Is There a Biological Basis for the Clustering of Symptoms?

doi:10.1016/j.soncn.2007.01.008

Seminars in Oncology Nursing

Volume 23, Issue 2, May 2007, Pages 99-105

https://doi.org/10.1016/j.soncn.2007.01.008 Get rights and content

Objectives

To examine symptom clusters in oncology patients; to determine if these symptom clusters might share a common biologic mechanism; and to describe potential biologic mechanisms that warrant investigation.

Data Sources

Synthesis of the theoretical and research papers on symptom clusters.

Conclusion

Definitive conclusions about whether there is a biologic basis for the clustering of symptoms cannot be determined at this time. The animal model of sickness behavior holds promise as a potential biologic mechanism for clustering symptoms.

Implications for Nursing Practice

Until more definitive studies of symptom clusters are performed, clinicians need to monitor patients for the co-occurrence of multiple symptoms and develop appropriate management plans.

Section snippets

Similarities and Differences in Symptom Clusters in Oncology Patients

The studies on symptom clusters in oncology patients can be categorized into two groups. In one group (summarized in Table 1),3, 4, 8 the investigators created an a priori cluster of symptoms and evaluated the impact of that symptom cluster on a patient outcome. In the second group (summarized in Table 2),4, 5, 6, 7, 8, 9, 10, 11, 12, 18 oncology patients completed a symptom inventory and in some of these studies, symptom clusters were identified empirically using either cluster analysis or

Cytokine-Induced Sickness Behavior

In a recent review, Cleeland et al²² suggest that the symptoms of cancer and cancer treatment may be due, in part, to a shared biologic mechanism, cytokine-induced sickness behavior. Sickness behavior can be observed in sick animals23, 24 or induced with the administration of the pathophysiologic components of bacteria (eg, lipopolysaccharide). Predictable physiologic responses occur in animals to lipopolysaccharide include fever, pain, wasting, and increased activity in the

Implications for Practice and Research

The science of symptom cluster research is still in its infancy. This line of inquiry is extremely important to reduce the symptom burden that patients experience on a daily basis. However, based on the symptom cluster studies conducted to date, it is not possible to draw definitive conclusions about whether or not there is a biologic basis for the symptom clustering.

The need exists to determine which symptoms co-occur within the context of a specific cancer diagnosis and cancer treatment

Christine Miaskowski, RN, PhD, FAAN: Professor, Department of Physiological Nursing, University of California, San Francisco, CA

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Cited by (68)

