- Email: [email protected]
The Association of Physical and Psychological Symptom Burden with Time to Death Among Palliative Cancer Outpatients
Vol. 37 No. 3 March 2009
Journal of Pain and Symptom Management
297
Original Article
The Association of Physical and Psychological Symptom Burden with Time to Death Among Palliative Cancer Outpatients Winson Y. Cheung, MD, Niusha Barmala, BSc, Sanaz Zarinehbaf, BSc, Gary Rodin, MD, Lisa W. Le, MSc, and Camilla Zimmermann, MD, MSc Division of Medical Oncology and Hematology (W.Y.C., C.Z.), Department of Medicine and Department of Psychiatry (G.R., C.Z.), University of Toronto; and Department of Psychosocial Oncology and Palliative Care (N.B., S.Z., G.R., C.Z.) and Department of Biostatistics (L.W.L.), Princess Margaret Hospital, University Health Network, Toronto, Canada
Abstract Previous studies have reported on the symptom burden of cancer inpatients, but outpatient studies have been few and have not examined the association of symptoms with time to death (TTD). Cancer patients seen in an oncology palliative care clinic from January 2005 to June 2006 and who subsequently died were identified from a palliative care database. Data from the last outpatient Edmonton Symptom Assessment Scale (ESAS) score completed in clinic were analyzed among patients who were followed during the last four months of life. Multiple linear regression analyses with Bonferroni adjustment were used to determine the association of ESAS total symptom distress score (TSDS), physical subscore (PHS), psychological subscore (PSS), and individual symptom scores with demographic parameters, disease characteristics, and TTD. Data from 198 patients were analyzed. All had stage IV cancer, the median age was 65, and 55% were men. There was no significant association between symptom burden and age, gender, or cancer site. TTD was significantly associated with TSDS (P ¼ 0.001) and PHS (P ¼ 0.001) but not with PSS (P ¼ 1.0). Individual symptoms most strongly associated with TTD were lack of appetite (P ¼ 0.001), drowsiness (P ¼ 0.006), dyspnea (P ¼ 0.009), and fatigue (P ¼ 0.01). There was no significant association between TTD and anxiety (P ¼ 1.0) or depression (P ¼ 1.0). Lack of appetite, drowsiness, dyspnea and fatigue represent a cluster of symptoms that tend to intensify at the end of life. The lack of intensification of psychological symptoms in relation to time to death is striking and needs to be further investigated using specific validated measures for depression and anxiety. J Pain Symptom Manage 2009;37:297e304. Ó 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Palliative care, symptom, time to death, Edmonton Symptom Assessment Scale, cancer
Address correspondence to: Camilla Zimmermann, MD, MSc, Department of Psychosocial Oncology and Palliative Care, Princess Margaret Hospital, 610 Ó 2009 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
University Avenue, 16-712, Toronto, Ontario, Canada M5G 2M9. E-mail: camilla.zimmermann@ uhn.on.ca 0885-3924/09/$esee front matter doi:10.1016/j.jpainsymman.2008.03.008
298
Cheung et al.
Vol. 37 No. 3 March 2009
Introduction
Methods
Cancer patients who are approaching the end of life represent a vulnerable population. In addition to experiencing substantial psychological distress, many individuals continue to suffer physical symptoms from their underlying illness, as well as side effects related to their treatment.1,2 In the oncology community, there is a growing recognition that comprehensive cancer management should emphasize not only measures that sustain and prolong life but also strategies that adequately address pain and symptom control. Accordingly, one of the main goals of palliative care is to improve, or at least maintain, the quality of life of dying patients by optimizing their physical, psychological, and social well-being.3 However, the task of providing appropriate symptom palliation can be a challenging endeavor requiring coordinated interdisciplinary collaboration, an approach that has generally not been emphasized in oncology training programs.4e6 Many studies have examined the complex dynamics of symptoms in the advanced cancer population.7 In the past, patients with poorly controlled or debilitating end-of-life symptoms were typically admitted to hospital for prolonged stays. For this reason, much of our current understanding of end-of-life symptomatology has been derived from research studies of palliative care inpatients.8e10 Although there has been an increasing emphasis on outpatient delivery of specialized palliative care, there are few reports of the symptomatology of outpatients with advanced cancer.11e13 Moreover, with notable exceptions,1,14 most prior studies of symptoms in advanced cancer patients have not measured or controlled for the association of symptoms with time to death (TTD). Conversely, studies specifically examining survival have focused on the predictive capacity of certain symptoms,15e17 rather than on providing a descriptive account of symptom epidemiology at the end of life. In the current study, our objectives were 1) to determine the physical and psychological symptom burden faced by patients who are assessed and followed in an outpatient palliative oncology clinic (OPOC) during the last four months of life, and 2) to evaluate the relationship of symptom intensity to TTD and demographic variables such as age and gender.
