- Email: [email protected]
Symptom Clusters in Individuals Living With Advanced Cancer
168
Seminars in Oncology Nursing, Vol 26, No 3 (August), 2010: pp 168-174
SYMPTOM CLUSTERS IN INDIVIDUALS LIVING WITH ADVANCED CANCER PEG ESPER OBJECTIVES: To discuss issues related to symptom clusters in patients living with advanced cancer.
DATA SOURCES: Research and review articles. CONCLUSION: The importance for symptom cluster evaluation in oncology has been documented; however, there remain a number of inconsistencies in the literature as to the best way to accomplish this. Individuals living with advanced cancer are often dealing with symptoms from their disease, as well as prior and current therapies. Research related to patients receiving longterm cancer therapies and the symptom clusters experienced by this group of individuals is needed.
IMPLICATIONS FOR NURSING PRACTICE: Understanding the intricacies of symptom clusters in this population is an area for future research.
KEY WORDS: Symptom clusters, advanced illness.
O
N THE horizon seems to hover a new dichotomy in oncology care - ‘‘living with cancer.’’ With deaths from cancer seeing a steady decline since the early 1990s, and survival rates increasing 16% since the mid 1970s, the diagnosis of cancer is starting to lose, at least to some degree, its death sentence
Peg Esper, MSN, MSA, RN, APRN-BC, AOCNÒ: Nurse Practitioner, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI. Address correspondence to Peg Esper, MSN, MSA, RN, APRN-BC, AOCNÒ, Nurse Practitioner, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, C429 MIB, SPC 5843, Ann Arbor, MI 48109-5843. e-mail: [email protected] Ó 2010 Elsevier Inc. All rights reserved. 0749-2081/2603-$32.00/0. doi:10.1016/j.soncn.2010.05.002
moniker.1 Clinicians have long anticipated the opportunity to discuss cancer treatment strategies with patients in the context of a ‘‘chronic illness.’’ The advent of novel targeted therapies has created a new paradigm in the treatment of individuals with cancer which has signaled hope for patients with some of the most historically treatmentresistant malignancies.2 Overall, cancer patients seem to be living longer. The reality of living with cancer elicits the question, ‘‘Can living with cancer really be living?’’ Veteran oncology clinicians can easily identify patients whom they observed having the last drop of chemotherapy administered almost synchronous to their taking their last breath, with no regard for the individual’s quality of life. As a result, proponents of palliative care have battled for some time and have only recently seen momentum in the promotion of educational
SYMPTOM CLUSTERS
efforts for all health care providers related to the provision of quality end-of-life care. Now, with the recent advances in medical science, therapies are being designed for long-term chronic administration that will likely become the norm.3 This has even been documented to result in a delay in admitting patients to hospice because of the increasing ability to keep patients moving from one targeted treatment to another. As with our cardiology and endocrinology colleagues, we are starting to experience more long-term relationships with patients who have the fortune (though some might argue use of this term) to be living with their cancer who are now experiencing long-term effects of both their disease as well as its treatment. This article will explore symptoms frequently seen in advanced cancer and discuss their relationship to therapies being administered in more chronic settings, as well as long-term sequelae of cancer diagnoses, and how these symptoms may cluster together. This discussion will also briefly address current and needed research in this area.
SYMPTOMS SEEN IN ADVANCED CANCER Patients with advanced cancer have been described as being ‘‘polysymptomatic.’’4 In fact, a study by Walsh et al5 found the median number of symptoms experienced by patients with advanced cancer to be eleven. In this study, the majority of patients were not receiving any anti-cancer therapy at the time. Other studies focusing on patients receiving palliative care have listed the average symptom burden to be at least six symptoms, with as many as 13.4 symptoms being reported.6-8 A list of the most frequently noted symptoms experienced by patients with advanced cancer are provided in Table 1.9-13 These symptoms were primarily identified in patients not currently undergoing cancer therapy. Table 2 lists the symptoms frequently identified in the literature for patients undergoing some form of cancer therapy.14-16 Neither list is intended to be exhaustive, but comparison of the lists demonstrates that many symptoms are present whether or not the patient is actively receiving treatment. Patients who are receiving any type of long-term therapy will likely experience a constellation of symptoms that can relate to both the acute therapy-related side effects, regardless of the type of treatment they are receiving, as well as chronic
169
TABLE 1. Common Symptoms in Patients With Advanced Cancer (Not Receiving Treatment)9-13 Pain Fatigue Weakness Dry mouth
Constipation Weight Loss Anorexia Decreased energy
Dyspnea Forgetfulness Taste changes Depression
symptoms that relate to previous treatments or the effects that the cancer may have already had on specific body systems. Chronic symptoms can include lymphedema from prior surgeries, hot flashes from therapy-induced hormonal effects, neuropathy from previous chemotherapy, and pain from tumor infiltration of bone. In conjunction with detailing lists of potential symptoms experienced by cancer patients either currently undergoing treatment or having undergone treatment, the question has been raised by multiple authors as to how various symptoms may occur together in known or predictable patterns. Defining these ‘‘symptom clusters’’ and their significance is an important focus of ongoing cancer research.
