INTRODUCTION
Patients with cancer frequently experience several physical and psychosocial symptoms such as fatigue, pain, and anxiety. These symptoms are due to the disease and disease-related treatments or comorbidities. Clinical experience and prior research in patients with cancer confirm that these symptoms co-occur to form symptom clusters [1–5], but our understanding of initiating mechanisms is limited [6–8].
This review of previous literature on symptom clusters found that most were descriptive studies and were conducted in heterogeneous patient populations [9–11]. In spite of the heterogeneity among studies, anxiety and depression were most often identified as a specific symptom cluster. A recent, descriptive factor analysis study identified three symptom clusters (fatigue-sickness symptoms, emotional distress, and a poor sense of well being) that were stable across most subpopulations in a population-based sample (n = 14 247) of cancer patients [12].
Progress has been slow in identifying the biological basis for symptoms clusters. Methodological issues in measuring the cytokines have been identified recently [13]. There have been limited numbers of recent prospective, controlled treatment trials that focused on specific symptom clusters in homogeneous samples. These limitations make it challenging for the researchers to design interventions with high likelihood of effectiveness.
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Research on interventions for symptom clusters in cancer has developed rather slowly but steadily during the past decade. Several recent review articles provide an overview of issues regarding the topic [11,14–17]. Numerous reports present descriptive data, but the topic is complicated by the wide number of symptoms experienced with varied types and stages of cancer, and if the patient is undergoing or after treatment.
PURPOSE AND METHODS
The purpose of this article was to review the recent intervention studies targeted to relieve any combination of two or more symptoms (clusters) in patients with any stage or type of cancer. We also aimed to identify the future directions for practice and for research related to symptom clusters.
We systematically searched peer-reviewed literature from 2011 to 2012 using MEDLINE, PsychInfo, CINAHL, and EMBASE for reviews, systematic reviews, and original studies related to the search terms ‘symptom clusters’, ‘cancer’, ‘palliative care’, ‘interventions’, and ‘pharmacological interventions’. We also searched using pairs of specific symptoms (e.g. ‘fatigue and sleep’) to locate additional studies. We did not locate interventions that had been tested in samples receiving palliative care for diagnoses other than cancer. Therefore, our strategy for article selection included interventions designed to impact two or more symptoms in adult cancer patients, a randomized clinical trial or a randomized design with wait-list control, a sample size of at least 20 subjects, patients in any stage of cancer trajectory, and published in English. We excluded program evaluations and retrospective chart reviews. Only 12 studies met these criteria from 2011 to 2012, so we expanded the publication dates to 2009–2012.
REVIEW OF STUDIES
Our search located 24 primary studies (26 publications) for inclusion in this review. Table 1 includes 18 intervention studies [18–25,26▪,27▪,28▪▪,29,30▪▪,31▪▪,32▪,33–37] in early stage and Table 2 includes 6 studies [38▪▪,39–43] in advanced-stage cancer patients. We divided the studies by the stage of cancer because we suspected that patients with regional or distant metastasis would be more likely than early stage patients to experience symptom clusters from cancer, prior and current cancer treatments, and comorbid diseases and associated treatments [15,44]. We also suspected interventions delivered to early stage patients would be more likely to report positive outcomes. The majority of the studies did not test potential mechanisms for the initiation of symptom clusters. Lack of understanding of the mechanisms that are activated in symptom clusters impedes development of interventions to target that mechanism.
Table 1-a: Interventions targeting symptom clusters in patients with early stage cancer
Table 1-b: Interventions targeting symptom clusters in patients with early stage cancer
Table 2: Interventions targeting symptom clusters in patients with advanced cancer
A variety of mind–body treatments have demonstrated beneficial effects on a single symptom, but few studies have focused on the response of concurrent symptoms to a single treatment strategy [16]. Likewise, the influence of symptom clusters on patient outcomes, such as functional status, quality of life (QOL), mortality, and depression, are important indicators but this area has been understudied [11].
In early stage patients, 5 of the 18 nonpharmacologic studies tested complementary therapy interventions. These interventions included acupuncture [27▪], mindfulness-based stress reduction (MBSR) [28▪▪,32▪], psychological therapy [36], and cranial stimulation [33]. One cognitive behavioral therapy (CBT) intervention study used the telephone [26▪] and two were delivered in person (two papers by Berger report on the same study) [19,20]. Four psychoeducational interventions were tested [18,25,29,31▪▪] and two of them also included automated alerts to providers when inadequate symptom management was reported [29,31▪▪]. Five studies tested exercise; papers by Cho and Dodd report on the same study [21–24,35,37]. One study combined exercise, relaxation, and psychoeducational strategies [30▪▪]. No studies tested only pharmacologic interventions to relieve symptom clusters in early stage patients.