Symptom cluster profiles following traumatic orthopaedic injuries
2022, Injury
Millions of Americans experience traumatic orthopaedic injuries (TOIs) annually. Post-injury symptoms of acute stress disorder (ASD), anxiety, depression, pain, and sleep disturbance are common. Symptoms often present in clusters. Symptom cluster profiles phenotypically characterize TOI survivors’ experiences with clustered symptoms. Expression of brain-derived neurotrophic factor (BDNF) may contribute to the biological underpinnings of symptom cluster profile membership.
We recruited hospitalized TOI survivors within 72 hours of injury. We measured symptoms of ASD with the Acute Stress Disorder Scale and symptoms of anxiety, depression, pain, and sleep disturbance with Patient-Reported Outcomes Measurement Information System (PROMIS) short forms. We measured serum BDNF concentrations with enzyme-linked immunosorbent assay (ELISA) and identified rs6265 genotypes with TaqMan real-time PCR. We performed latent profile analysis to identify the symptom cluster profiles. We identified the variables associated with symptom cluster profile membership with unadjusted and adjusted multinomial logistic regression.
We identified 4 symptom cluster profiles characterized by symptom severity that we labelled Physical Symptoms Only, and Mild, Moderate, and Severe Psychological Distress. Age, self-identified Black race, resilience, and serum BDNF concentrations were associated with lower odds, and female sex with higher odds, of being in the Psychological Distress clusters. Clinical characteristics and rs6265 genotypes were not associated with symptom cluster profile membership.
TOI survivors experience distinct symptom cluster profiles. Sociodemographic characteristics and serum BDNF concentrations, not clinical characteristics, were associated with symptom cluster profile membership. These findings support comprehensive symptom screening and treatment for all TOI survivors and further evaluating BDNF as a biomarker of post-injury symptom burden.
Stability of Symptom Clusters in Patients With Gastrointestinal Cancers Receiving Chemotherapy
2019, Journal of Pain and Symptom Management
Limited evidence suggests that patients with gastrointestinal (GI) cancers receiving chemotherapy (CTX) experience an average of 13 co-occurring symptoms. An alternative to counting symptoms is to evaluate for symptom clusters.
In a sample of patients with GI cancers receiving CTX (n = 399), we evaluated the occurrence, severity, and distress of 38 symptoms in the week before patients' second or third cycle of CTX (Time 1 [T1]), approximately one week after CTX (Time 2 [T2]), and approximately two weeks after CTX (Time 3 [T3]); evaluated for differences in the number and types of symptom clusters at each of these three assessments using ratings of occurrence, severity, and distress; and evaluated for changes in symptom clusters over time.
Modified version of the Memorial Symptom Assessment Scale collected data on 38 common symptoms. Exploratory factor analyses were used to create the symptom clusters.
Five distinct symptom clusters were identified across the three symptom dimensions and the three assessments (i.e., psychological, CTX-related, weight change, GI, and epithelial). Psychological, CTX-related, and weight change clusters were relatively stable across all three symptom dimensions and time. Across all three symptom dimensions, GI cluster was identified only at T1 and epithelial cluster was identified at T2 and T3.
The number and types of symptom clusters appear to be relatively stable over time and across the symptom dimensions. Ongoing assessment and management of these clusters is warranted across the entire course of CTX. The underlying mechanism for these clusters warrants investigation.
The Effect of the Pain Symptom Cluster on Performance in Women Diagnosed with Advanced Breast Cancer: The Mediating Role of the Psychoneurological Symptom Cluster
2018, Pain Management Nursing
Background: Pain, depression, anxiety, sleep disturbances, and constipation were reported in different symptom clusters at different stages of breast cancer. Managing symptom clusters rather than individual symptoms can improve performance status. Aim: The study examined the effect of pain symptom cluster (pain and constipation) on performance when mediated by the psychoneurological symptom cluster (depression, anxiety, and sleep disturbances) using age as a moderator. Design: A secondary analysis. Settings: Palliative care center at a tertiary medical center in northeast Ohio. Participants: Eighty-six women diagnosed with advanced breast cancer. Method: A quantitative cross-sectional approach. Results: Ordinal logistic regression showed that pain symptom cluster did not have a significant mediation effect on performance. Odds ratio indicated that subjects with pain symptom cluster were 63% more likely to be bedridden (odds ratio = 1.63, confidence interval = .69-3.84). Women who reported pain symptom cluster were 5% more likely to have psychoneurological symptom cluster (odds ratio = 1.05, confidence interval = .400-2.774). Stratified analysis of age showed no differences in performance. Post-hoc analysis showed that the components of pain symptom cluster had a significant effect on psychoneurological symptom cluster (odds ratio: 3 [1.18-7.62]). Conclusions: Pain, constipation, depression, anxiety, and sleep disturbances were highly prevalent in women with advanced breast cancer. However, they tended to cluster in different symptom clusters. Although some findings were not significant, they all supported the direction of the tested hypotheses. Variations in symptom clusters research, including methodology, instruments, statistical tests, and chosen symptom cluster correlation coefficient, should be addressed.
Older Age, Early Symptoms and Physical Function are Associated with the Severity of Late Symptom Clusters for Men Undergoing Radiotherapy for Prostate Cancer
2018, Clinical Oncology
Citation Excerpt :
Clinical practice often focuses on single symptoms [41,42]. However, the association and interaction between cancer symptoms should be explored [43–45]. In addition to the clinical consideration of symptoms in groups, symptom clusters allow a flexible and sample-specific way of analysing PROs [46].
To identify symptom clusters and predisposing factors associated with long-term symptoms and health-related quality of life after radiotherapy in men with prostate cancer.
Patient-reported outcomes (PROs) data from the Medical Research Council RT01 radiotherapy with neoadjuvant androgen deprivation therapy trial of 843 patients were used. PROs were collected over 5 years with the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI) and the 36 item Short-Form Health Survey (SF-36). Symptom clusters were explored using hierarchical cluster analysis. The association of treatment dose, baseline patient characteristics and early symptom clusters with the change in severity of PROs over 3 years was investigated with multivariate linear mixed effects models.
Seven symptom clusters of three or more symptoms were identified. The clusters were stable over time. The longitudinal profiles of symptom clusters showed the onset of acute symptoms during treatment for all symptom clusters and significant recovery by 6 months. Some clusters, such as physical health and sexual function, were adversely affected more than others by androgen deprivation therapy, and were less likely to return to pretreatment levels over time. Older age was significantly associated with decreased long-term physical function, physical health and sexual function (P < 0.001). Both baseline and acute symptom clusters were significant antecedents for impaired function and health-related quality of life at 3 years.
Men with poorer physical function and health before or during treatment were more likely to report poorer PROs at year 3. Early assessment using PROs and lifestyle interventions should be used to identify those with higher needs and provide targeted rehabilitation and symptom management.
Differences in symptom clusters before and twelve months after breast cancer surgery
2018, European Journal of Oncology Nursing
Citation Excerpt :
While it is common to require that each item load strongly on only one factor, in this study, items that loaded with an absolute value of ≥0.40 on two factors (i.e., cross loaded), were retained and used to define both factors. The cross loading of symptoms on more than one factor may be beneficial in the interpretation of potential causal mechanisms, especially when oblique rotation is employed (Brown, 2015; Browne, 2001; Miaskowski and Aouizerat, 2007). EFA was used to identify symptom clusters from the occurrence rates and the severity ratings of 24 out of the 46 MSS symptoms.
Given the inter-relatedness among symptoms, research efforts are focused on an evaluation of symptom clusters. The purposes of this study were to evaluate for differences in the number and types of menopausal-related symptom clusters assessed prior to and at 12-months after surgery using ratings of occurrence and severity and to evaluate for changes in these symptom clusters over time.
Prior to and at 12 months after surgery, 392 women with breast cancer completed the Menopausal Symptoms Scale. Exploratory factor analyses were used to identify the symptom clusters.
Of the 392 women evaluated, the mean number of symptoms (out of 46) was 13.2 (±8.5) at enrollment and 10.9 (±8.2) at 12 months after surgery. Using occurrence and severity, three symptom clusters were identified prior to surgery. Five symptom clusters were identified at 12 months following surgery. Two symptom clusters (i.e., pain/discomfort and hormonal) were relatively stable across both dimensions and time points. Two symptom clusters were relatively stable across both dimensions either prior to surgery (i.e., sleep/psychological/cognitive) or at 12 months after surgery (i.e., sleep). The other four clusters (i.e., irritability, psychological/cognitive, cognitive, psychological) were identified at one time point using a single dimension.
While some menopausal-related symptom clusters were consistent across time and dimensions, the majority of symptoms clustered together differently depending on whether they were evaluated prior to or at 12 months after breast cancer surgery. An increased understanding of how symptom clusters change over time may assist clinicians to focus their symptom assessments and management strategies.
Stability of Symptom Clusters in Patients With Breast Cancer Receiving Chemotherapy
2018, Journal of Pain and Symptom Management
Patients with breast cancer who undergo chemotherapy (CTX) experience between 10 and 32 concurrent symptoms. An evaluation of how these symptoms cluster together and how these symptom clusters change over time may provide insights into how to treat these multiple co-occurring symptoms.
The purposes of this study were to determine the occurrence rates and severity ratings for 38 common symptoms, evaluate for differences in the number and types of symptom clusters, and evaluate for changes over time in these symptom clusters (i.e., before CTX, the week after CTX, and two weeks after CTX).
At each of the assessments, a modified version of the Memorial Symptom Assessment Scale was used to assess the occurrence and severity of the 38 symptoms. Exploratory factor analyses were used to extract the symptom clusters.
Although across the two symptom dimensions (i.e., occurrence and severity) and the three assessments, eight distinct symptom clusters were identified, only five were relatively stable across both dimensions and across time (i.e., psychological, hormonal, nutritional, gastrointestinal, and epithelial). Two of the additional clusters varied by time but not by symptom dimension (i.e., sickness behavior and weight change). The CTX neuropathy cluster was identified only at the assessment performed in the week after CTX.
These findings provide insights into the most common symptom clusters in patients undergoing CTX for breast cancer. In addition, the most common symptoms within each cluster appear to be relatively stable across the two dimensions, as well as across time.