SYMPTOM CLUSTERS IN ADVANCED CANCER Establishing a Common Language Both the definition as well as the best way to approach studying symptom clusters in oncology continues to be a topic of discussion. In the earliest definitions, a symptom cluster was reported by Dodd and colleagues17 to involve three symptoms occurring together that were related but could have different etiologies. Some authors have suggested that symptom clusters should be
TABLE 2. Common Symptoms in Patients With Advanced Cancer (Receiving Treatment)14-16 Anorexia Cachexia Dyspnea Nausea/Vomiting Sleep alterations Cutaneous changes Headache Insomnia
Fatigue Constipation Diarrhea Alopecia Memory loss Hot flashes Dysuria Arthralgias
Dry mouth Cough Neuropathy Delirium Pain Stomatitis Indigestion Mood alteration
170
P. ESPER
TABLE 3. Common Symptom Clusters Seen in Cancer Patients (Individual) Anxiety / Agitation / Delirium Cough / Breathlessness / Fatigue Depression / Anxiety Fatigue / Anorexia-Cachexia Fatigue / Drowsiness / Nausea / Decreased Appetite / Dyspnea Fatigue / Pain / Anxiety / Depression Fatigue / Somnolence Nausea / Anorexia / Dehydration Nausea / Appetite Loss / Constipation Pain / Depression / Fatigue Pain / Dyspnea / Numbness
experiencing both symptoms related to previous effects of their cancer and cancer treatment, as well as the effects of potential long-term treatments they are currently receiving. Research Related to Symptom Clusters
looked at as they specifically apply to a unique cancer diagnosis (such as lung or breast cancer), while others have suggested that the clustering of certain symptoms is more specific to the type of treatment received regardless of the specificcancer diagnosis.15,18 Table 3 lists a number of symptom clusters that have been identified in the oncology literature. Categorization of selected symptom clusters with their associated symptoms has been a common method of reporting; examples of this are noted in Table 4.6,19,20 While the scholarly significance of variations between frameworks could be presented, it is not the focus of this article. Logic would tell us that there is very likely overlap and that symptom clusters certainly exist that are specific to unique cancer diagnoses, but equally exist based on receiving specific classifications of treatment. The latter is perhaps more applicable to this article, which focuses on patients living with advanced cancer. These individuals are typically
Research related to the study of symptom clusters has most often been compartmentalized into either patients who have incurable illness and have been referred to palliative care programs or patients who are in the midst of acute therapy such as chemotherapy or radiation therapy (XRT).21-27 In a study reported by Walsh and Rybicki,9 seven specific symptom clusters were identified in over 900 patients that had been referred for palliative care. However, in a review by Fan et al,7 only one of these symptom clusters was consistently identified in a large review of symptom clusters research. An evaluation of the statistical methods used for this area of research finds that, there is also variability but most often factor analysis and cluster analysis have been utilized.28 Inconsistency is also seen in the type of measurement instrument being used in this area of research, the number of items being evaluated, and the scales by which items are measured. There are numerous measurement instruments currently being utilized in symptom cluster research.7,28-31 Many of these are listed in Table 5. Such variation limits the ability to make generalizations and move forward the body of knowledge associated with symptom clusters. Several important criteria have been identified in the selection of an instrument to measure cancer symptoms and include: comprehensiveness of content, user and statistically friendly measurement scale, strong validity, minimal responder burden, and
TABLE 4. Common Symptom Clusters Seen in Cancer Patients (Grouped)6,9,19,20 Symptom Cluster Category
Associated Symptoms
Aerodigestive Affective Emotional Gastrointestinal – General Menopausal
Dysphagia / Dyspnea / Cough / Hoarseness Emotional Distress / Sadness Distress / Sadness Nausea / Vomiting / Lack of Appetite Hot Flashes / Weight Gain / Tiredness / Decreased Libido / Vaginal Dryness Sleep Problems / Depression / Anxiety Pain / Constipation Insomnia / Breathing / Cough
Neuropsychological Pain Respiratory Distress
SYMPTOM CLUSTERS
TABLE 5. Symptom Measurement Instruments Utilized in Symptom Clusters Research7,28-31 Brief Fatigue Inventory Brief Pain Inventory Center for Epidemiologic Studies – Depression (CES-D) Distress Thermometer Edmonton Symptom Assessment Scale (ESAS) EORTC QLQ-C30 Functional Assessment of Chronic Illness Therapy for Breast Cancer Hospital Anxiety and Depression Scale MD Anderson Symptom Inventory (MDASI) Memorial Symptom Assessment Scale (MSAS) Prostate Symptom Self Report Rotterdam Symptom Checklist Symptom Distress Scale
quality of information provided.29 Conceptual models have looked at both grouping symptoms to create clusters, as well as grouping individuals who experience similar symptoms with an identified cluster.32 A thorough critique of the various statistical approaches commonly used in symptom cluster research has been reported by Kim and Abraham,28 and is recommended for a more indepth discussion of this issue. Another attempt to filter the multitude of variables that can and must be considered in the analysis of symptom clusters has been to consider the concept of a sentinel symptom. This symptom is the driving symptom of a cluster and interventions targeted in treating this symptom may, in turn, effectively address other symptoms in the cluster.33 This has also been discussed in the context of symptom severity and symptom burden, whereby the constellation of symptoms being realized by the individual is assessed based on the level to which the symptoms are affecting patient function and, for those patients undergoing treatment, may be critical in the decision to delay, reduce, or discontinue treatment.27 The importance of being able to duplicate the existence of symptom clusters in like groups of cancer patients and determine the specific clusters that impact patient outcomes and then translate this into early intervention remains a very underserved area of research.6,23,34 Significance of Identifying Symptom Clusters Historically, symptom clusters have been used for many years as diagnostic criteria for identifying specific illnesses. More recent work has also
171
suggested the identification of symptom clusters as another means to evaluate the effectiveness of treatment, in that efficacy of therapy could be demonstrated by resolution of the symptom cluster.18 The lack of consistency within oncology symptom cluster research could beg the question as to whether there is merit in pursuing this field of scientific inquiry. Despite the seemingly disparate approaches, symptom cluster research remains a field in its infancy and researchers are still ‘‘finding their way.’’ Consensus does seem to prevail in the focus identified for this research. Improving patient outcomes remains the goal. As previously stated, the patient’s functional status, which is often used as a measurement of outcome, plays an important role in decisions related to the delivery of treatment. Additional benefits that have previously been identified in the literature include the capability to decrease polypharmacy which has both patient centered as well as economic corollaries.11 The ability to accurately identify symptom clusters and at what point to proactively intervene has the potential to significantly influence patient outcomes. Applying Symptom Cluster Research in Advanced Cancer As previously noted, much of the work in the field of symptom cluster identification and research has included patients who are no longer receiving cancer therapy and have been referred for palliative care consultations. This leaves a gap in the literature for those patients who have undergone primary treatments such as surgery, radiation, and chemotherapy, and have either had recurrences for which they are receiving ‘‘maintenance’’ type therapies such as hormone sensitive prostate cancer, or are being treated with one of the newer novel targeted therapies that allow cancer to be treated with a ‘‘chronic’’ versus ‘‘terminal’’ approach. This is an area where the literature is relatively deficient of symptom cluster research. The breast cancer and lung cancer patient populations have been the recipients of some of the limited work done in this area to date. The time point at which they were in therapy appeared to play an important role in the severity of symptoms noted within clusters.35,36 It is likely that the type(s) of treatment previously received and clusters of symptoms previously experienced will also have an impact on those symptom clusters within these patient populations.
