effect), digestive symptoms (20.2% of the total effect), and nausea (14.3% of the total effect). The concurrent effect of radiotherapy on insomnia symptoms was significantly mediated by dyspnea (19.8% of the total effect [partial mediation]) and night sweats (14.9% of the total effect). The lagged radiotherapy effect was significantly mediated by headache (35.9% of the total effect) and nausea (3.9% of the total effect). Finally, the concurrent effect of hormone therapy on ISI scores was significantly mediated by night sweats (100% of the total effect), digestive symptoms (21.8% of the total effect), and headache (15.4% of the total effect), whereas the lagged effect was significantly mediated by digestive symptoms only (36.7% of the total effect).
Prostate cancer
Again, concurrent effects were more frequent (4 significant effects from 4 tests) than lagged effects (only 1 significant effect). The concurrent effect of androgen deprivation therapy on symptoms of insomnia was significantly mediated by night sweats (48.6% of the total effect), dyspnea (18.0% of the total effect), urinary symptoms (16.6% of the total effect), and pain (13.8% of the total effect), whereas the lagged effect was significantly mediated by night sweats only (45.8% of the total effect).
DISCUSSION
The current longitudinal study assessed, within the context of breast and prostate cancer, the role of adjuvant treatments in the evolution of insomnia symptoms over an 18-month period and the mediating role of somatic symptoms potentially caused by these treatments. In patients with breast cancer, the findings indicated that chemotherapy (at T2) and radiotherapy (overall effect), but not hormone therapy, were associated with an aggravation of insomnia symptoms after controlling for the effect of the other 2 treatments. In this group, the effect of chemotherapy and radiotherapy on insomnia levels was significantly mediated by a variety of somatic symptoms likely to be their side effects. Although hormone therapy was not found to be associated with a significant exacerbation of insomnia symptoms in that group, its effect was significantly mediated by night sweats. In patients with prostate cancer, androgen deprivation therapy was consistently associated with increased insomnia symptoms, an effect that was strongly mediated by night sweats. Given that nearly all mediating effects in both groups were total mediations, this suggests that somatic symptoms explain a major percentage of the relationship between cancer treatments and insomnia.
In patients with breast cancer, chemotherapy was associated with increased insomnia symptoms, an effect that was significant at T2 when 51.3% of the women were receiving this treatment. These results are consistent with some evidence pointing to a deleterious effect of chemotherapy on sleep.1, 27-29 Although other mechanisms are possible (eg, psychological reaction, disruption of circadian rhythms, or immune response4, 30), the current results supporting the mediating role of a variety of somatic symptoms suggest that this negative impact is significantly due to its side effects, in particular headache, nausea and digestive symptoms, urination, and night sweats.
Some chemotherapeutic agents can induce headache (eg, 5-fluorouracil) and a bidirectional relationship between headache and insomnia appears to exist.31 Indeed, the discomfort associated with headache may interfere with falling and staying asleep throughout the night, but disturbed sleep can also cause headache. A deleterious impact of chemotherapy-induced nausea and digestive symptoms on sleep has already been shown.32 However, it should be noted that this effect could also be explained by the use of antiemetic medications that can alter sleep as well (eg, dexamethasone33). Increased urination, another possible side effect of chemotherapy, was associated with greater severity of insomnia, which is consistent with an increasing body of literature indicating a link between nocturia and poor sleep in the general population.34 Finally, findings regarding night sweats are consistent with studies performed within the context of breast cancer using objective measures (polysomnography and sternal skin conductance) supporting a concurrent association between nocturnal hot flashes and various sleep impairments.35, 36
In the subsample of patients with breast cancer, radiotherapy was found to be associated with a significantly increased severity of insomnia overall. The strongest mediating effect was found for headache. Because irradiating the breast is not likely to induce headache, this may indicate an inverse relationship in which headache is induced by insomnia. Other significant mediating effects were noted for dyspnea, night sweats, and nausea, but they explained a smaller percentage of the total effect. Overall, somatic symptoms, at least those assessed in the current study, appear to explain to a lesser extent the relationship between radiotherapy and insomnia in patients with breast cancer. Future studies should investigate the possible mediating role of fatigue. Fatigue is significantly correlated with insomnia within the context of radiotherapy,37 and our previous findings using the same sample revealed that fatigue was a significant predictor of insomnia.38
Hormone therapy also was found to be associated with significantly greater insomnia scores, but only in men with prostate cancer. In that group, the effect was significant overall and at each time point, except T3, when only 6.9% of patients received this treatment. Although analyses revealed a small mediating role of other symptoms (ie, dyspnea, urinary symptoms, and pain), the most influential mediator was night sweats. Findings of the current study are consistent with those of another recent longitudinal study that demonstrated a deleterious effect of androgen deprivation therapy for prostate cancer on insomnia levels through the mediating role of night sweats and hot flashes.13 It is interesting to note that even though hormone therapy was not associated with significantly increased insomnia in patients with breast cancer in the current study, night sweats explained 100% of the relationship between this treatment and insomnia, thereby emphasizing the importance of this symptom as a risk factor for insomnia in this group as well. The finding that hormone therapy was not associated with a significant exacerbation of insomnia in patients with breast cancer is surprising but may be due to some ceiling effect. Indeed, women with breast cancer had already, on average, clinical levels of insomnia before receiving hormone therapy (at T2), thus leaving less room for further aggravation of their symptoms because of its introduction.
The current study is characterized by several strengths, including the use of a large population-based sample and of a longitudinal design with 6 time points over the entire cancer care trajectory. Given that treatment regimens and side effect profiles may vary across cancers, the separate investigation of the most common cancer types is also a strength. One limitation is the relatively large time frame between the study measurements, thus making causal inferences difficult. Indeed, participants were considered to be exposed to a particular treatment if they had received it since the time of the last assessment. Given the large intervals between time points (2-4 months), this means that treatments may have ended days and even weeks before insomnia (and somatic symptoms) was measured, thus potentially weakening the strength of the association between treatments and the severity of insomnia. This may also explain why concurrent associations were more frequent than longitudinal ones. Finally, given the large variety of treatments received in the current study sample, the analyses could not assess the differential impact of each type of chemotherapy regimen and hormone therapy.
Although the etiology of insomnia comorbid with cancer is most likely multifactorial, the results of the current study suggest that adjuvant cancer treatments are associated with increased severity of insomnia through the mediating effect of their side effects. The results of the current study highlight the importance of the appropriate management of the side effects of cancer treatments to prevent the occurrence or aggravation of sleep difficulties.
FUNDING SUPPORT
Supported by a grant from the Canadian Institutes of Health Research (MOP-69073).
CONFLICT OF INTEREST DISCLOSURES
Dr. Morin has served as consultant for Merck, Novartis, and Valeant and received research support from Novartis for work performed outside of the current study.
