https://orcid.org/0000-0003-3227-9475
Abstract
Background
Fatigue, insomnia and pain are some of the most common and distressing symptoms experienced during breast cancer (BC) treatment and survivorship. The symptoms have been found to impact one another and to form a symptom cluster, and greater severity of the symptoms may be negatively associated with physical and emotional functioning in survivorship. In exploratory analyses from a randomized controlled trial examining the effect of progressive resistance training on the development of lymphedema after BC, we aimed to examine the burden of the symptom cluster fatigue-pain-insomnia, and its prognostic value for long-term symptom severity as well as emotional and physical functioning
Material and Methods
Latent profile analysis was used to identify groups with similar severity of pain, fatigue and insomnia among 158 patients with BC two weeks after surgery. Mixed effects Tobit regression models were used to estimate fatigue, pain, insomnia, and physical and emotional functioning 20 weeks, 1 year and 3.5 years after surgery.
Results
Two symptom burden groups were identified: 80% of women had a low severity while 20% of women had a high severity of the three symptoms after BC surgery. 3.5 years later, the women with high symptom burden post-surgery still had higher pain, insomnia and fatigue scores than women with low symptom burden. High symptom burden post-surgery was associated with worse physical functioning 3.5 years later, while emotional functioning was only negatively impacted during the first year.
Discussion
These findings warrant larger studies investigating if symptom burden early in BC trajectory can be used for risk stratification for persistent symptoms and diminished physical functioning with the purpose of developing and implementing targeted interventions.
Introduction
Breast cancer (BC) is the most common cancer among women in high-income countries, and advances in diagnostics and treatment have improved survival considerably. Many women with BC, however, experience a multitude of symptoms due to cancer treatment or psychological strain. For most women, these symptoms diminish after primary treatment, but for some, symptoms may persist or develop years after primary treatment [Citation1,Citation2]. Fatigue, pain and insomnia are among the most common complaints in BC survivors that interfere with everyday life [Citation3], with a prevalence of 20-49% for fatigue and pain and 19% for insomnia 5 years after primary treatment [Citation1]. The symptoms have been found to impact one another [Citation4] and co-exist in a so-called symptom cluster both before, during and after treatment [Citation5]. Symptom clusters are defined as two or more symptoms that are related to each other in a relatively stable manner and can but are not required to, share an underlying etiology and can be measured according to symptom severity i.e., symptom burden [Citation6]. A recent systematic review has established the cluster of fatigue-pain-insomnia as prevalent among BC patients and survivors [Citation5].
The presence of fatigue, insomnia and pain individually before and during cancer treatment has been found to be associated with persistent symptoms in survivorship, as well as negative effects on physical and psychological functioning [Citation7,Citation8]. High symptom burden has also been associated with diminished functioning one year after the start of chemotherapy [Citation9] but studies extending beyond the first 2 years of survivorship are lacking [Citation4]. Quality of life (QOL) measures may be affected by psychosocial adaption and response shift, with BC survivors rating their QOL similarly to women without BC despite a higher severity of symptoms [Citation10,Citation11]. Therefore, symptom burden is crucial to understanding the differential, long-term effects of cancer treatment and the importance of early intervention against persistent symptoms and diminished functioning. In this longitudinal study, we examined the burden of the symptom cluster fatigue-pain-insomnia among women shortly after BC surgery and investigate if symptom burden after surgery is a prognostic factor for long-term changes in symptom severity and emotional and physical functioning.
Materials and methods
Study design
This study was a secondary analysis of the single-blinded randomized controlled trial (RCT) LYCA. The aim of the LYCA trial was to investigate the effect of progressive resistance training on lymphedema and QOL in women diagnosed with BC. The LYCA trial has been described in detail elsewhere [Citation12,Citation13]. In brief, participants were recruited from three hospitals covering East Denmark between August 2015 and January 2017. Eligible patients were women between the ages of 18–75 with primary unilateral BC and no distant metastases, undergoing BC surgery with axillary lymph node dissection (ALND). All participants received radiotherapy and where indicated, chemotherapy (Epirubicin, Docetaxel/Paclitaxel, and Cyclophosphamide) was administered according to protocol. Hormone treatment was given according to receptor status, and Human epidermal growth factor receptor 2 (HER2)-positive patients were offered Trastuzumab. The intervention consisted of progressive resistance training three times a week, supervised during the first 20 weeks, and self-administered for the following 30 weeks. The control arm received usual care consisting of the availability of, but not consistent referral to, physiotherapy in the municipality, focusing on upper limb movement and function. Computer randomization was performed after baseline measurements 2 weeks after surgery. Follow-up measurements were performed at 20 weeks, 1 year and approximately 3.5 years after surgery.