172
P. ESPER
Pryce et al37 reported on differences between patients who returned and did not return to work during treatment. The majority of this cohort was breast cancer patients and a symptom cluster of fatigue and stress were identified. It was not clear as to the type of treatment these individuals were receiving at the time of their return to work. A study of breast cancer patients on hormonal therapy (both acute and long-term) identified a menopausal symptom cluster that correlated with alterations in quality of life.19 Patients on long-term cancer treatments with oral agents do not require as frequent office visits as their counterparts receiving parenteral therapies. As a result, there are fewer opportunities for clinicians to identify what clusters of symptoms these patients are experiencing and even fewer chances to assess and manage symptoms appropriately. No current research was found related to symptom clusters in patients receiving oral anti-angiogenesis agents, but speculation might find symptom clusters that could include fatigue, headache, and hypertension. Additional Considerations Another patient population for which symptom cluster research is limited is cancer survivors. According to the Centers for Disease Control, at the start of 2006, 11.4 million individuals with a previous cancer diagnosis were alive in the United States.38 Many of these ‘‘survivors’’ will not necessarily be cured long term. These individuals are facing numerous challenges at home, in the workplace, in social and family settings, and in their interactions with health care providers.39 The long-term effects of treatments may have begun to impact quality of life. Fox and Lyon40 reported research in survivors of ovarian cancer in which a symptom cluster of fatigue and depression were identified. The cluster accounted for 41% of the variation in quality-of-life scores. It would be anticipated that symptom cluster identification in cancer survivor populations will be impacted by a constellation of factors involving the individual patient’s treatment trajectory and will create even more challenges for researchers in this area.
CASE STUDY R.C. was a 49-year-old African American man who was referred to a urologist after he began experiencing symptoms of urinary frequency and
urgency. He was found to have a prostatespecific antigen (PSA) of 10.8 ng/dL. A prostate biopsy followed with identification of a Gleason 8 adenocarcinoma of the prostate. He chose to undergo a radical prostatectomy. Following this, his PSA became undetectable. R.C. and his wife were very pleased with the results of the surgery. Although he initially had some mild urinary incontinence postoperatively, this resolved after 3 or 4 months. He returned to his teaching position at a local high school and continued coaching the girl’s basketball team. The patient continued routine follow-up with his urologist. Approximately 9 months following his prostatectomy, his PSA was found to be 0.4 ng/dL. A bone scan was negative for any evidence of metastatic disease as was a CT scan of the abdomen and pelvis. After consultation with his urologist and the hospital’s genitourinary tumor board, he was presented with the option of salvage radiation therapy (XRT) or initiation of androgen deprivation therapy. He chose to proceed with XRT to the prostatic bed. He experienced significant urinary symptoms during XRT and continued to have difficulties with urinary incontinence to what he considered a moderate degree. He wore pads that typically required changing 3 to 4 times daily. Following radiation, he also found that his ability to have and maintain erections was significantly affected. He received prescriptions for silendafil (Viagra; Pfizer, NY, New York) from his urologist, which he stated allowed him to remain sexually active, though not at the level to which he would have preferred. Six months post XRT, his PSA had risen to 1.4. He then elected to begin androgen deprivation therapy with every-4-month leuprolide injections. His PSA at first follow-up was undetectable. Twelve months into therapy, his PSA level is still <0.01 ng/dL. The patient receives a leuprolide injection once every 4 months. Unfortunately, he also experiences a clustering of symptoms that includes: hot flashes, nipple discomfort, decreased libido, sexual dysfunction, and weight gain. He had read that these were all anticipated side effects of treatment, so he did not contact his physician regarding these symptoms between visits. At his 12-month evaluation he shared his frustration with the current symptoms and was able to verbalize his concerns. His oncologist discussed the option of intermittent hormonal ablation. Following the discussion, he elected to discontinue therapy and closely monitor his PSA for a rise that would signal the need to re-institute
SYMPTOM CLUSTERS
treatment. Within 2 months of discontinuing his androgen blockade he noted that the breast tenderness had subsided along with the hot flashes. He felt he was able to lose some weight with a little bit of effort, but was not having any benefit from the use of Viagra. He continued to experience mild urinary incontinence with pad changes 2 to 3 times daily. Case Discussion R.C. is an example of a patient living with advanced cancer who was experiencing a number of ‘‘clustered symptoms’’ related to his current treatment and diagnosis. The fact that he was not being seen more frequently than every 4 months made identification of this cluster of symptoms more difficult. In this situation, an intervention was offered that addressed the etiology of the majority of the symptoms he was experiencing – androgen blockade. This intervention might or might not have been a possibility earlier, had R.C. been given the opportunity or took the initiative to make his health care provider aware of how this was affecting his quality of life. The symptom cluster associated with his prior surgery and XRT (urinary incontinence and erectile dysfunction) persisted. Unfortunately, at some point, R.C. will likely need to resume his androgen deprivation therapy and the cluster of symptoms will return.
173
At that point, communication will be key in helping to address his ability to address those symptoms in the most effective way possible.
CONCLUSION Symptom cluster identification in cancer care has been established as an important area of ongoing research.7,41 To date, however, consistent frameworks for definitions, statistical analysis, and translation of findings have not been fully established.42 In the interim, more oncology patient populations who would benefit from this research are being identified. This includes those patients being treated long-term on hormonal or novel targeted therapies who are now ‘‘living’’ with advanced cancer. The confounding variables in these patients can include effects of prior surgery, radiation, or previous chemotherapies, or side effects of current treatment as well as preexisting co-morbidities. Additionally, psychological, cultural, and cognitive influences must be evaluated for their potential role in symptoms that patients experience. The ability to identify symptom clusters in these patient populations and determine the effect they have on patient outcomes is an area in need of more extensive nursing research.
REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics 2009. CA Cancer J Clin 2009;59:225-249. 2. Rini BI. VEGF-targeted therapy in metastatic renal cell carcinoma. Oncologist 2005;10:191-197. 3. Mintzer DM, Zagrabbe K. On how increasing numbers of newer cancer therapies further delay referral to hospice: the increasing palliative care imperative. Am J Hosp Palliat Care 2007;2:126-130. 4. Miaskowski C, Dodd M, Lee K. Symptom clusters: the new frontier in symptom management research. J Natl Cancer Inst Monogr 2004;32:17-21. 5. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer 2000;8:175-179. 6. Chen M, Lin C. Cancer symptom clusters: a validation study. J Pain Symptom Manage 2007;34:590-599. 7. Fan G, Filipczak L, Chow E. Symptom clusters in cancer patients: a review of the literature. Curr Oncol 2007;14:173-179. 8. Hadi S, Fan G, Hird AE, et al. Symptom clusters in patients with cancer with metastatic bone pain. J Palliat Med 2008;11:591-600. 9. Walsh D, Rybicki L. Symptom clustering in advanced cancer. Support Care Cancer 2006;14:831-836.
10. Potter J, Hami F, Bryan T, et al. Symptoms in 400 patients referred to palliative care services: prevalence and patterns. Palliat Med 2008;17:310-314. 11. Esper P, Heidrich D. Symptoms clusters in advanced illness. Semin Oncol Nurs 2005;21:20-28. 12. Yalcin B, Buyukcelik A, Senler FC, et al. Frequency of symptoms in patients with advanced cancer. Turk J Cancer 2005;35:177-180. 13. Cheung WY, Le LW, Zimmermann C. Symptom clusters in patients with advanced cancers. Support Care Cancer 2009;17:1223-1230. 14. Lagman RL, Davis MP, LeGrand SB, et al. Common symptoms in advanced cancer. Surg Clin North Am 2005;85:237-255. 15. Honea N, Brant J, Beck SL. Treatment-related symptom clusters. Semin Oncol Nurs 2007;23:142-151. 16. Yamagishi A, Morita T, Miyashita M, et al. Symptom prevalence and longitudinal follow-up in cancer outpatients receiving chemotherapy. J Pain Symptom Manage 2009;37:823-830. 17. Dodd MJ, Miaskowski C, Lee KA. Occurrence of symptom clusters. J Natl Cancer Inst Monogr 2004;32:76-78. 18. Gift AG. Symptom clusters related to specific cancers. Semin Oncol Nurs 2007;23:136-141.
174
P. ESPER
19. Glaus A, Boehme CH, Thurlimann B, et al. Fatigue and menopausal symptoms in women with breast cancer undergoing hormonal cancer treatment. Ann Oncol 2006;17:801806. 20. Ivanova MO, Inova TI, Kalyadina SA, et al. Cancerrelated symptom assessment in Russia: validation and utility of the Russian M.D. Anderson Symptom Inventory. J Pain Symptom Manage 2005;30:443-453. 21. 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. 22. Gift AG, Stommel M, Jablonski A, et al. A cluster of symptoms over time in patients with lung cancer. Nurs Res 2003;52:393-400. 23. Henoch I, Ploner A, Tishelman C. Increasing stringency in symptom cluster research: a methodological exploration of symptom clusters in patients with inoperable lung cancer. Oncol Nurs Forum 2009;36:E283-E292. 24. Kim HJ, Barsevick AM, Tulman L, et al. Treatment-related symptom clusters in breast cancer: a secondary analysis. J Pain Symptom Manage 2008;36:468-479. 25. Rainbird K, Perkins J, Sanson-Fisher R, et al. The needs of patients with advanced, incurable cancer. Br J Cancer 2009;101:759-764. 26. Wang XS, Fairclough DL, Liao Z, et al. Longitudinal study of the relationship between chemoradiation therapy for nonsmall-cell lung cancer and patient symptoms. J Clin Oncol 2008;24:4485-4491. 27. Given BA, Given CW, Sikorskii A, et al. Symptom clusters and physical function for patients receiving chemotherapy. Semin Oncol Nurs 2007;23:121-126. 28. Kim H, Abraham IL. Statistical approaches to modeling symptom clusters in cancer patients. Cancer Nurs 2008;31:E1E10. 29. Kirkova J, Davis MP, Walsh D, et al. Cancer symptom assessment instruments: a systematic review. J Clin Oncol 2006;24:1459-1473.
30. Barsevick AM, Whitmer K, Nail LM, et al. Symptom cluster research: conceptual design, measurement, and analysis issues. J Pain Symptom Manage 2006;31:85-95. 31. Chang VT, Hwang SS, Thaler HT, et al. Memorial symptom assessment scale. Expert Rev Pharmacoecon Outcomes Res 2004;4:171-178. 32. Miaskowski C, Aouizerat BE, Dodd M, et al. Conceptual issues in symptom clusters research and their implications for quality-of-life assessment in patients with cancer. J Natl Cancer Inst Monogr 2007;37:39-46. 33. Lacasse C, Beck SL. Clinical assessment of symptom clusters. Semin Oncol Nurs 2007;23:106-112. 34. Williams LA. Clinical management of symptom clusters. Semin Oncol Nurs 2007;23:113-120. 35. So WKW, Marsh G, Ling WM, et al. The symptom cluster of fatigue, pain, anxiety, and depression and the effect on the quality of life of women receiving treatment for breast cancer: a multicenter study. Oncol Nurs Forum 2009;36:E205-E214. 36. Dodd MJ, Cho MH, Cooper BA, et al. The effect of symptom clusters on functional status and quality of life in women with breast cancer. Eur J Oncol Nurs 2010;14:101-110. 37. Pryce J, Munir F, Haslam C. Cancer survivorship and work: symptoms, supervisor response, co-worker disclosure and work adjustment. J Occup Rehabil 2007;17:83-92. 38. Centers for Disease Control and Prevention. Basic information about cancer survivorship. Available at: http://www.cdc. gov/cancer/survivorship/basic_info/index.htm. (accessed Nov. 28, 2009). 39. Bradley CJ, Bednarek HL. Employment patterns of longterm cancer survivors. Psychooncology 2002;11:188-198. 40. Fox SW, Lyon D. Symptom clusters and quality of life in survivors of ovarian cancer. Cancer Nurs 2007;30:354-361. 41. Miaskowski C. Symptom clusters: establishing the link between clinical practicum and symptom management research. Support Care Cancer 2006;14:792-794. 42. Beck SL. Symptom clusters: impediments and suggestions for solutions. J Natl Cancer Inst Monogr 2004;32:137-138.
