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Update on interventions focused on symptom clusters: what has been tried and what have we learned?

Berger, Ann M.a; Yennu, Sriramb; Million, Ritac,d

Current Opinion in Supportive and Palliative Care: March 2013 - Volume 7 - Issue 1 - p 60–66
doi: 10.1097/SPC.0b013e32835c7d88
SYMPTOM CLUSTERS IN CANCER AND PALLIATIVE CARE: Edited by Andrea M. Barsevick and Aynur Aktas

Purpose of review Although clinicians and researchers acknowledge symptom clusters, the focus has been on relieving a single symptom. This review summarizes the recent literature on interventions that focus on relief of symptom clusters in patients with cancer.

Recent findings Twelve intervention studies meeting inclusion criteria were published in 2011–2012. The timeframe was expanded to 2009–2012 and 24 studies met the criteria: 18 in early stage and 6 in advanced-stage cancer patients. Several cognitive behavioral therapy, complementary therapy, and exercise interventions demonstrated positive outcomes in relieving a variety of symptom clusters in several cancer types. Most psychoeducational interventions using traditional formats or those combined with automated clinician alerts demonstrated effectiveness in reducing a variety of clusters. Clusters that included fatigue and anxiety or depression were reduced by exercise in early stage patients and by methylphenidate in advanced-stage patients. Current NIH R01 funded studies verified the trends in the types of interventions being tested.

Summary Few interventions have been tested and found to be effective in relieving the specific symptom clusters in early and advanced-stage cancer patients. Future research needs to expand our understanding of the mechanisms that initiate co-occurring symptoms. Mechanism-targeted interventions need to be identified and tested in homogeneous samples with specific symptom clusters. Interventions need to be replicated before guidelines can be established.

aCollege of Nursing, University of Nebraska Medical Center, Omaha, Nebraska

bDepartment of Palliative Care and Rehabilitation Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas

cSchool of Nursing, University of Nevada, Las Vegas, Las Vegas, Nevada

dUniversity of Nebraska Medical Center, Omaha, Nebraska, USA

Correspondence to Ann M. Berger, PhD, APRN, AOCNS, FAAN, Professor and Dorothy H. Olson Endowed Chair in Nursing, Advanced Practice Nurse-Oncology, College of Nursing, University of Nebraska Medical Center, 985330 NE MED CENTER, Omaha, NE 68198-5330, USA. Tel: +1 402 559 4957; e-mail:

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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.

Box 1

Box 1

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.

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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.

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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

Table 1-a

Table 1-b

Table 1-b

Table 2

Table 2

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.

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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.

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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.

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The authors acknowledge Marcia Shade, MSN, RN, and PhD student in Nursing at UNMC for her assistance in preparing the manuscript.

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Conflicts of interest

There are no conflicts of interest.

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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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A RCT which demonstrated significant positive benefits of a 16-week, telephone-administered CBT intervention on PTSD, depression, and distress symptoms across three follow-up assessments in hematopoietic stem-cell transplantation survivors.

27▪. Feng Y, Wang X, Li S, et al. Clinical research of acupuncture on malignant tumor patients for improving depression and sleep quality. J Tradit Chin Med 2011; 31:199–202.

A RCT which demonstrated positive benefits of acupuncture compared with 20 mg fluoxetine on depression and insomnia in Chinese mixed group tumor patients.

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A RCT which tested 8 weeks of MBSR (Kabat-Zinn) compared with the standard of care (SOC) for improving mood, breast, endocrine-related symptoms, quality of life and well being after primary therapy for breast cancer. The results are important because they add to the evidence that MBSR may be effective in reducing symptom clusters.

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A RCT which compared a supervised and structured exercise program, progressive relaxation, and psychoeducational intervention to a control group receiving SOC and physiotherapy during hospitalization for allogeneic stem-cell transplantation. Important because the intervention group experienced significant reductions in symptom intensity over time for mucositis, cognitive, gastrointestinal, and functional symptom clusters.

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A RCT which determined that telecare symptom management coupled with an automated symptom monitoring intervention was more effective than usual care in relieving pain and depression in breast, lung, and gastrointestinal cancer patients.

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A RCT which demonstrated positive benefits of a 6-week MBSR in breast cancer patients in the first 18 months after treatment. Results suggest that MBSR modestly decreases fatigue and sleep disturbances but has a greater effect on how symptoms interfere with life.

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This trial examined the effectiveness of a psychoeducational intervention (PEI) on the symptom cluster of anxiety, breathlessness, and fatigue, compared with usual care in advanced lung cancer. Important because PEI group had significantly better patterns of change in breathlessness, fatigue, anxiety, and functional ability than the usual care group.

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cancer; intervention; palliative care; symptom cluster

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