Outcomes
The patient-reported outcomes were assessed with The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) which has been validated for use in cancer patients [Citation14]. Items concerning symptom and function experiences in the last week were scored from 1–4 and trans-formed to a scale from 0 to 100. Higher scores on the fatigue, insomnia and pain scales indicated worse symptoms, and higher scores on the emotional and physical functioning scales indicated better functioning [Citation15].
Information on clinical and treatment variables was obtained through the Danish Breast Cancer Group database, including tumor size, number of positive lymph nodes, estrogen receptor status, HER2-status, histology, type of surgery, chemotherapy and hormone treatment. A baseline questionnaire assessed employment, cohabitation, education, weight, height, self-reported daily physical activity, alcohol consumption and smoking. Clinically relevant lymphedema at 12 months was defined as a combination of clinical assessment (>3% increased interlimb volume difference and the presence of 2 or more clinical criteria (skin thickness of hand and wrist, visibility of veins in the lower arm and hand and pitting oedema), as well as 2 or more points on Numeric Rating Scale combined for “heaviness” “swelling” and “pain” [Citation12].
Statistical analysis
We used latent profile analysis and as described by Spurk and colleagues [Citation16] to test models with one to four groups with different severities of fatigue, pain and insomnia two weeks after surgery. Estimation of the different models was carried out by using the expectation-maximization algorithm and starting values for estimation were derived from hierarchical clustering, as determined in the mclust package in R [Citation17]. Estimation of models included mean symptom scores of groups, and participants’ probabilities of belonging to groups. Fit indices were calculated to determine which number of groups best fit the data and included the Akaike information criteria (AIC), Bayesian information criteria (BIC), Size adjusted Bayesian information criteria (SABIC), Bootstrapped likelihood ratio test (BLRT) and entropy [Citation16]. The process of choosing which model best-fitted data was performed by first assessing which models had lowest information criteria (IC) values, then ensuring entropy was >0.8, and that BLRT p-value was <0.05. When evaluating model fit, we aimed to only include groups that were distinct from one another and included a minimum of 25 participants, as recommended by Spurk and colleagues [Citation16]. After choosing the model with the best fit, each participant was assigned to the symptom burden group to which they had the highest probability of belonging.
Descriptive statistics were calculated for the groups found, with tests of association with baseline characteristics, including χ2-test for categorical variables and t-test of equality of means for continuous variables [Citation18].
To estimate the changes in symptoms and functioning over time for each group, mixed effects Tobit regression models were applied [Citation19]. Fixed effects in each model were follow-up visit, symptom burden group, RCT study arm and an interaction term between follow-up visit and symptom burden group. Additional analyses were performed with an interaction term between the symptom burden group and hormone treatment status added to previous models due to the unequal distribution of hormone treatment among symptom groups. Estimates represent changes in symptom and functioning scores with 95% confidence intervals (CI) and were presented graphically. A possible correlation between observations on the same individual was considered with a random effect on a subject level with an unstructured covariance matrix.
Latent profile analysis was performed using R version 4.1.0 and all other analyses were performed using Stata version 16.1.
Results
Latent profile analysis of symptom burden two weeks post-surgery
A 2-group model was chosen based on higher entropy and p-value <0.05 for the BLRT, compared to a 3-group model that had similarly low AIC, BIC and SABIC values (). The two groups emerged as i) the low symptom burden group consisting of 80% of participants (n = 127), and ii) the high symptom burden group consisting of 20% of participants (n = 31) (). The high symptom burden group had more participants in the control arm (65% vs. 44%), were slightly younger (49.2 vs. 52.8 years), more often received hormone treatment (42% vs. 22%) and more were treated with a mastectomy (61% vs. 43%) ().
Table 1. Fit indices for one-four group models in latent profile analysis at baseline to determine which number of groups best fit the data in 158 women at high risk for symptoms after surgery for breast cancer participating in the LYCA study.
