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Are there efficacious treatments for treating the fatigue–sleep disturbance–depression symptom cluster in breast cancer patients? A Rapid Evidence Assessment of the Literature (REAL©)

Authors Jain S, Boyd C, Fiorentino L, Khorsan R, Crawford C

Received 7 May 2013

Accepted for publication 18 November 2013

Published 2 September 2015 Volume 2015:7 Pages 267—291

DOI https://doi.org/10.2147/BCTT.S25014

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Shamini Jain,1 Courtney Boyd,2 Lavinia Fiorentino,1 Raheleh Khorsan,3 Cindy Crawford2

1Department of Psychiatry, University of California San Diego, San Diego, CA, USA; 2Samueli Institute, Alexandria, VA, USA; 3Samueli Institute, Corona Del Mar, CA, USA

Purpose: While fatigue, sleep disturbance, and depression often co-occur in breast cancer patients, treatment efficacy for this symptom cluster is unknown. A systematic review was conducted to determine whether there are specific interventions (ie, medical, pharmacological, behavioral, psychological, and complementary medicine approaches) that are effective in mitigating the fatigue–sleep disturbance–depression symptom cluster in breast cancer patients, using the Rapid Evidence Assessment of the Literature (REAL©) process.
Methods: Peer-reviewed literature was searched across multiple databases; from database inception – October 2011, using keywords pre-identified to capture randomized controlled trials (RCT) relevant to the research question. Methodological bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) 50 checklist. Confidence in the estimate of effect and assessment of safety were also evaluated across the categories of included interventions via the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology.
Results: The initial search yielded 531 citations, of which 41 met the inclusion criteria. Of these, twelve RCTs reported on all three symptoms, and eight of these were able to be included in the GRADE analysis. The remaining 29 RCTs reported on two symptoms. Studies were of mixed quality and many were underpowered. Overall, results suggest that there is: 1) promising evidence for the effectiveness of various treatment types in mitigating sleep disturbance in breast cancer patients; 2) mixed evidence for fatigue; 3) little evidence for treating depression; and 4) no clear evidence that treatment of one symptom results in effective treatment for other symptoms.
Conclusion: More high-quality studies are needed to determine the impact of varied treatments in mitigating the fatigue–sleep disturbance–depression symptom cluster in breast cancer patients. Furthermore, we encourage future studies to examine the psychometric and clinical validity of the hypothesized relationship between the symptoms in the fatigue–sleep disturbance–depression symptom cluster.

Keywords: fatigue, sleep disturbance, depression, symptom cluster, breast cancer, Rapid Evidence Assessment of the Literature

Introduction

Treatments for breast cancer presently provide more hope than ever in terms of treating the cancer and reducing mortality. For nearly all women in the US, with the exception of Native American/Alaska Natives, breast cancer mortality continues to decline,1 suggesting that our methods of screening and treatment are steadily improving for breast cancer treatment. While survival rates for breast cancer patients continue to improve, behavioral and psychosocial side effects from breast cancer and its treatment remain a large problem for these patients, impacting their day-to-day functioning as well as quality of life. Among the most common complaints reported by breast cancer patients during and after treatment are fatigue, sleep disturbance, and depression. These symptoms have often been found to co-occur in breast cancer populations both during and after treatment.24 The co-occurrence of these and other related symptoms in breast and other cancers has spurred lively discussion about the existence of symptom clusters; an area of study that is relatively in its infancy with no consistent clinical or psychometric measurements.5,6

The etiology of each of these symptoms as well as the potential reasons for their co-occurrence is complex, with psychosocial and physical functioning, type of cancer treatment, and medical diagnostic variables all potentially playing roles in both the onset and maintenance of these symptoms. Current evidence suggests that inflammatory and neuroendocrine dysregulation are associated with, and may help perpetuate the co-occurrence of these symptoms within cancer and other populations,79 through a process often termed “sickness behavior”.10 Chronic low-grade inflammation (which is thought to be primarily initiated by the cancer and some forms of cancer treatment) facilitates the manifestation of behavioral symptoms including sleep disturbance, fatigue, and depression in the patient. Evidence also suggests that the occurrence and perpetuation of sickness behavior responses to cancer and cancer treatment may be moderated by dispositional factors, including genetic polymorphisms in genes regulating inflammatory responses11 and premorbid psychosocial functioning.12

While mechanistic research efforts continue to elucidate the pathophysiology underlying the co-occurrence and persistence of these symptoms, there is consistent evidence that a greater number of co-occurrence of symptoms leads to poorer quality of life,13 increased neuropathic pain,14 and impaired overall functioning15 in breast cancer patients. It is therefore important to understand what types of treatments may be most successful not only in treating one symptom, but in potentially successfully treating symptoms that co-occur. Finding interventions that efficiently treat symptom clusters may yield better outcomes for patients as well as lead to greater cost-efficiency in terms of providing interventions that may target more than one symptom.

