Authors
- Nguyen, Ly Thuy
- Yates, Patsy
- Annoussamy, Lourdes Clemenceau
- Truong, Trung Quang
Abstract
Review question/objective: To what extent are non-pharmacological interventions effective in reducing symptom clusters in terms of presence, frequency and severity, compared with standard care?
More specifically, the objectives are to:
* Identify the effectiveness of non-pharmacological interventions in reducing symptom clusters in terms of presence, frequency, distress and severity, and their impacts on adult cancer patients.
* Examine the characteristics of effective interventions (e.g. intervention components, delivery methods and clinical contexts) in decreasing symptom clusters in terms of presence, frequency and severity, and their impacts on adult cancer patients.
Center conducting the review: The Hanoi Medical University Nursing Research Center for Evidence Based Health Care: a Collaborating Centre of the Joanna Briggs Institute; and Centre for Evidence-based Healthy Aging: an Affiliate Centre of the Joanna Briggs Institute, School of Nursing, Queensland University of Technology, Australia.
Article Content
Background
Cancer patients often experience a variety of symptoms as a consequence of their disease and treatment. A number of studies identify that cancer patients report multiple symptoms simultaneously.1-3 A review of literature indicates that depending on the patient sample, the methodology employed and the various measurements used, approximately 40-61% of cancer patients, across diverse diagnostic groups at different times of their disease trajectory in any phase of treatment experience at least two symptoms.4 Among those, around 22-30% of patients experience more than five symptoms. A core set of 12 common cancer-related symptoms has been recommended to be included in adult cancer effective interventions by a panel of symptom assessment experts from the Centre for Medical Technology Policy.5,6 The core symptom concept is supported by two systematic reviews of observational studies focusing on multi-symptom prevalence with large patient samples in different diagnosis groups.4,7 A number of literature reviews indicate that across numerous studies using different approaches, various combinations of multiple core symptoms form different clusters, according to host factors, cancer types and treatments.8-17
The pioneering researchers, Dodd et al., define a "symptom cluster" as three or more concurrent symptoms that are related to each other.18(p.465) In contrast, Molassiotis et al. define a symptom cluster as "two or more symptoms that are clinically meaningful together, related to each other at a given time and share a significant variance in their cluster".19(p.857) Although there are similarities between these definitions in terms of the strong correlations that coexist among symptoms within the group, there are conceptual disagreements about some of the essential elements in the definitions of a symptom cluster. For example, some researchers have identified the relationship by the correlation between symptoms,20 whereas others have measured the relationship by the effect of symptoms on outcomes.21 Researchers have varying ideas about whether a symptom can be put exclusively in one cluster22,23 or it can be shared by different clusters.19,24,25 Another discrepancy in the definition of symptom clusters is the longitudinal stability of clusters19,26-28 or whether all symptoms in a cluster should be present at the same time.19,29 These differing understandings of the concept, along with variations in methods and study samples, result in differing findings from intervention studies on managing symptom clusters.
Symptom clusters can interfere with adherence to treatments and consequently impact compliance with therapeutic regimen and lead to interruption or cessation.30 Moreover, there is evidence that symptom clusters have a clinical outcome that differs according to individual symptoms,18,19,23 although it has been noted that the total impact of a cluster may be greater than the sum of the impact of the individual symptoms.31 This is supported by a growing number of studies which report that the presence of symptom clusters can result in poor performance status,32-35 reduced physical functioning,35-38 poor quality of life,35,39-41 shorter survival time34,42 and interference with daily functioning.43,44 For this reason, researchers need to understand the complexity of the patients' symptom cluster experiences and their underlying causes, to identify effective symptom management strategies. However, the mechanisms that are both necessary and sufficient to induce the development of cancer symptom clusters are complex and insufficiently understood.
According to Cleeland et al.,45 cancer symptom clusters can share biological mechanisms. This hypothesis is supported by several studies proposing that proinflammatory cytokines, which are associated with sickness behavior in animals, can contribute to the production of the symptom clusters of fatigue, pain, sleep disturbance, cognitive dysfunction, depression and anxiety in patients with cancer.46-50 Moreover, other possible biological pathways, such as the monoamine neurotransmission system and the hypothalamic-pituitary-adrenal axis49,51 or cytokine genes,52 are also identified as linking with a cluster of fatigue, pain, sleep disturbance and depression. In contrast, symptoms within a cluster may share a biological mechanism, but this does not imply that they have the same etiologies (e.g. pain from bone metastasis, fatigue from treatment and depression from financial problems).53 Although it is acknowledged that symptom clusters might not necessarily share the same etiologies,23 it is reasonable to develop an intervention that targets one symptom to relieve other symptoms.54-59 Equally important, a specific intervention can be designed for managing multiple concurrent symptoms when they share the same biological mechanisms.60-66 However, it is not well understood which of these two approaches might be more effective for certain symptom clusters, as inconsistencies were revealed across a number of studies concerning the efficacy of interventions for different patient groups.