Table 2. Association between baseline characteristics and symptom burden groups in 158 women at high risk for symptoms after surgery for breast cancer participating in the LYCA study.
Trends in symptoms and functioning over time
The estimated fatigue and pain scores for the low symptom burden group decreased throughout the 3.5 years of follow-up (). For the high symptom burden group, fatigue and pain scores decreased during the first 20 weeks and increased (fatigue) or remained stable (pain) at 12 months. At 3.5 years fatigue and pain severity increased further, with symptom scores being 2-3 times higher than the low symptom burden group. Conversely, the insomnia score for the low symptom burden group increased during the first year after surgery and decreased slightly during the following period until 3.5 years after surgery. For the high symptom burden group, insomnia decreased steadily over time, although the score was twice as high as the low symptom burden group at 3.5 years ().
Figure 1. Estimated mean symptom scores with 95% confidence intervals at 20 weeks, 1 year and 3.5 years for 127 women with low symptom burden at baseline (blue circle) and 31 women with high symptom burden at baseline (orange triangle) after breast cancer surgery with axillary lymph node dissection, LYCA, Denmark, 2015–2018. Higher symptom scores reflect higher symptom severity. (a) Mean pain severity. (b) Mean insomnia severity. (c) Mean fatigue severity.
For the low symptom burden group, physical functioning improved during the first year after surgery and remained stable at 3.5 years. Conversely, for the high symptom burden group, physical functioning was stable during the first 20 weeks, but decreased consistently hereafter. At 3.5 years the high symptom burden group had an estimated physical functioning that was almost 20 points lower than the low symptom burden group (). Emotional functioning improved over time for the low symptom burden group. In the high symptom burden group, it decreased during the first year and was then improved at 3.5 years, with no statistically significant difference between groups (). Estimates of changes in symptom severity and functioning can be found in Supplementary Table S1 and S2.
Figure 2. Estimated mean functioning scores with 95% confidence intervals at 20 weeks, 1 year and 3.5 years for 127 women with low symptoms (blue circle) and 31 women with high symptoms (orange triangle) after breast cancer surgery with axillary lymph node dissection, LYCA, Denmark, 2015–2018. Higher functioning scores reflect better functioning. (a) Mean emotional functioning. (b) Mean physical functioning.
In the additional analyses where we accounted for interaction between the symptom burden group and hormone treatment, we found that women with high symptom burden receiving hormone treatment had higher pain scores and worse physical functioning than high symptom burden women not receiving hormone treatment (Tables S3 and S4).
Discussion
In this study, we were able to identify two distinct symptom burden groups two weeks after BC surgery – a large group of women with low severity and a smaller group of women with high severity of coexisting pain, fatigue and insomnia. Among women, who at the time of surgery reported a high symptom burden, clinically important differences [Citation20] in pain, insomnia and fatigue scores persisted 3.5 years later compared to the low symptom burden group. While the two groups had similar physical functioning shortly after BC surgery, physical functioning deteriorated throughout the 3.5 years of follow-up for women with high symptom burden, while women with low symptom burden post-surgery had consistent high physical functioning.
The symptom cluster of fatigue, pain, and insomnia has been frequently reported by women with BC in the years after primary treatment, although the severity of these symptoms varies greatly on the individual level. In the present study, 20% of patients experienced a high symptom burden shortly after surgery, while the rest had symptom scores similar to EORTC QLQ-C30 reference values for pretreatment BC patients aged 50–59 [Citation21]. Other studies examining the burden of the symptom cluster also report high and low symptom burden groups after surgery, with the high symptom burden group encompassing from 7 to 30% of the patients [Citation9,Citation22–25]. Our study recruited patients that may be considered at higher risk of symptoms, due to ALND and radiotherapy and the associated risk of lymphedema [Citation26], which is why a considerable proportion with high symptom scores can be expected.
The fatigue, insomnia and pain cluster is often named a psychoneurological symptom cluster, which has been found to exist before and during chemotherapy [Citation22] and in long-term survivorship [Citation27]. Some studies further include psychological components such as cognitive impairment, depression, anxiety, or distress in the psychoneurological cluster. Studies performing latent profile analysis (n = 391–1500) have found groups with moderate to high severity of fatigue, insomnia, and pain both with and without a psychological component present [Citation25,Citation28,Citation29]. We were unable to determine if an additional group with a psychological component was present in the study population because such a factor was not measured at baseline. Women with high symptom burden experienced a worsening of emotional functioning during the first year, but this recovered to a high emotional functioning at 3.5 years, similar to women with low symptom burden. This could indicate a response shift among participants, where adaptation to life as a BC survivor and symptom burden understandably takes longer for women with more severe symptoms.