Seminars in Oncology Nursing, Vol 26, No 3 (August), 2010: pp 168-174
SYMPTOM CLUSTERS IN INDIVIDUALS LIVING WITH ADVANCED CANCER PEG ESPER OBJECTIVES: To discuss issues related to symptom clusters in patients living with advanced cancer.
DATA SOURCES: Research and review articles. CONCLUSION: The importance for symptom cluster evaluation in oncology has been documented; however, there remain a number of inconsistencies in the literature as to the best way to accomplish this. Individuals living with advanced cancer are often dealing with symptoms from their disease, as well as prior and current therapies. Research related to patients receiving longterm cancer therapies and the symptom clusters experienced by this group of individuals is needed.
IMPLICATIONS FOR NURSING PRACTICE: Understanding the intricacies of symptom clusters in this population is an area for future research.
KEY WORDS: Symptom clusters, advanced illness.
O
N THE horizon seems to hover a new dichotomy in oncology care - ‘‘living with cancer.’’ With deaths from cancer seeing a steady decline since the early 1990s, and survival rates increasing 16% since the mid 1970s, the diagnosis of cancer is starting to lose, at least to some degree, its death sentence
Peg Esper, MSN, MSA, RN, APRN-BC, AOCNÒ: Nurse Practitioner, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI. Address correspondence to Peg Esper, MSN, MSA, RN, APRN-BC, AOCNÒ, Nurse Practitioner, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, C429 MIB, SPC 5843, Ann Arbor, MI 48109-5843. e-mail: [email protected] Ó 2010 Elsevier Inc. All rights reserved. 0749-2081/2603-$32.00/0. doi:10.1016/j.soncn.2010.05.002
moniker.1 Clinicians have long anticipated the opportunity to discuss cancer treatment strategies with patients in the context of a ‘‘chronic illness.’’ The advent of novel targeted therapies has created a new paradigm in the treatment of individuals with cancer which has signaled hope for patients with some of the most historically treatmentresistant malignancies.2 Overall, cancer patients seem to be living longer. The reality of living with cancer elicits the question, ‘‘Can living with cancer really be living?’’ Veteran oncology clinicians can easily identify patients whom they observed having the last drop of chemotherapy administered almost synchronous to their taking their last breath, with no regard for the individual’s quality of life. As a result, proponents of palliative care have battled for some time and have only recently seen momentum in the promotion of educational
SYMPTOM CLUSTERS
efforts for all health care providers related to the provision of quality end-of-life care. Now, with the recent advances in medical science, therapies are being designed for long-term chronic administration that will likely become the norm.3 This has even been documented to result in a delay in admitting patients to hospice because of the increasing ability to keep patients moving from one targeted treatment to another. As with our cardiology and endocrinology colleagues, we are starting to experience more long-term relationships with patients who have the fortune (though some might argue use of this term) to be living with their cancer who are now experiencing long-term effects of both their disease as well as its treatment. This article will explore symptoms frequently seen in advanced cancer and discuss their relationship to therapies being administered in more chronic settings, as well as long-term sequelae of cancer diagnoses, and how these symptoms may cluster together. This discussion will also briefly address current and needed research in this area.
SYMPTOMS SEEN IN ADVANCED CANCER Patients with advanced cancer have been described as being ‘‘polysymptomatic.’’4 In fact, a study by Walsh et al5 found the median number of symptoms experienced by patients with advanced cancer to be eleven. In this study, the majority of patients were not receiving any anti-cancer therapy at the time. Other studies focusing on patients receiving palliative care have listed the average symptom burden to be at least six symptoms, with as many as 13.4 symptoms being reported.6-8 A list of the most frequently noted symptoms experienced by patients with advanced cancer are provided in Table 1.9-13 These symptoms were primarily identified in patients not currently undergoing cancer therapy. Table 2 lists the symptoms frequently identified in the literature for patients undergoing some form of cancer therapy.14-16 Neither list is intended to be exhaustive, but comparison of the lists demonstrates that many symptoms are present whether or not the patient is actively receiving treatment. Patients who are receiving any type of long-term therapy will likely experience a constellation of symptoms that can relate to both the acute therapy-related side effects, regardless of the type of treatment they are receiving, as well as chronic
169
TABLE 1. Common Symptoms in Patients With Advanced Cancer (Not Receiving Treatment)9-13 Pain Fatigue Weakness Dry mouth
Constipation Weight Loss Anorexia Decreased energy
Dyspnea Forgetfulness Taste changes Depression
symptoms that relate to previous treatments or the effects that the cancer may have already had on specific body systems. Chronic symptoms can include lymphedema from prior surgeries, hot flashes from therapy-induced hormonal effects, neuropathy from previous chemotherapy, and pain from tumor infiltration of bone. In conjunction with detailing lists of potential symptoms experienced by cancer patients either currently undergoing treatment or having undergone treatment, the question has been raised by multiple authors as to how various symptoms may occur together in known or predictable patterns. Defining these ‘‘symptom clusters’’ and their significance is an important focus of ongoing cancer research.