To our knowledge, there are no systematic reviews exploring the treatments for the co-occurring symptoms of fatigue, sleep disturbance, and depression in breast cancer patients and survivors. We conducted a systematic review to examine which treatments are the most efficacious for treating the fatigue–sleep disturbance–depression symptom cluster in breast cancer patients. The specific objectives of this review were to: 1) survey the literature on treatments addressing at least two of the three symptoms in the fatigue–sleep disturbance–depression symptom cluster; 2) examine and assess the quantity, quality and efficacy based on studies as reported in the literature; 3) characterize the treatments as behavioral, psychosocial, complementary/alternative medicine (CAM), medical, or pharmacological to better compare treatment types; 4) critically evaluate the efficacy and safety of interventions that examined the impact on the three symptoms based on the literature; and 5) identify gap areas that exist in the literature in order to suggest next steps in research based on our analysis of the pooled literature.

Methods

To conduct this systematic review, we utilized the Rapid Evidence Assessment of the Literature (REAL©; Samueli Institute, Alexandria, VA, USA) methodology, which is an expedient approach for conducting systematic reviews.16,17 REAL© reviews primarily focus on synthesis of peer-reviewed randomized controlled trials (RCTs) published in the English language, and utilize searching across multiple databases. Details on the REAL© methodology for this review are described to follow.

Search strategy

The following databases were searched from database inception through October 2011: PubMed, EMBASE, CINAHL, Cochrane, and PsycINFO. The following four initial searches, as entered into PubMed, were combined to produce the final search: 1) (breast cancer) and (depression or depress* or “negative affect” or “negative mood”); 2) (breast cancer) and (fatigue or “vital exhaustion”); 3) (breast cancer) and (“sleep disturbance” or “insomnia” or “sleep disruption” or sleep); and 4) (breast cancer) and (“symptom cluster”). The Medical Subject Headings (MeSH) terms and explosions across the terms were applied where applicable and relevant; where MeSH did not apply, variations of the search strategy were used. As this REAL© focused on the fatigue–sleep disturbance–depression cluster components, we considered the terms depressed mood, dysthymia, negative affect, emotional distress and negative mood to be synonymous with depression; insomnia and sleep disruption synonymous with sleep disturbance; and vital exhaustion and cancer-related fatigue synonymous with fatigue. The complete search strategies in each of the databases searched can be obtained by contacting the primary author.

Inclusion/exclusion criteria

The inclusion criteria were developed in accordance with the Population, Intervention, Control, and Outcome18 (PICO) framework. Articles were included if they met the following criteria: 1) RCT study design; 2) population consisting of active patients and/or survivors of breast cancer who participated in any treatment intervention; and 3) included at least two of the three cluster symptoms of fatigue, sleep disturbance, and depression (as defined via the search strategy).

Two screeners (CL, RK) screened titles and abstracts for relevance based on the inclusion criteria. Once sufficient inter-rater reliability (Cohen’s Kappa >88%) was achieved, the screeners screened the remaining articles independently, resolving arising queries through discussion with either the review manager (CC) and/or the subject matter experts (SMEs; SJ, LF).

Quality assessment and data extraction

Methodological quality of the included studies was assessed by two reviewers (CL, RK) using the Scottish Intercollegiate Guidelines Network (SIGN 50) checklist for RCTs, a widely accepted, reliable, and validated assessment tool19 (see Figure 1). The reviewers were fully trained in the methodology.