A recent systematic review of symptom clusters at different stages in the BC trajectory found that the composition of clusters changed over time, with fatigue, insomnia and pain being core symptoms before and during treatment, while only fatigue and insomnia were core symptoms after treatment [Citation5]. In a qualitative study, Kvekkeboom et al. investigated the relationship between symptoms, as understood by cancer patients themselves (n = 38, 24% BC). Insomnia was found to be an intermittent symptom, while fatigue and pain were the most common, persistent symptoms [Citation30]. Further, they found high variability in the symptom clusters described by the cancer patients. Only 9 symptom clusters out of the 72 reported were replicated, with the most frequent clusters being a variation of fatigue-pain-insomnia, with the occasional inclusion of depression and anxiety [Citation30]. The available evidence suggests that fatigue, insomnia and pain are frequently reported as core symptoms in clusters in BC populations, although the combination of symptoms in a cluster and in particular which clusters can be identified may depend largely on statistical methodology, symptom assessment, demography of study populations, disease stage and treatment [Citation5,Citation31].
Previous studies as well as the present study show that symptom clusters persist for a smaller group of women in survivorship. Bjerkeset et al. found that 13% of 834 BC survivors experienced a symptom cluster of pain, fatigue and psychological distress 2–6 years after surgery, while 63% of survivors experienced at least one symptom [Citation32]. A recent study from Nielsen et al. investigated symptom burden trajectories in 968 BC patients, and found groups with an initial low symptom burden with decreasing fatigue, pain and insomnia over time and an initial high symptom burden with decreasing fatigue, and increasing pain and insomnia over time [Citation33]. This differs slightly from our study, in that fatigue increased and insomnia decreased among women with high symptom burden. This could be due to differences in surgical extent (only 40% received ALND vs. 100% in our study) measurement over time (12-month time slots vs. fixed time points) or different analytical methods used (growth mixture modeling vs. Tobit mixed effects models).
In the present study, women with a high symptom burden after surgery had a reduced mean physical functioning 3.5 years later, despite having physical functioning like women with low symptom burden post-surgery. Other studies also find that patients with a high symptom burden experience diminished function during treatment [Citation30,Citation34,Citation35], shortly after chemotherapy [Citation25], 1 year after the end of chemotherapy [Citation9] and 2 years after surgery [Citation36]. A review found that BC survivors experience more unmet needs than other cancer survivors, with 49-88% reporting at least one unmet need, which in turn was associated with greater symptom burden and negatively impacted physical well-being and QOL [Citation37]. Furthermore, persistently declining physical functioning in the first 2 years after BC treatment predicted worse 10-year survival in a study of 689 BC patients [Citation38]. This indicates that BC survivors with a high symptom burden, which in the present study constitutes one in five women, may have unmet rehabilitation needs associated with worsened physical functioning and perhaps even excess mortality.
The high symptom burden group were younger, and more received mastectomy (vs. lumpectomy) and hormone treatment (vs. none). In the literature, one of the most consistent characteristics associated with high symptom burden in BC is younger age [Citation23,Citation28,Citation29,Citation38–40]. Other characteristics include unemployment [Citation29,Citation39], living alone [Citation28,Citation40], low-performance status [Citation39,Citation40], and the existence of comorbidities [Citation29,Citation40]. The combination of several treatments such as chemotherapy, radiation therapy and extensive surgery seems to be associated with a higher symptom burden [Citation25] and adjuvant hormone treatment may worsen existing symptoms [Citation41]. Further, BC patients treated with ALND and radiation therapy are at great risk of developing lymphedema [Citation26], which in turn is linked to fatigue [Citation7], lower HRQOL, worsened pain and physical functioning [Citation42]. In the present study, there were no differences between symptom burden groups in the development of lymphedema at 12 months () although available literature suggests that both pain and fatigue may be associated factors [Citation43,Citation44]. However, in the present study, we found an interaction between hormone treatment and symptom burden, implying that women with a high symptom burden experienced more pain and reduced physical functioning. Similar results were found in a large cohort study of BC survivors (n = 4262), although the effects of hormone treatment seemed to differ with menopausal status [Citation45].
