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 .
Progress has been slow in identifying the biological basis for symptoms clusters. Methodological issues in measuring the cytokines have been identified recently . 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.
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.
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 . 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 .
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 , and cranial stimulation . 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  and expressive writing [41,42]. One study combined a psychoeducational intervention [38▪▪] and one used a CBT intervention delivered using technology . Only one study tested pharmacologic therapy, using titrated doses of methylphenidate versus placebo . 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.
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 . 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 . 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.
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.
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).
1. Cheung WY, Le LW, Zimmermann C. Symptom clusters in patients with advanced cancers. Support Care Cancer 2009; 17:1223–1230.
2. Chow E, Fan G, Hadi S, Filipczak L. Symptom clusters in cancer patients with bone metastases. Support Care Cancer 2007; 15:1035–1043.
3. Dodd M, Janson S, Facione N, et al. Advancing the science of symptom management. J Adv Nurs 2001; 33:668–676.
4. Dodd MJ, Miaskowski C, Paul SM. Symptom clusters and their effect on the functional status of patients with cancer. Oncol Nurs Forum 2001; 28:465–470.
5. Walsh D, Rybicki L. Symptom clustering in advanced cancer. Support Care Cancer 2006; 14:831–836.
6. Kim H, McGuire D, Tulman L, Barsevick AM. Symptom clusters: concept analysis and clinical implications for cancer nursing. Cancer Nurs 2005; 28:270–284. [corrected, published erratum appears in Cancer Nurs 2005 sep–oct; 28(5):Ii]
7. Lee BN, Dantzer R, Langley KE, et al. A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation 2004; 11:279–292.
8. Miaskowski C, Aouizerat BE. Is there a biological basis for the clustering of symptoms? Semin Oncol Nurs 2007; 23:99–105.
9. Aktas A, Walsh D, Rybicki L. Symptom clusters and prognosis in advanced cancer. Support Care Cancer 2012; 20:1–7.
10. Francoeur RB. The relationship of cancer symptom clusters to depressive affect in the initial phase of palliative radiation. J Pain Symptom Manage 2005; 29:130–155.
11. Xiao C. The state of science in the study of cancer symptom clusters. Eur J Oncol Nurs 2010; 14:417–434.
12. Howell D, Husain A, Seow H, et al. Symptom clusters in a population-based ambulatory cancer cohort validated using bootstrap methods. Eur J Cancer 2012; 48:3073–3081.
13. Gilbertson-White S, Aouizerat BE, Miaskowski C. Methodologic issues in the measurement of cytokines to elucidate the biological basis for cancer symptoms. Biol Res Nurs 2011; 13:15.
14. Aktas A, Walsh D, Rybicki L. Symptom clusters: myth or reality? Palliat Med 2010; 24:373–385.
15. Esper P. Symptom clusters in individuals living with advanced cancer. Semin Oncol Nurs 2010; 26:168–174.
16. Kwekkeboom KL, Cherwin CH, Lee JW, Wanta B. Mind–body treatments for the pain–fatigue–sleep disturbance symptom cluster
in persons with cancer. J Pain Symptom Manage 2010; 39:126–138.
17. Skerman HM, Yates PM, Battistutta D. Multivariate methods to identify cancer-related symptom clusters. Res Nurs Health 2009; 32:345–360.
18. Barsevick A, Beck SL, Dudley WN, et al. Efficacy of an intervention for fatigue and sleep disturbance during cancer chemotherapy. J Pain Symptom Manage 2010; 40:200–216.
19. Berger A, Kuhn BR, Farr L, et al. Behavioral therapy intervention trial to improve sleep quality and cancer-related fatigue. Psychooncology 2009; 18:634–646.
20. Berger A, Kuhn BR, Farr L, et al. One-year outcomes of a behavioral therapy intervention trial on sleep quality and cancer-related fatigue. J Clin Oncol 2009; 27:6033–6040.
21. Bower JE, Garet D, Sternlieb B, et al. Yoga for persistent fatigue in breast cancer survivors: a randomized controlled trial. Cancer 2012; 118:3766–3775.
22. Carson JW, Carson KM, Porter LS, Keefe FJ, et al. Yoga of awareness program for menopausal symptoms in breast cancer survivors: results from a randomized trial. Support Care Cancer 2009; 17:1301–1309.
23. Cho MH, Dodd MJ, Cooper BA, Miaskowski C. Comparisons of exercise dose and symptom severity between exercisers and nonexercisers in women during and after cancer treatment. J Pain Symptom Manage 2012; 43:842–854.
24. Dodd MJ, Cho MH, Miaskowski C, et al. A randomized controlled trial of home-based exercise for cancer-related fatigue in women during and after chemotherapy with or without radiation therapy. Cancer Nurs 2010; 33:245–257.