Figure 1 SIGN 50 checklist for RCT Study Design.
Note: Adapted from Scottish Intercollegiate Guidelines Network (SIGN). A Guideline Developer’s Handbook. Edinburgh: SIGN; 2001. (SIGN publication no. 50). [cited 24 June 2014]. Available from URL: http://www.sign.ac.uk.19 Adapted from Crawford C, Wallerstedt DB, Khorsan R, Clausen SS, Jonas WB, Walter JA. A systematic review of biopsychosocial training programs for the self-management of emotional stress: potential applications for the military. Evid Based Complement Alternat Med. 2013;747694. Epub 2013 Sep 23.72
Abbreviations: RCT, randomized controlled trial; SIGN, Scottish Intercollegiate Guidelines Network.

The following information was extracted from each included study: population; initial sample and dropout rates; treatment and control interventions; relevant outcomes and results; the reporting and severity of adverse events; the informed consent process; power calculations; effect sizes; and author’s main conclusions.

Patients were grouped into the following categories: non-metastatic, metastatic, mixed (ie, population included both metastatic and non-metastatic patients), and survivors (those who were no longer receiving active treatment). Treatment interventions were grouped into the following categories: behavioral (eg, exercise), psychosocial (eg, cognitive–behavioral therapy and supportive counseling), CAM (eg, yoga and herbal medicine), medical procedures (eg, radiation, ovarian ablation), or pharmacological (eg, anti-depressants).

Data synthesis and analysis

Once the quality assessment of individual studies was completed, two SMEs (SJ and LF) performed a quality assessment of the overall literature pool for each treatment intervention and patient population using a modified version of the Grading of Recommendation Assessment, Development and Evaluation (GRADE), an internationally accepted approach to grading the quality of evidence and strength of recommendations.20 SMEs used the GRADE to examine the results of the review for each population and treatment type in order to: 1) examine the confidence in and magnitude of the estimate of the effect; 2) assign a safety grade; and 3) develop recommendations (such as strong or weak recommendations in favor of or against the use of such treatments) for the included literature pool based on the REAL© results. The SMEs received formal training in the modified GRADE, conducted the GRADE independently, and then met as a team to resolve any discrepancies and come to consensus on overall recommendations.

Results

The main objective of this systematic review was to focus on the three symptom cluster for breast cancer. However, due to our comprehensive search strategy, the authors also found several articles that focused on two of the three symptoms. Due to resources and the main objective of this review however, the authors only report on the three symptom cluster in detail assessing the overall literature pool to come up with recommendations using GRADE methodology. The authors share the two symptom cluster studies in Table 1 as a frame of reference only and hope to perform future analysis of these studies in the future. The studies on two symptoms can be found in Table 12149 and three symptoms in Table 2.5061

Table 1 Characteristics and SIGN 50 score of included studies, grouped by population and treatment type, that address two cluster components (n=29)
Notes: 31% of the studies did not have sufficient statistical power and 41% of studies did not report a power calculation: apatients receiving surgery; bpatients receiving chemotherapy; cpatients receiving radiation; dpatients receiving surgery, chemotherapy, and radiation; epatients receiving surgery and chemotherapy; fpatients receiving chemotherapy and radiation; gpatients receiving hormone therapy; htreatment received not described; ieffect size not reported.
Abbreviations: 95% CI, 95% Confidence Interval; BDI, Beck Depression Inventory; BFI, Brief Fatigue Inventory; BSF, Berlin Mood Questionnaire; C, control Group; CBT, Cognitive Behavioral Therapy; CES-D, Center for Epidemiological Studies-Depression Scale; CFS, Chalder Fatigue Scale; CHT, chemotherapy; CRF, Case Report Form; EORTC QLC-C30, European Organization for Research and Treatment of Cancer Health Related Quality of Life Questionnaire; EoT, end of treatment; FACIT-F, Functional Assessment of Chronic Illness Therapy; FACT-A, Functional Assessment of Cancer Therapy-Anemia; FSCL, Fatigue Symptom Checklist; FSI, Fatigue Symptom Inventory; FU, follow-up; GBB, Geissen Complaints Inventory; GHQ, General Health Questionnaire; HADS, Hospital Anxiety Depression Score; HDRS, Hamilton Depression Rating Scale; hr, hour; HSCL-25, Hopkins Symptom Checklist-25; iv, intravenous; ISI, Insomnia Severity Index; MAF, Multidimensional Assessment of Fatigue; Max, maximum; MD, mean difference; MDA BFI, Anderson Brief Fatigue Inventory; MFI, Multidimensional Fatigue Inventory; Min, minutes; Mon(s), month(s); MSQ, Mini Sleep Questionnaire; NCI-CTC, National Cancer Institute Common Toxicity Criteria; ND, not described; NFQ, Norwegian Fatigue Questionnaire; NS, not significant; PANAS, Positive and Negative Affect Scale; PFS, Piper Revised Fatigue Scale; POMS-DD, Monopolar Profile of Mood States; POMS, Profile of Mood States; PSQI, Pittsburgh Sleep Quality Index; QOL, quality of life; RT, radiation therapy; reps, repetitions; SAS, Self-rating Anxiety Scale; SCD, Self Care Diary; SD, standard deviation; SE, side effect; T, treatment group; SIGN, Scottish Intercollegiate Guidelines Network; UC, usual care; VDBP, van den Borne and Pruyn; wk(s), week(s); wkly, weekly.