Strengths and limitations
Strengths of this study include the long-term follow-up with prospectively collected clinical and patient-reported data. Further, the use of mixed effects Tobit regression allowed an optimal strategy for repeated measures and handling missing data under the assumption of missing at random [Citation46]. The use of latent profile analysis enabled forming of symptom groups that were relevant for the study population, rather than using cut-points not suited to the population at hand. The two-group solution had a high entropy, which suggests that symptom burden groups were distinct from one another. Furthermore, baseline measurement before initiation of chemotherapy and radiotherapy enabled us to form latent symptom groups without the influence of chemotherapy and radiotherapy on symptom burden in patients.
A limitation of the study was the relatively small population size, which diminished the ability to identify smaller groups and more nuanced symptom experiences. Sample size also hindered investigation of whether the intervention had a differential impact on symptoms and functioning in the two groups over time, with earlier LYCA studies finding no consistently significant differences in pain between the control and intervention groups [Citation13]. Further, as there were no suitable measurements for a psychological component or comorbidity, we could not include this in our analysis. The original study was conducted as an RCT examining the effect of resistance training. This presents a potential risk of self-selection, in that healthier patients and more physically able post-surgery would choose to participate in such an intervention study [Citation47]. This may limit the reliability of our results for patients with BC in general. However, the study was conducted in a tax-paid healthcare system with free access to services at all levels from the GP to the highly specialized hospital department, reducing this risk of impaired reliability as the majority of patients were offered physiotherapy post-operatively.
Clinical and research implications
This study highlights that a significant portion of women with BC already exhibits a high symptom burden shortly after surgery that persists years into survivorship and is associated with permanently reduced physical functioning. This calls for prospective surveillance of symptom burden, and emotional and physical functioning throughout the care continuum to provide timely management and prevent late effects. Characteristics such as young age, hormone treatment and a number of treatment modalities may add to disparities in symptom burden and should be considered in surveillance. While the concept of symptom clusters is still being defined, a key element going forward should be the synergistic effect between symptoms [Citation48]. Focus on symptom burden and relationships between symptoms in conversation with the patient can guide healthcare professionals to a better understanding of the effects of treatment and accommodate symptom management. The systematic use of patient-reported outcomes may enable healthcare professionals to better observe which symptoms interfere most with QOL and functioning [Citation49]. Few RCT’s targeting whole symptom clusters rather than individual symptoms exist, and as indicated by a recent systematic review, interventions in the first post-operative year are feasible and may reduce fatigue, pain and insomnia but large-scale studies are lacking [Citation50]. The focus going forward should be the establishment of larger cohorts of cancer patients including long-term follow-up interventions targeting the total symptom burden and core symptoms.
Conclusions
In this study, we found that one out of five high-risk women with BC experience a high symptom burden from coexisting pain, insomnia, and fatigue shortly after surgery. These women still experience consistently higher and clinically significant symptom severity and diminished physical functioning compared to women with low symptom burden 3.5 years after surgery. This warrants assessment of symptom burden early in the treatment phase of breast cancer to facilitate timely interventions.
Author contributions
Conceptualization, F.E, G.A, T.H, S.D and I.A.; methodology, F.E., G.A and S.D; software, F.E.; formal analysis, F.E.; investigation, G.A.; data curation, G.A, B.Z; writ-ing—original draft preparation, F.E.; writing—review and editing, F.E., G.A, T.H., I.A., C.J., B.Z. and S.D; visualization, F.E.; supervision, G.A. and S.D; project administration, G.A, C.J. and S.D.; funding acquisition, G.A., S.D. and C.J. All authors have read and agreed to the published version of the manuscript.
Ethics
The LYCA study adhered to the World Medical Association Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Informed consent was obtained from all subjects involved in the study. LYCA was approved by the ethics committee of the Capital Region of Denmark (H-15002714) and was registered at ClinicalTrials.gov (NCT02518477) before recruitment.
Supplemental Material
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No potential conflict of interest was reported by the author(s).
Data availability
Anonymized data in the LYCA study is available upon reasonable request.
Additional information
Funding
References
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