25. Cleeland CS, Wang XS, Shi Q, et al. Automated symptom alerts reduce postoperative symptom severity after cancer surgery: a randomized controlled clinical trial. J Clin Oncol 2011; 29:994–1000.
26▪. DuHamel KN, Mosher CE, Winkel G, et al. Randomized clinical trial of telephone-administered cognitive-behavioral therapy to reduce posttraumatic stress disorder and distress symptoms after hematopoietic stem-cell transplantation. J Clin Oncol 2010; 28:3754–3761.
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.
28▪▪. Hoffman CJ, Ersser SJ, Hopkinson JB, et al. Effectiveness of mindfulness-based stress reduction in mood, breast- and endocrine-related quality of life, and well being in stage 0 to III breast cancer: a randomized, controlled trial. J Clin Oncol 2012; 30:1335–1342.
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.
29. Jahn P, Renz P, Stukenkemper J, et al. Reduction of chemotherapy-induced anorexia, nausea, and emesis through a structured nursing intervention: a cluster-randomized multicenter trial. Support Care Cancer 2009; 17:1543–1552.
30▪▪. Jarden M, Baadsgaard MT, Hovgaard DJ, et al. A randomized trial on the effect of a multimodal intervention on physical capacity, functional performance and quality of life in adult patients undergoing allogeneic SCT. Bone Marrow Transplant 2009; 43:725–737.
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.
31▪▪. Kroenke K, Theobald D, Wu J, et al. Effect of telecare management on pain and depression in patients with cancer: a randomized trial. JAMA 2010; 304:163–171.
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.
32▪. Lengacher CA, Reich RR, Post-White J, et al. Mindfulness based stress reduction in posttreatment breast cancer patients: an examination of symptoms and symptom clusters. J Behav Med 2012; 35:86–94.
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.
33. Lyon DE, Schubert C, Taylor AG. Pilot study of cranial stimulation for symptom management in breast cancer. Oncol Nurs Forum 2010; 37:476–483.
34. Ritterband LM, Bailey ET, Thorndike FP, et al. Initial evaluation of an internet intervention to improve the sleep of cancer survivors with insomnia. Psychooncology 2011; 21:695–705.
35. Rogers LQ, Hopkins-Price P, Vicari S, et al. Physical activity and health outcomes three months after completing a physical activity behavior change intervention: persistent and delayed effects. Cancer Epidemiol Biomarkers Prev 2009; 18:1410–1418.
36. Thornton LM. A psychological intervention reduces inflammatory markers by alleviating depressive symptoms: secondary analysis of a randomized controlled trial. Psychosom Med 2009; 71:715–724.
37. Wang YJ, Boehmke M, Wu YW, et al. Effects of a 6-week walking program on Taiwanese women newly diagnosed with early-stage breast cancer. Cancer Nurs 2011; 34:E1–13.
38▪▪. Chan CWH, Richardson A, Richardson J. Managing symptoms in patients with advanced lung cancer during radiotherapy: results of a psychoeducational randomized controlled trial. J Pain Symptom Manage 2011; 41:347–357.
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.
39. Kerr CW, Drake J, Milch RA, et al. Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 2012; 43:68–77.
40. Lim JTW, Wong ET, Aung SKH. Is there a role for acupuncture in the symptom management of patients receiving palliative care for cancer? A pilot study of 20 patients comparing acupuncture with nurse-led supportive care. Acupunct Med 2011; 29:173–179.
41. Low CA, Stanton AL, Bower JE, Gyllenhammer L. A randomized controlled trial of emotionally expressive writing for women with metastatic breast cancer. Health Psychol 2010; 29:460–466.
42. Mosher CE, Duhamel KN, Lam J, et al. Randomised trial of expressive writing for distressed metastatic breast cancer patients. Psychol Health 2012; 27:88–100.
43. Sikorskii A, Given CW, Given B, et al. Differential symptom reporting by mode of administration of the assessment: automated voice response system versus a live telephone interview. Med Care 2009; 47:866–874.
44. Visovsky CG, Berger A, Kosloski KD, Kercher K. Methodological challenges of symptom management research in recurrent cancer. Cancer Nurs 2008; 31:175–181.
45. Yennurajalingam S, Willey JS, Palmer JL, et al. The role of thalidomide and placebo for the treatment of cancer-related anorexia–cachexia symptoms: results of a double-blind placebo-controlled randomized study. J Palliat Med 2012; 15:1059–1064.
46. Kirkova J, Aktas A, Walsh D, Davis MP. Cancer symptom clusters: clinical and research methodology. J Palliat Med 2011; 14:1149–1166.