Table 2 Characteristics and SIGN 50 score of included studies, grouped by population and treatment type, that address three cluster components (n=12)
Notes: 33% of studies did not have sufficient statistical power, and 33% of studies did not report a power calculation: apatients receiving surgery; bpatients receiving chemotherapy; cpatients receiving radiation; dpatients receiving surgery, chemotherapy, and radiation; epatients receiving surgery and chemotherapy; fpatients receiving chemotherapy and radiation; gpatients receiving hormone therapy; htreatment received not described; ieffect size not reported; ***Negative affect index was calculated as the combination of standardized scores on four questionnaires: the POMS-Short Form total mood disturbance score (excluding fatigue), the negative affect subscale of the PANAS, the CES-D, and the Ham-D.
Abbreviations: 95% CI, 95% Confidence Interval; BFI, Brief Fatigue Inventory; BSF, Berlin Mood Questionnaire; C, control group; CBT, Cognitive Behavioral Therapy; BDI, Beck Depression Inventory; CES-D, Center for Epidemiological Studies-Depression Scale; CFS, Chalder Fatigue Scale; CHT, chemotherapy; CRF, Case Report Form; EORTC QLC-C30, European Organization for Research and Treatment of Cancer Health Related Quality of Life Questionnaire; EoT, end of treatment; FACIT-F, Functional Assessment of Chronic Illness Therapy; FACT-A, Functional Assessment of Cancer Therapy-Anemia; FSCL, Fatigue Symptom Checklist; FSI, Fatigue Symptom Inventory; FU, follow-up; GBB, Geissen Complaints Inventory; GHQ, General Health Questionnaire; HADS, Hospital Anxiety Depression Score; HDRS, Hamilton Depression Rating Scale; HR, hour; HSCL-25, Hopkins Symptom Checklist-25; ISI, Insomnia Severity Index; MAF, Multidimensional Assessment of Fatigue; MD, mean difference; MDA BFI, Anderson Brief Fatigue Inventory; MFI, Multidimensional Fatigue Inventory; Min, minutes; Mon(s), month(s); MSQ, Mini Sleep Questionnaire; NCI-CTC, National Cancer Institute Common Toxicity Criteria; ND, not described; NFQ, Norwegian Fatigue Questionnaire; NS, not significant; PANAS, Positive and Negative Affect Scale; PFS, Piper Revised Fatigue Scale; POMS-DD, Monopolar Profile of Mood States; POMS, Profile of Mood States; PSQI, Pittsburgh Sleep Quality Index; QOL, quality of life; RT, radiation therapy; reps, repetitions; SAS, Self-rating Anxiety Scale; SCD, Self Care Diary; SD, standard deviation; SE, side effect; SIGN, Scottish Intercollegiate Guidelines Network; T, treatment group; UC, usual care; VDBP, van den Borne and Pruyn; Wk(s), week(s).

Of the 531 citations yielded from the database searches, 41 RCTs fit the inclusion criteria and were subsequently included in the quality assessment and data extraction phase of the REAL©. Of these, 29 RCTs reported on two component clusters; Table 1 categorizes these by treatment type and population, and reports their individual characteristics and overall SIGN 50 scores. The remaining twelve RCTs reported on all three component clusters (Table 2), eight of which were able to be included in the GRADE analysis (Figure 2).

Figure 2 Flow chart.
Abbreviations: CAM, complementary/alternative medicine; RCT, randomized controlled trial.

Both Tables 1 and 2 categorize studies according to treatment type (behavioral, CAM, medical procedures, psychosocial, or pharmacological) and across four population types including non-metastatic, metastatic, mixed (comprised of both non-metastatic and metastatic patients), and survivors.