As symptoms are often a subjective experience, non-pharmacological management has the potential value as adjuncts to pharmacological interventions. Non-pharmacological interventions designed to manage cancer symptoms have the advantage of identifying multiple symptoms and are acceptable to most patients.67-70 A number of systematic reviews on non-pharmacological interventions gives more attention to prospectively controlling a single symptom and measuring the impact on the other symptoms, such as fatigue,71,72 pain,73-75 sleep disturbance,76,77 along with depression and anxiety.78,79 Recently, there has been an increasing number of systematic reviews involving randomized controlled trials targeting management of multiple symptoms.80-85 There have been previous reviews that were restricted to particular treatments86 for individual symptoms within specific clusters86,87 in certain patient groups 87 as well as cancer-free survivors.86-88 Specifically, the first review that focused only on clusters of fatigue, sleep disturbance and depression was presented in a symposium without full-text publication.87 Similarly, the second review particularly included mind-body treatment for pain, fatigue and sleep disturbance.86 The third review included different interventions for various multiple symptoms.88 However, there was neither evidence of critical appraisal of the included studies nor data extraction in these reviews. Recommendations and review conclusions were drawn from a simple summary of included studies, regardless of the lack of systematic review process. In addition, these reviews did not comprehensively focus on studies that targeted symptom clusters per se, because of a lack of the concept of a symptom cluster in inclusion criteria. Moreover, in these reviews, there was no detailed analysis of the characteristics of the effective interventions and their significant impacts on individual and multiple symptoms within clusters. Evidence, therefore, is limited on examination of the relative effectiveness of non-pharmacological interventions on symptom cluster management among oncology patients. As a result, conclusions cannot yet be drawn about whether specific interventions or specific components with certain delivery methods are more effective for certain symptom clusters in particular contexts.
A preliminary search of the Cochrane Library of Systematic Reviews, the Joanna Briggs Institute (JBI) Database of Systematic Reviews and Implementation Reports, PROSPERO-International prospective register of systematic review, PubMed and CINAHL has indicated that there has been no systematic review of the available evidence evaluating the effectiveness of non-pharmacological interventions for various symptom clusters in heterogeneous cancer patient groups. Such a review is crucial for informing health professionals of the effectiveness of management strategies for cancer patients experiencing multiple concurrent symptoms. Given the complexity of findings indicated for non-pharmacological interventions across a number of studies, a systematic review of experimental studies is clearly warranted and may provide insight into critical issues in the literature.
The overall aim of the present systematic review is to evaluate published and unpublished non-pharmacological intervention studies, to identify the discrepancy in symptom cluster concepts used, the most common symptom cluster targeted, the features of effective interventions for managing cancer-related symptom clusters, the outcomes assessed and the methodological quality of these studies. From such information, researchers, educators and health professionals will have evidence to inform interventions in practice and guide further empirical studies.
Inclusion criteria
Types of participants
This review will consider studies that include patients over 16 years of age who were diagnosed with cancer, regardless of gender, tumor stage, tumor type and treatment type. Participants may be undergoing palliative or curative treatment. Studies that combine patients currently diagnosed with cancer and cancer survivors will be excluded, unless the studies feature separate results for the impacts of the interventions on the respective types of participants. For the purpose of this review, a "cancer survivor" will be defined as someone who has completed their active treatment phase and is not undergoing palliative care, as suggested by Cancer Council Australia.89
Types of interventions
This systematic review will consider studies that aim to evaluate the effects of non-pharmacological interventions on reducing symptom clusters. Although there is no consensus on the definition of a symptom cluster, for the purpose of this review, a symptom cluster will be considered as two or more distinct but related symptoms that are present at the same time. The interventions can be specifically designed to manage multiple symptoms within clusters or prospectively target one or more specific symptoms to alleviate other symptoms within identified clusters. According to the Oncology of Nursing Society, as highly specific content approaches, cognitive behavioral therapies are identified as separate interventions, rather than incorporated into overall psychoeducation.90 Therefore, non-pharmacological interventions are defined here as a broad range of activities that are categorized into different groups: psychoeducational interventions (e.g. education, counseling and supportive interventions), cognitive behavioral methods (e.g. meditation, relaxation or techniques and guided imagery), exercise, complementary therapies (e.g. acupuncture, acupressure, electrical stimulation, yoga, herbs and massage) and multimodal interventions (combined more than one type of interventions). The interventions can be delivered either at individual or group levels, may include a single session or a series of sessions and take place in any setting. Comparators include other non-pharmacological interventions, usual care, waitlist controls or a combination thereof. Studies that aim to test the efficacy of pharmacological interventions on managing symptom clusters will be excluded from this review.