SYMPTOM CLUSTERS IN ADVANCED CANCER Establishing a Common Language Both the definition as well as the best way to approach studying symptom clusters in oncology continues to be a topic of discussion. In the earliest definitions, a symptom cluster was reported by Dodd and colleagues17 to involve three symptoms occurring together that were related but could have different etiologies. Some authors have suggested that symptom clusters should be
TABLE 2. Common Symptoms in Patients With Advanced Cancer (Receiving Treatment)14-16 Anorexia Cachexia Dyspnea Nausea/Vomiting Sleep alterations Cutaneous changes Headache Insomnia
Fatigue Constipation Diarrhea Alopecia Memory loss Hot flashes Dysuria Arthralgias
Dry mouth Cough Neuropathy Delirium Pain Stomatitis Indigestion Mood alteration
170
P. ESPER
TABLE 3. Common Symptom Clusters Seen in Cancer Patients (Individual) Anxiety / Agitation / Delirium Cough / Breathlessness / Fatigue Depression / Anxiety Fatigue / Anorexia-Cachexia Fatigue / Drowsiness / Nausea / Decreased Appetite / Dyspnea Fatigue / Pain / Anxiety / Depression Fatigue / Somnolence Nausea / Anorexia / Dehydration Nausea / Appetite Loss / Constipation Pain / Depression / Fatigue Pain / Dyspnea / Numbness
experiencing both symptoms related to previous effects of their cancer and cancer treatment, as well as the effects of potential long-term treatments they are currently receiving. Research Related to Symptom Clusters
looked at as they specifically apply to a unique cancer diagnosis (such as lung or breast cancer), while others have suggested that the clustering of certain symptoms is more specific to the type of treatment received regardless of the specificcancer diagnosis.15,18 Table 3 lists a number of symptom clusters that have been identified in the oncology literature. Categorization of selected symptom clusters with their associated symptoms has been a common method of reporting; examples of this are noted in Table 4.6,19,20 While the scholarly significance of variations between frameworks could be presented, it is not the focus of this article. Logic would tell us that there is very likely overlap and that symptom clusters certainly exist that are specific to unique cancer diagnoses, but equally exist based on receiving specific classifications of treatment. The latter is perhaps more applicable to this article, which focuses on patients living with advanced cancer. These individuals are typically
Research related to the study of symptom clusters has most often been compartmentalized into either patients who have incurable illness and have been referred to palliative care programs or patients who are in the midst of acute therapy such as chemotherapy or radiation therapy (XRT).21-27 In a study reported by Walsh and Rybicki,9 seven specific symptom clusters were identified in over 900 patients that had been referred for palliative care. However, in a review by Fan et al,7 only one of these symptom clusters was consistently identified in a large review of symptom clusters research. An evaluation of the statistical methods used for this area of research finds that, there is also variability but most often factor analysis and cluster analysis have been utilized.28 Inconsistency is also seen in the type of measurement instrument being used in this area of research, the number of items being evaluated, and the scales by which items are measured. There are numerous measurement instruments currently being utilized in symptom cluster research.7,28-31 Many of these are listed in Table 5. Such variation limits the ability to make generalizations and move forward the body of knowledge associated with symptom clusters. Several important criteria have been identified in the selection of an instrument to measure cancer symptoms and include: comprehensiveness of content, user and statistically friendly measurement scale, strong validity, minimal responder burden, and
TABLE 4. Common Symptom Clusters Seen in Cancer Patients (Grouped)6,9,19,20 Symptom Cluster Category
Associated Symptoms
Aerodigestive Affective Emotional Gastrointestinal – General Menopausal
Dysphagia / Dyspnea / Cough / Hoarseness Emotional Distress / Sadness Distress / Sadness Nausea / Vomiting / Lack of Appetite Hot Flashes / Weight Gain / Tiredness / Decreased Libido / Vaginal Dryness Sleep Problems / Depression / Anxiety Pain / Constipation Insomnia / Breathing / Cough
Neuropsychological Pain Respiratory Distress
SYMPTOM CLUSTERS
TABLE 5. Symptom Measurement Instruments Utilized in Symptom Clusters Research7,28-31 Brief Fatigue Inventory Brief Pain Inventory Center for Epidemiologic Studies – Depression (CES-D) Distress Thermometer Edmonton Symptom Assessment Scale (ESAS) EORTC QLQ-C30 Functional Assessment of Chronic Illness Therapy for Breast Cancer Hospital Anxiety and Depression Scale MD Anderson Symptom Inventory (MDASI) Memorial Symptom Assessment Scale (MSAS) Prostate Symptom Self Report Rotterdam Symptom Checklist Symptom Distress Scale
quality of information provided.29 Conceptual models have looked at both grouping symptoms to create clusters, as well as grouping individuals who experience similar symptoms with an identified cluster.32 A thorough critique of the various statistical approaches commonly used in symptom cluster research has been reported by Kim and Abraham,28 and is recommended for a more indepth discussion of this issue. Another attempt to filter the multitude of variables that can and must be considered in the analysis of symptom clusters has been to consider the concept of a sentinel symptom. This symptom is the driving symptom of a cluster and interventions targeted in treating this symptom may, in turn, effectively address other symptoms in the cluster.33 This has also been discussed in the context of symptom severity and symptom burden, whereby the constellation of symptoms being realized by the individual is assessed based on the level to which the symptoms are affecting patient function and, for those patients undergoing treatment, may be critical in the decision to delay, reduce, or discontinue treatment.27 The importance of being able to duplicate the existence of symptom clusters in like groups of cancer patients and determine the specific clusters that impact patient outcomes and then translate this into early intervention remains a very underserved area of research.6,23,34 Significance of Identifying Symptom Clusters Historically, symptom clusters have been used for many years as diagnostic criteria for identifying specific illnesses. More recent work has also
171
suggested the identification of symptom clusters as another means to evaluate the effectiveness of treatment, in that efficacy of therapy could be demonstrated by resolution of the symptom cluster.18 The lack of consistency within oncology symptom cluster research could beg the question as to whether there is merit in pursuing this field of scientific inquiry. Despite the seemingly disparate approaches, symptom cluster research remains a field in its infancy and researchers are still ‘‘finding their way.’’ Consensus does seem to prevail in the focus identified for this research. Improving patient outcomes remains the goal. As previously stated, the patient’s functional status, which is often used as a measurement of outcome, plays an important role in decisions related to the delivery of treatment. Additional benefits that have previously been identified in the literature include the capability to decrease polypharmacy which has both patient centered as well as economic corollaries.11 The ability to accurately identify symptom clusters and at what point to proactively intervene has the potential to significantly influence patient outcomes. Applying Symptom Cluster Research in Advanced Cancer As previously noted, much of the work in the field of symptom cluster identification and research has included patients who are no longer receiving cancer therapy and have been referred for palliative care consultations. This leaves a gap in the literature for those patients who have undergone primary treatments such as surgery, radiation, and chemotherapy, and have either had recurrences for which they are receiving ‘‘maintenance’’ type therapies such as hormone sensitive prostate cancer, or are being treated with one of the newer novel targeted therapies that allow cancer to be treated with a ‘‘chronic’’ versus ‘‘terminal’’ approach. This is an area where the literature is relatively deficient of symptom cluster research. The breast cancer and lung cancer patient populations have been the recipients of some of the limited work done in this area to date. The time point at which they were in therapy appeared to play an important role in the severity of symptoms noted within clusters.35,36 It is likely that the type(s) of treatment previously received and clusters of symptoms previously experienced will also have an impact on those symptom clusters within these patient populations.