View all citing articles on Scopus

Christine Miaskowski, RN, PhD, FAAN: Professor, Department of Physiological Nursing, University of California, San Francisco, CA

Bradley E. Aouizerat, PhD: Assistant Professor, Department of Physiological Nursing, University of California, San Francisco, CA

: Supported in part by grants from the National Cancer Institute, the National Institute of Nursing Research, the Academic Senate of the University of California, San Francisco and the Oncology Nursing Society.

View full text

Is There a Biological Basis for the Clustering of Symptoms?

Objectives

Data Sources

Conclusion

Implications for Nursing Practice

Section snippets

Similarities and Differences in Symptom Clusters in Oncology Patients

Cytokine-Induced Sickness Behavior

Implications for Practice and Research

J Pain Symptom Manage

J Pain Symptom Manage

J Pain Symptom Manage

Semin Oncol Nurs

Neurosci Biobehav Rev

Vet Clin North Am Small Anim Pract

Vet Clin North Am Food Anim Pract

Trends Neurosci

Neurosci Biobehav Rev

Eur J Pharmacol

Neuropsychopharmacology

Symptom clusters: establishing the link between clinical practice and symptom management research

Support Care Cancer

Symptom clusters: the new frontier in symptom management research

J Natl Cancer Inst Monogr

Symptom clusters and their effect on the functional status of patients with cancer

Oncol Nurs Forum

Pain, sleep disturbance, and fatigue in patients with cancer: using a mediation model to test a symptom cluster

Oncol Nurs Forum

An analytic strategy for modeling multiple-item responses: a breast cancer symptom example

Nurs Res

Symptom clusters in elderly patients with lung cancer

Oncol Nurs Forum

A cluster of symptoms over time in patients with lung cancer

Nurs Res