Outcomes
Primary outcomes
This review will consider studies that include symptoms within clusters, measured individually or in a constellation in terms of presence, frequency and severity. The instruments used to measure symptoms within clusters were specifically designed to assess individual symptoms or multiple symptoms. For example, a cluster of depression and anxiety can be assessed by different instruments, such as individual symptom questionnaires: the Beck Depression Inventory91 and the State-Trait Anxiety Inventory,92 or by a multiple-symptom questionnaire, such as the Hospital Anxiety and Depression Scale.93 Studies will be included when the researchers directly or indirectly stated that a relationship exists between the symptoms in the clusters. Studies will be excluded if they only focus on the severity of multiple symptoms or individual symptoms without making reference to the term "cluster" or its synonyms and their interactions.
Secondary outcomes
Secondary outcomes will include self-management, adherence to interventions and the impacts of symptom clusters, such as symptom interference with daily life, physical functioning, performance status and quality of life.
Types of studies
This review will consider for inclusion all randomized controlled trials that enable the identification of current best evidence on the effectiveness of non-pharmacological interventions. If there are no randomized controlled trials identified, then other experimental study designs including non-randomized controlled trials and quasi-experimental studies will be considered for inclusion.
Search strategy
Electronic searches
The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized. An initial limited search of MEDLINE, CINAHL (via EBSCO) and EMBASE will be undertaken, followed by an analysis of the text words contained in the title and abstract, as well as the index terms used to describe the reviews. A second search using all identified keywords and index terms will then be undertaken across all included databases. Finally, the reference lists of all identified reports and articles will be searched for additional studies. Only studies published in English will be considered for inclusion. To obtain a comprehensive range of studies reviewed, no limits on date of publication will be set.
The databases to be searched include MEDLINE, CINAHL, EMBASE, PsycINFO, Cochrane Central Register for Controlled Trials, ProQuest Nursing and Allied Health Source, OTseeker and PEDro.
The search for unpublished studies will include:
* Searching ongoing studies from clinicaltrials.gov, World Health Organization International Clinical Trials Registry Platform and EU Clinical Trials Register
* Searching conference proceedings for published abstracts and obtaining full data, if possible, by contacting the authors
* Searching Google Scholar
* Searching Dissertation Abstracts International
* Searching for articles presented at conferences as well as guides and documents disseminated by scientific societies. Oncological scientific societies include ACS (American Cancer Society), ECCO (European Cancer Organisation), ONS (Oncology Nursing Society) and NCCN (National Comprehensive Cancer Network).
Initial keywords will be:
* Neoplasm, cancer, leukemia, malignance/malignant, tumor/tumour, carcinoma, lymphoma, adenocarcinoma, radiotherapy, irradiate/irradiation, radio-chemotherapy, chemotherapy and adjuvant.
* Symptom cluster/concurrence/constellation and interrelated symptoms.
* Randomised/randomized controlled trial/study.
Keywords will be combined using Boolean operators, such as "OR" and "AND" for the search. These key terms will be expanded and adapted according to the rules of each database. Two review authors (L.T.N. and L.C.A.) will first screen titles and abstracts and dismiss those clearly not relevant to the review. The reviewers will, on an ongoing basis, screen the remaining titles and abstracts for their eligibility for inclusion, based on the criteria defined earlier. Two independent reviewers (L.T.N. and L.C.A.) will screen and retrieve full article copies if the title and abstract do not provide all the information concerning the criteria.
In cases of uncertainty following retrieving of full article copies, study authors will be contacted to obtain additional information so as to assess the studies against inclusion criteria. Where disagreement or uncertainty occurs, the final decision about inclusion will be made through consultation with the other independent reviewer (P.Y.).
Assessment of methodological quality
Quantitative articles selected for retrieval will be assessed by two independent reviewers (L.T.N. and T.Q.T.) for methodological validity prior to inclusion in the review, using standardized critical appraisal instruments for "Randomised and Pseudo-Randomised studies" from the JBI Meta-analysis of Statistics Assessment and Review Instrument (Appendix I). The articles that are graded under four will be considered to be of insufficient methodological quality to be included. Any disagreements that arise between the reviewers will be resolved through discussion. If a decision can still not be reached, the other reviewer (P.Y.) will be asked to make the final decision.
Data extraction
Quantitative data will be extracted from articles included in the review using the standardized data extraction tool from the JBI (Appendix II). The data extracted will include specific details about the context, interventions, populations, study objectives, methods and outcomes of significance to the review question and specific objectives. Specifically, extracted data will include details about the characteristics of the interventions - such as date of conduct, intervention team members, settings of interventions, number and duration of sessions, formats and delivery methods. Details of eligible studies will be extracted and summarized independently by two reviewers (L.T.N. and P.Y.).
Data synthesis
Once the data is extracted, it will be assessed for possibility of meta-analysis. The clinical heterogeneity between studies will be evaluated by considering the key characteristics of studies, such as settings, populations, interventions and outcomes. Heterogeneity will be assessed statistically using the standard [chi]2 and also explored using subgroup analyses based on the different quantitative study designs included in this review. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis of outcomes. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation wherever appropriate.
Acknowledgements
The authors would like to express their great thanks to the Vietnamese Atlantic Philanthropies project for supporting the present review.
Appendix I: Appraisal instruments
Appendix II: Data extraction form
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