In advanced-stage cancer patients, nonpharmacologic complementary therapy intervention studies tested acupuncture [40] and expressive writing [41,42]. One study combined a psychoeducational intervention [38▪▪] and one used a CBT intervention delivered using technology [43]. Only one study tested pharmacologic therapy, using titrated doses of methylphenidate versus placebo [39]. No studies were found that tested exercise in advanced-stage cancer patients. We found more interventions have been tested for symptom clusters in early stage patients and outcomes have been both positive and negative in both cancer stages.
We observed there were a limited number of published studies of interventions for symptom clusters from 2009 to 2012. We did not find many similarities among interventions designed to reduce specific symptom clusters in early stage and advanced stage. Two MBSR intervention studies had some similarities but differed in outcomes. We examined the currently NIH-funded R01 studies. Interventions currently being tested include cognitive behavioral therapy for insomnia (CBT-I) plus a pharmacologic, yoga, relaxation acupressure, MBSR, and a tele-health symptom management intervention. The most common symptom clusters included in these studies are fatigue, anxiety, depression, and insomnia.
SUMMARY
The studies in Tables 1 and 2 not only suggest a positive trend toward more testing of interventions for symptom clusters, but also reveal a lack of studies targeting the causative mechanisms of symptoms clusters (which are still not clearly defined).
What have we learned? Most of the interventions tested to date have had positive outcomes using CBT, complementary (except expressive writing), psychoeducational, and exercise types of nonpharmacological interventions. This finding is congruent with the positive outcomes for efficacy and sometimes for the effectiveness of interventions tested for single symptoms. The most innovative interventions included technology with automated alerts as a delivery method. Technology is helpful because most intervention studies in advanced cancer have challenges with attrition. Technology may potentially reduce the attrition. However, further studies are required to confirm [45]. We were unable to determine that any specific symptom cluster was more likely to respond to an intervention. We conclude that it is premature to suggest a specific intervention for any specific cluster for dissemination in practice.
Limitations of these studies include issues of definition of clusters, need for unifying models, measurement issues, a lack of threshold of symptom cluster severity in inclusion/exclusion criteria, a lack of identification of predictors of severe clusters from the medical/demo history, biological and behavioral risk factors, physical and mental health status, and limited understanding of what is defined as a clinically significant improvement of the symptom clusters by a given intervention. Taxonomy of symptom clusters and their inter-relationships would be helpful to design and test interventions.
We identified a need for intervention studies to include multidisciplinary team approaches, rigorous designs and adequate power, samples from a broad range of cultures and socioeconomic status, designs that identify biological and behavioral predictors of response to interventions, designs that identify a sentinel symptom (a single symptom that is associated with the likelihood of a symptom cluster), and measurement of the impact of specific clusters and the intervention on multiple aspects of functioning and QOL. We support testing nonpharmacological, pharmacological, and combined interventions that have been effective in managing single symptoms. We recommend special consideration if pain and emotional distress are present as they may likely be the sentinel symptom that lead to the development of other symptoms in the cluster [46]. We need to learn what intervention works, for whom, in what context (dose, type, frequency), when (on/off treatment), and for how long (duration). This will require studies to determine the mechanisms and common pathways that lead to the development of symptom clusters.
CONCLUSION
Research on interventions to relieve symptom clusters in cancer patients is at a critical developmental stage. On the translational science continuum, preclinical, epidemiology, and mechanism-scientific discovery studies are needed that focus on co-occurring symptoms. Tests of well designed, promising interventions (Phase I, II, and III trials) will advance knowledge and provide evidence for review and lead to future recommendations and policies. Although no specific interventions can be recommended, clinicians can select interventions that have demonstrated effectiveness in relieving the sentinel symptom and efficacy in reducing clusters that contain similar symptoms in similar populations.
Acknowledgements
The authors acknowledge Marcia Shade, MSN, RN, and PhD student in Nursing at UNMC for her assistance in preparing the manuscript.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 121–122).
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