Characteristics of included studies

Methodological quality of included studies according to SIGN 50 criteria

According to SIGN 50 criteria19 (see Figure 1), the majority (63.4%) of the studies received an overall SIGN 50 score of + (high quality), with the remaining (26.8%) articles receiving scores of – (low quality), and fewer (9.8%) receiving a score of ++ (excellent quality).

Most of the 41 RCTs (92.6%) included in the review addressed an appropriate and clearly focused question either well or adequately. Almost half of the articles addressed randomization poorly (46.3%), with 22.0% of articles doing so adequately, and 31.7% doing so well. The majority of articles (65.8%) poorly addressed allocation concealment, with less than a third of articles addressing this criterion either well (22.0%) or adequately (12.2%). Baseline similarities between treatment and control groups were well addressed in the majority of articles (70.7%) with a small percentage of studies addressing it adequately (19.5%) or poorly (9.8%). Outcome reliability and validity was addressed well by 41.4% of articles with the remaining articles addressing this criterion adequately (22.0%) or poorly (36.6%). Although many studies (53.7%) reported attrition rates adequately or well, many articles also poorly addressed intention-to-treat analyses (46.3%).

Three criteria, blinding, treatment group differences, and multi-site differences, were not applicable to all studies (ie, blinding not possible, treatment groups are too inherently different from each other, study only conducted at one site). Consequently, we only assessed the articles where these criteria were applicable. Of the twelve RCTs where blinding was possible, blinding of treatment allocation was addressed well and adequately in 41.7% and 25.0% of the studies, respectively; approximately 33.3% of these studies addressed this criterion poorly. We were able to assess twelve RCTs for treatment difference between groups; many of these articles did so either well (33.3%) or adequately (41.7%), with 25.0% of the articles doing so poorly. Lastly, only a small number of studies (n=12) were conducted at multiple sites; the majority of these poorly addressed (66.6%) similarity of site results, with the remaining articles doing either well (16.7%) or adequately (16.7%).

Safety assessment

Of the 41 articles included in our review, only 16 reported on adverse events with four studies30,36,46,55 reporting no adverse events. Ten studies reported adverse events including gastrointestinal problems,31,32,43,53 dizziness,31,32 changes in blood pressure,31,34,60 weakness,31 anemia,32 pain/discomfort,24,34,47 headache,43,60 insomnia,53 palpitations,53 anxiety,53 skin rashes and angioedema,51 jaundice/liver damage,51 dry mouth,21 changes in taste,21,51 and disease progression.24 Additionally, two studies22,23 reported adverse events occurred but did not describe them.

GRADE analysis

The GRADE analysis was conducted on studies addressing all three symptoms (fatigue, sleep disturbance, and depression) in order to provide recommendations regarding treatment of the symptom cluster as a whole. While we present the tables on studies that examined two of the three symptoms to familiarize the reader with the breadth of literature available on examining intervention effects on co-occurring symptoms within this cluster, as our primary interest was on examining studies that investigated effects on the symptom cluster as defined by sleep disturbance, depressed mood, and fatigue, we chose to conduct the GRADE on studies that examined these three symptoms. There were twelve RCTs that addressed all three symptoms that were included in this review; of these, one study50 (examining a psychosocial intervention) reported results in metastatic breast cancer patients, five studies (two examining behavioral interventions,54,55 two examining medical interventions,51,52 and one examining a CAM intervention)53 reported results in non-metastatic breast cancer patients, three studies (two examining psychosocial interventions,57,58 one examining a pharmacological intervention)56 reported results in mixed (metastatic and non-metastatic) breast cancer patients, and three studies (two examining pharmacological interventions,59,60 one examining a CAM intervention)61 reported results on survivors (patients who had completed adjuvant or neo-adjuvant treatment).

Because GRADE analyses require at least two studies per category, only eight of these three RCTs addressing three symptoms were included in the final analysis; four studies50,53,56,61 were excluded because they were the only studies in their respective categories (ie, CAM treatment for non-metastatic and survivor populations, pharmacological treatment for mixed population, psychosocial treatment for metastatic population).

The GRADE results are presented in Table 3 and briefly summarized below. In this GRADE synthesis, we noted that most studies did not report effect sizes, nor describe the presence or absence of adverse events. Our final GRADE recommendations, therefore, are given considering these major omissions of reporting in the reviewed studies.