172
P. ESPER
Pryce et al37 reported on differences between patients who returned and did not return to work during treatment. The majority of this cohort was breast cancer patients and a symptom cluster of fatigue and stress were identified. It was not clear as to the type of treatment these individuals were receiving at the time of their return to work. A study of breast cancer patients on hormonal therapy (both acute and long-term) identified a menopausal symptom cluster that correlated with alterations in quality of life.19 Patients on long-term cancer treatments with oral agents do not require as frequent office visits as their counterparts receiving parenteral therapies. As a result, there are fewer opportunities for clinicians to identify what clusters of symptoms these patients are experiencing and even fewer chances to assess and manage symptoms appropriately. No current research was found related to symptom clusters in patients receiving oral anti-angiogenesis agents, but speculation might find symptom clusters that could include fatigue, headache, and hypertension. Additional Considerations Another patient population for which symptom cluster research is limited is cancer survivors. According to the Centers for Disease Control, at the start of 2006, 11.4 million individuals with a previous cancer diagnosis were alive in the United States.38 Many of these ‘‘survivors’’ will not necessarily be cured long term. These individuals are facing numerous challenges at home, in the workplace, in social and family settings, and in their interactions with health care providers.39 The long-term effects of treatments may have begun to impact quality of life. Fox and Lyon40 reported research in survivors of ovarian cancer in which a symptom cluster of fatigue and depression were identified. The cluster accounted for 41% of the variation in quality-of-life scores. It would be anticipated that symptom cluster identification in cancer survivor populations will be impacted by a constellation of factors involving the individual patient’s treatment trajectory and will create even more challenges for researchers in this area.
CASE STUDY R.C. was a 49-year-old African American man who was referred to a urologist after he began experiencing symptoms of urinary frequency and
urgency. He was found to have a prostatespecific antigen (PSA) of 10.8 ng/dL. A prostate biopsy followed with identification of a Gleason 8 adenocarcinoma of the prostate. He chose to undergo a radical prostatectomy. Following this, his PSA became undetectable. R.C. and his wife were very pleased with the results of the surgery. Although he initially had some mild urinary incontinence postoperatively, this resolved after 3 or 4 months. He returned to his teaching position at a local high school and continued coaching the girl’s basketball team. The patient continued routine follow-up with his urologist. Approximately 9 months following his prostatectomy, his PSA was found to be 0.4 ng/dL. A bone scan was negative for any evidence of metastatic disease as was a CT scan of the abdomen and pelvis. After consultation with his urologist and the hospital’s genitourinary tumor board, he was presented with the option of salvage radiation therapy (XRT) or initiation of androgen deprivation therapy. He chose to proceed with XRT to the prostatic bed. He experienced significant urinary symptoms during XRT and continued to have difficulties with urinary incontinence to what he considered a moderate degree. He wore pads that typically required changing 3 to 4 times daily. Following radiation, he also found that his ability to have and maintain erections was significantly affected. He received prescriptions for silendafil (Viagra; Pfizer, NY, New York) from his urologist, which he stated allowed him to remain sexually active, though not at the level to which he would have preferred. Six months post XRT, his PSA had risen to 1.4. He then elected to begin androgen deprivation therapy with every-4-month leuprolide injections. His PSA at first follow-up was undetectable. Twelve months into therapy, his PSA level is still <0.01 ng/dL. The patient receives a leuprolide injection once every 4 months. Unfortunately, he also experiences a clustering of symptoms that includes: hot flashes, nipple discomfort, decreased libido, sexual dysfunction, and weight gain. He had read that these were all anticipated side effects of treatment, so he did not contact his physician regarding these symptoms between visits. At his 12-month evaluation he shared his frustration with the current symptoms and was able to verbalize his concerns. His oncologist discussed the option of intermittent hormonal ablation. Following the discussion, he elected to discontinue therapy and closely monitor his PSA for a rise that would signal the need to re-institute
SYMPTOM CLUSTERS
treatment. Within 2 months of discontinuing his androgen blockade he noted that the breast tenderness had subsided along with the hot flashes. He felt he was able to lose some weight with a little bit of effort, but was not having any benefit from the use of Viagra. He continued to experience mild urinary incontinence with pad changes 2 to 3 times daily. Case Discussion R.C. is an example of a patient living with advanced cancer who was experiencing a number of ‘‘clustered symptoms’’ related to his current treatment and diagnosis. The fact that he was not being seen more frequently than every 4 months made identification of this cluster of symptoms more difficult. In this situation, an intervention was offered that addressed the etiology of the majority of the symptoms he was experiencing – androgen blockade. This intervention might or might not have been a possibility earlier, had R.C. been given the opportunity or took the initiative to make his health care provider aware of how this was affecting his quality of life. The symptom cluster associated with his prior surgery and XRT (urinary incontinence and erectile dysfunction) persisted. Unfortunately, at some point, R.C. will likely need to resume his androgen deprivation therapy and the cluster of symptoms will return.
173
At that point, communication will be key in helping to address his ability to address those symptoms in the most effective way possible.
CONCLUSION Symptom cluster identification in cancer care has been established as an important area of ongoing research.7,41 To date, however, consistent frameworks for definitions, statistical analysis, and translation of findings have not been fully established.42 In the interim, more oncology patient populations who would benefit from this research are being identified. This includes those patients being treated long-term on hormonal or novel targeted therapies who are now ‘‘living’’ with advanced cancer. The confounding variables in these patients can include effects of prior surgery, radiation, or previous chemotherapies, or side effects of current treatment as well as preexisting co-morbidities. Additionally, psychological, cultural, and cognitive influences must be evaluated for their potential role in symptoms that patients experience. The ability to identify symptom clusters in these patient populations and determine the effect they have on patient outcomes is an area in need of more extensive nursing research.
REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics 2009. CA Cancer J Clin 2009;59:225-249. 2. Rini BI. VEGF-targeted therapy in metastatic renal cell carcinoma. Oncologist 2005;10:191-197. 3. Mintzer DM, Zagrabbe K. On how increasing numbers of newer cancer therapies further delay referral to hospice: the increasing palliative care imperative. Am J Hosp Palliat Care 2007;2:126-130. 4. Miaskowski C, Dodd M, Lee K. Symptom clusters: the new frontier in symptom management research. J Natl Cancer Inst Monogr 2004;32:17-21. 5. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer 2000;8:175-179. 6. Chen M, Lin C. Cancer symptom clusters: a validation study. J Pain Symptom Manage 2007;34:590-599. 7. Fan G, Filipczak L, Chow E. Symptom clusters in cancer patients: a review of the literature. Curr Oncol 2007;14:173-179. 8. Hadi S, Fan G, Hird AE, et al. Symptom clusters in patients with cancer with metastatic bone pain. J Palliat Med 2008;11:591-600. 9. Walsh D, Rybicki L. Symptom clustering in advanced cancer. Support Care Cancer 2006;14:831-836.
10. Potter J, Hami F, Bryan T, et al. Symptoms in 400 patients referred to palliative care services: prevalence and patterns. Palliat Med 2008;17:310-314. 11. Esper P, Heidrich D. Symptoms clusters in advanced illness. Semin Oncol Nurs 2005;21:20-28. 12. Yalcin B, Buyukcelik A, Senler FC, et al. Frequency of symptoms in patients with advanced cancer. Turk J Cancer 2005;35:177-180. 13. Cheung WY, Le LW, Zimmermann C. Symptom clusters in patients with advanced cancers. Support Care Cancer 2009;17:1223-1230. 14. Lagman RL, Davis MP, LeGrand SB, et al. Common symptoms in advanced cancer. Surg Clin North Am 2005;85:237-255. 15. Honea N, Brant J, Beck SL. Treatment-related symptom clusters. Semin Oncol Nurs 2007;23:142-151. 16. Yamagishi A, Morita T, Miyashita M, et al. Symptom prevalence and longitudinal follow-up in cancer outpatients receiving chemotherapy. J Pain Symptom Manage 2009;37:823-830. 17. Dodd MJ, Miaskowski C, Lee KA. Occurrence of symptom clusters. J Natl Cancer Inst Monogr 2004;32:76-78. 18. Gift AG. Symptom clusters related to specific cancers. Semin Oncol Nurs 2007;23:136-141.
174
P. ESPER
19. Glaus A, Boehme CH, Thurlimann B, et al. Fatigue and menopausal symptoms in women with breast cancer undergoing hormonal cancer treatment. Ann Oncol 2006;17:801806. 20. Ivanova MO, Inova TI, Kalyadina SA, et al. Cancerrelated symptom assessment in Russia: validation and utility of the Russian M.D. Anderson Symptom Inventory. J Pain Symptom Manage 2005;30:443-453. 21. 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. 22. Gift AG, Stommel M, Jablonski A, et al. A cluster of symptoms over time in patients with lung cancer. Nurs Res 2003;52:393-400. 23. Henoch I, Ploner A, Tishelman C. Increasing stringency in symptom cluster research: a methodological exploration of symptom clusters in patients with inoperable lung cancer. Oncol Nurs Forum 2009;36:E283-E292. 24. Kim HJ, Barsevick AM, Tulman L, et al. Treatment-related symptom clusters in breast cancer: a secondary analysis. J Pain Symptom Manage 2008;36:468-479. 25. Rainbird K, Perkins J, Sanson-Fisher R, et al. The needs of patients with advanced, incurable cancer. Br J Cancer 2009;101:759-764. 26. Wang XS, Fairclough DL, Liao Z, et al. Longitudinal study of the relationship between chemoradiation therapy for nonsmall-cell lung cancer and patient symptoms. J Clin Oncol 2008;24:4485-4491. 27. Given BA, Given CW, Sikorskii A, et al. Symptom clusters and physical function for patients receiving chemotherapy. Semin Oncol Nurs 2007;23:121-126. 28. Kim H, Abraham IL. Statistical approaches to modeling symptom clusters in cancer patients. Cancer Nurs 2008;31:E1E10. 29. Kirkova J, Davis MP, Walsh D, et al. Cancer symptom assessment instruments: a systematic review. J Clin Oncol 2006;24:1459-1473.
30. Barsevick AM, Whitmer K, Nail LM, et al. Symptom cluster research: conceptual design, measurement, and analysis issues. J Pain Symptom Manage 2006;31:85-95. 31. Chang VT, Hwang SS, Thaler HT, et al. Memorial symptom assessment scale. Expert Rev Pharmacoecon Outcomes Res 2004;4:171-178. 32. Miaskowski C, Aouizerat BE, Dodd M, et al. Conceptual issues in symptom clusters research and their implications for quality-of-life assessment in patients with cancer. J Natl Cancer Inst Monogr 2007;37:39-46. 33. Lacasse C, Beck SL. Clinical assessment of symptom clusters. Semin Oncol Nurs 2007;23:106-112. 34. Williams LA. Clinical management of symptom clusters. Semin Oncol Nurs 2007;23:113-120. 35. So WKW, Marsh G, Ling WM, et al. The symptom cluster of fatigue, pain, anxiety, and depression and the effect on the quality of life of women receiving treatment for breast cancer: a multicenter study. Oncol Nurs Forum 2009;36:E205-E214. 36. Dodd MJ, Cho MH, Cooper BA, et al. The effect of symptom clusters on functional status and quality of life in women with breast cancer. Eur J Oncol Nurs 2010;14:101-110. 37. Pryce J, Munir F, Haslam C. Cancer survivorship and work: symptoms, supervisor response, co-worker disclosure and work adjustment. J Occup Rehabil 2007;17:83-92. 38. Centers for Disease Control and Prevention. Basic information about cancer survivorship. Available at: http://www.cdc. gov/cancer/survivorship/basic_info/index.htm. (accessed Nov. 28, 2009). 39. Bradley CJ, Bednarek HL. Employment patterns of longterm cancer survivors. Psychooncology 2002;11:188-198. 40. Fox SW, Lyon D. Symptom clusters and quality of life in survivors of ovarian cancer. Cancer Nurs 2007;30:354-361. 41. Miaskowski C. Symptom clusters: establishing the link between clinical practicum and symptom management research. Support Care Cancer 2006;14:792-794. 42. Beck SL. Symptom clusters: impediments and suggestions for solutions. J Natl Cancer Inst Monogr 2004;32:137-138.