Table 3 GRADE analysis: quality of the overall literature pool by population/intervention type for studies assessing three cluster components
Notes: *Due to the small number of studies in these categories, four studies35,40,42,43 were not assessed via the GRADE; There are four major domains that comprise the core of the modified GRADE methodology: (1) confidence in the estimate of the effect was categorized into the following groups using pre-defined criteria: A) High: further research is very unlikely to change confidence in the estimate of effect; several high quality RCTs with consistent results or in special cases, or one large, high quality, multi-center RCT; B) Moderate: further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate; one high quality RCT or several RCTs with some limitations; C) Low: further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate; one or more RCTs with severe limitations; D) Very Low: any estimate of effect is very uncertain; expert opinion, no direct research evidence or one or more RCTs with severe limitations. (2) magnitude of the effect was categorized into five levels of none (<0.2), small (0.2–0.5), moderate (0.5–0.8), large (> 0.8), or not described (authors did not describe or report effect size for this review’s outcomes of interest due to the lack of author reporting). (3) safety grade is dependent on the frequency and severity of adverse events and interactions. Safety was categorized into one of the following grades: +2, appears safe with infrequent adverse events and interactions; +1, appears relatively safe but with frequent but not serious adverse events and interactions; 0, safety not well understood or conflicting; −1, appears to have safety concerns that include infrequent but serious adverse events and/or interactions or; −2, has serious safety concerns that include frequent and serious adverse events and/or interactions. (4) strength of the recommendation can be determined using the following categories and criteria: strong recommendation in favor of or against – very certain that benefits do, or do not, outweigh risks and burdens; no recommendation – no recommendations can be made or; weak recommendation in favor of or against – benefits and risks and burdens are finely balanced, or appreciable uncertainty exists about the magnitude of benefits and risks.
Abbreviations: CAM, complementary/alternative medicine; GRADE, Grading of Recommendation Assessment, Development and Evaluation; RCT, randomized controlled trial.

Non-metastatic population

Behavioral treatment

Two studies54,55 comparing walking exercise programs to usual care in a non-metastatic population, were poor (–) quality and reported improvements in sleep disturbance, but no significant differences for depression. Results were mixed for fatigue symptoms, as one study55 reported improvement in fatigue levels while the second study54 reported no such differences. Adverse events were only discussed in one study,55 which reported no adverse events. Because effect sizes were not reported, and both the quality and power of these studies was low, no recommendation could be given for this treatment type.

Medical treatment

Two studies51,52 examined medical procedures as treatment options for reducing fatigue, sleep disturbance, and depression in this population. The higher (+) quality study,51 comparing radiotherapy to no radiotherapy, reported improvements in insomnia with radiotherapy, but no significant differences between groups for depression and fatigue. The second study52 was of poor (–) quality, and compared ovarian ablation with chemotherapy. This study reported lower levels of fatigue, sleep disturbance, and depression in the ovarian ablation versus chemotherapy group. Effect sizes were not reported in either study, and only one study51 reported adverse events (such as skin rashes, angioedema, taste changes, jaundice, and liver damage). Consequently, a weak recommendation in favor was given for the usage of medical treatment methods for impacting the symptoms examined for this population.

CAM treatment

There was only one study (of high [++] quality)53 examining a CAM treatment in a non-metastatic population. Although fatigue and sleep disturbance symptoms were improved following administration of the herbal compound guarana, no such improvements in depression were found. Adverse events including insomnia, palpitations, nausea, and anxiety were reported. Because this was the only study in this treatment and population category, however, it was not included in the GRADE analysis.

Metastatic population

Psychosocial treatment

One high (+) quality study50 investigating psychosocial (cognitive behavioral therapy) treatment for metastatic patients reported mixed results for depression, and null results for fatigue and insomnia. Because this was the only study in this population, it could not be examined via GRADE.

Mixed population

Psychosocial treatment

Both studies57,58 examining psychosocial treatments were of high (+) quality and reported significant improvements in insomnia, no improvements in fatigue and mixed results for depression. Specifically, the first study,57 comparing psychosocial support with either a nurse or psychologist to usual care, found significant improvements in insomnia, but no differences for fatigue or depression symptoms. The second study58 compared cognitive behavioral therapy to a wait list control. Results showed improvements in both insomnia and depression, but no differences in fatigue. Adverse events were not reported in either study. Given the promising results for sleep improvement in these adequate quality studies, but a lack of information on adverse events, a weak recommendation in favor of psychosocial treatments was given.

Medical treatment

Although one high (+) quality study56 investigating chemotherapy dosages with tamoxifen reported lower fatigue and depression with the lower versus higher dose of chemotherapy, because there was only one study in this category, a GRADE recommendation could not be provided for medical treatments for a mixed population.

Survivor population

Pharmacological treatment

One high (+) quality and one poor (–) quality study investigating pharmacological treatments cited mixed results for sleep improvement and no improvement in either fatigue or depression. The higher quality study60 compared low and high dosages of venlafaxine to placebo and found no significant differences for any of the cluster symptoms. The poor quality study59 also did not find differences for depression or fatigue, however, the authors reported improvements in insomnia. Effect sizes were not reported in either of the two studies, and only one study60 reported an adverse event (ie, hypertension). Consequently, no recommendation could be given.

CAM treatment

One high (+) quality CAM study61 reported improvements in sleep disturbance and fatigue symptoms of breast cancer survivors following a yoga intervention, but no differences in negative mood. Because this was the only CAM study for a survivor population, however, it was not included in the GRADE analysis.

Discussion

The purpose of this review was to identify and systematically evaluate the current literature that examined the impact of interventions for the fatigue–sleep disturbance–depression symptom cluster in breast cancer patients and survivors. Of the 41 RCTs included in this review, 29 articles reported on two of the three symptom clusters and twelve reported on all three symptoms. It is important to note that many of these studies did not specify these symptoms as primary aims; in fact, 75% of the studies with three symptoms did not overtly specify the primary aim, and 58% of the studies with two symptoms did not specify the primary aim. Many of the studies assessed fatigue and insomnia via the European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-30) subscales; while these subscales are considered reliable and valid, they are not as comprehensive in their measurement as some other scales that focus solely on those respective symptoms.

Our systematic evaluation of the literature concerning quality using the SIGN 50 checklist suggested that overall, studies were of high quality, with over a quarter (n=12) of studies being of poor quality and only a few (n=4) being of very high quality. Studies could generally improve in their reporting of randomization and allocation concealment, as well as ensuring that the reliability and validity of outcomes reported are referenced appropriately. While it is not common practice that subscales of self-report questionnaires are referenced in terms of their reliability and validity, if analyses are conducted and conclusions are to be drawn by authors based on subscale results, we suggest that authors of studies should make reference to the reliability and validity of subscales that they examine. We also note that many studies were limited in their sample size.

Overall GRADE results suggest that, out of the three symptoms we reviewed, the one most likely to improve with treatment is sleep disturbance, with many studies reporting a significant effect on sleep disturbance, regardless of type of intervention. In these studies, sleep disturbance was generally reflected by reduced insomnia, and was generally measured using self-report questionnaires such as the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), and the EORTC-QLQ-30 insomnia subscale. Interventions were generally applied post-surgery, and during the active course of breast cancer treatment (examples are chemotherapy and/or radiation), with duration of treatments ranging from 3 weeks to 2 years, and generally being of about 6 weeks. It is interesting to note that only one study included in the GRADE analysis58 utilized an intervention that specifically targeted insomnia. This suggests that self-reported sleep disturbance is a more easily modifiable target in breast cancer patients undergoing active treatment, regardless of the type of intervention. Breast cancer patients report high levels of sleep disturbance at all stages of the breast cancer experience: before diagnosis, after diagnosis and before cancer treatment, during cancer treatment, and even years after the end of cancer treatment.62 Persistent and pervasive sleep problems are debilitating, exacerbate physical pain and psychological distress, and have been shown to impair the immune system; disrupting inflammation signaling and the hypothalamic-pituitary-adrenal axis (HPA) stress response.63 Hence targeting sleep disturbance might be the fastest way to improve quality of life and health in breast cancer patients, ultimately decreasing recurrence and hence increasing longevity. Future research should test the validity of these hypotheses.

Our GRADE results indicated mixed findings for interventions on improving fatigue, and little support for depression. These results suggest that while the clustering of sleep disturbance, fatigue, and depression is common, the successful treatment of one symptom does not necessarily result into adequate treatment of related symptoms. Findings suggested that reduction of fatigue sometimes, but not always, followed successful reduction of insomnia in breast cancer patients. The strong co-morbidity of fatigue and sleep disturbance has been previously noted in terms of its occurrence prior to, during, and after active treatment for cancer, 2,64,65 with some studies suggesting some commonality in dysregulation of inflammatory pathways9,66,67 associated with fatigue and sleep disturbance during treatment. However, persistent fatigue is also associated with HPA axis dysregulation,7 which may require other forms of intervention in addition to modifying sleep. Results for the concomitant modification of depression along with sleep were not promising. Interestingly, depression was more likely to improve with improvements in fatigue, although generally speaking, depression was the least likely symptom of the three to improve during the study period. This suggests that while depression often occurs with fatigue and sleep disturbance during cancer treatment, it may be harder to treat effectively, especially during the course of breast cancer therapy. These findings echo similar conclusions derived from meta-analyses of psychological and pharmacological therapies for depression, where evidence appears mixed for pharmacotherapy, and while somewhat promising for certain psychosocial approaches, is still relatively limited in certain cancer populations.68,69

We note that the majority of our studies generally focused on interventions of a single modality, such as a sole behavioral (exercise), psychosocial (psychotherapy), complementary medicine (herb), or pharmacological (drug) treatment. It is unknown, however, whether more integrative, multi-modal treatments that focus on all aspects of the person and therefore address more than one symptom at once (ie, a multi-modal or “whole systems” approach) may show more promise in being able to effectively treat the symptom cluster to enable breast cancer patients to achieve and maintain a healthier and more regulated state during and after treatment. Multi-modal treatment options, as compared to single modality treatments, have emerged as an important option in the management of many disorders and have the potential to simultaneously address the dynamic nature of the disease process over time. It is the authors’ recommendation that future studies consider more multi-modal or whole-systems approaches to addressing these types of symptom clusters associated with disease states.

There are limitations associated with this systematic review. First, because this is a Rapid Evidence Assessment of the Literature, the authors only examined the RCT study designs reported on in the English language to explore this research question. Second, due to the general lack of studies reporting examination of all three symptoms examined in the review, and the challenge of existing studies having inadequate power and lack of adverse events reporting, it is challenging to make recommendations about particular types of interventions for this symptom cluster. While we were able to extract data for the studies that included two of the three symptoms as outcomes, we were unable to conduct the GRADE on studies that reported only two of the three symptoms for this review, and this may be seen as a limitation. However, our primary objective was to determine the impact of interventions that addressed all three components of the targeted symptom cluster of depression, fatigue, and sleep disturbance. The information from this review may guide further reviews that may choose to examine more specifically the impact of interventions on two of the three symptoms (such as fatigue and sleep disturbance). We encourage researchers in the field to take into consideration where we have noted the quality of reporting can be improved in future studies and some of the interventions, outcomes, and symptom cluster relationships that we have discovered throughout this process to produce powerful results in future work.

Conclusion

In summary, results from our systematic review, using the REAL© process, suggest that among the clustered symptoms of fatigue, sleep disturbance, and depression, sleep disturbance appears to be the symptom that responds best to interventions currently studied, with some studies also showing promise for fatigue. It is unclear whether treatment of sleep disturbance will necessarily result in effective improvements in other symptoms. Results also suggest that compared to sleep disturbance and fatigue, depression may be more difficult to treat for breast cancer patients and that treatment of sleep disturbance and fatigue do not necessarily translate to adequate treatment of depression. We highly recommend that future studies examine the psychometric and clinical validity of the hypothesized relationship among the sleep/fatigue/depression symptom cluster in breast cancer patients, including examining the relationships of these symptoms over time. In addition we encourage the development and testing of new treatment modalities, including multi-modal treatments, which may prove to be more efficacious than those presently studied for this cluster of symptoms.

Acknowledgments

The authors have not presented this data and information before in any journal. This data was presented in a poster at the MASCC/ISOO International Symposium on Supportive Care in Cancer in June 201270 as well as at the American Psychosocial Oncology Society in February 2013.71 The authors have no professional relationships with companies or manufacturers who will benefit from the results of this present study. This material is based upon work supported by the US Army Medical Research and Materiel Command under Award No W81XWH-06-1-0279. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other documentation.

Disclosure

The authors report no conflicts of interest in this work.


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