Characteristics of Study Hospital and Symptom Assessment Tool Princess Margaret Hospital (PMH) is a large tertiary cancer center located in Toronto, Canada. The institution has a comprehensive, multidisciplinary psycho-oncology department and a palliative care program, which consists of a 12-bed acute palliative care inpatient unit, a consultation service that assesses urgent cases on a same-day basis, and a daily OPOC. Approximately 1000 new patients are seen by the PMH palliative care service yearly, of which 80% are outpatients.18 Patients are referred to the OPOC by their oncologists for pain management, control of other symptoms, and palliative care planning.11 Follow-up is carried out in the palliative care clinic and also by telephone, especially if there are severe symptoms requiring daily assessment and titration of medications. When the patient is too ill to continue to come to the clinic or desires home-based care, referral is made to a home palliative care team.18 Since 2005, all patients who have been referred to and seen by a palliative care physician in the OPOC are requested to complete the Edmonton Symptom Assessment Scale (ESAS) questionnaire as a routine component of the initial consultation and at each subsequent clinic visit. The ESAS is a standardized, validated assessment tool that is commonly used by palliative care teams to evaluate the severity of nine physical and psychological symptoms, namely pain, dyspnea, appetite, nausea, fatigue, drowsiness, anxiety, depression, and general wellbeing.19,20 Patients grade each of the nine items on a scale from 0 to 10, with a score of 10 indicating the highest symptom intensity. Serial ESAS scores can provide a longitudinal measure of an individual’s symptom profile and response to palliative interventions. Results of ESAS assessments for all patients in the OPOC are prospectively entered into the PMH palliative care clinical database. A recent random chart audit for a provincial palliative care project that includes our cancer center21 found that the completion rate of the ESAS in our palliative care clinic was more than 90%.
Patient Selection and Data Collection This study was conducted on obtaining full research ethics approval from the institutional
Vol. 37 No. 3 March 2009
Cancer Symptom Burden and Time to Death
review board at PMH. Consecutive advanced cancer patients who were seen in consultation in the OPOC between January 1, 2005 and June 31, 2006, who died within four months of their last clinic assessment, and who responded to more than 50% of the items in the ESAS questionnaire during the latter assessment, were considered for inclusion in the study. Patients with early cancers (stage I to III as per the American Joint Committee on Cancer system) and patients without reliable mortality data were excluded from the analyses. The PMH palliative cancer symptoms database was used to identify all eligible subjects. Corresponding records and database entries for these patients were reviewed to extract baseline patient demographics, tumor characteristics, symptom information based on ESAS scores, and date of death. Demographics were also recorded for patients who did not meet inclusion criteria but who were assessed in the OPOC during the study period.
Statistical Analyses The last ESAS assessment before death was used for all analyses, whether this was an initial visit or a follow-up visit. The ESAS total symptom distress score (TSDS) was defined as the sum of individual scores from each of the nine symptom items on the questionnaire.19 In addition, the ESAS was categorized into a physical subscore (PHS) and a psychological subscore (PSS). The individual scores from the physical symptom domain (pain, dyspnea, appetite, nausea, fatigue, drowsiness) and the psychological symptom domain (anxiety, depression) were summated to generate PHS and PSS, respectively. Because ‘‘general wellbeing’’ is a measure of both physical and psychological manifestations of disease, this item was excluded from the subscores. For cases in which the questionnaire was not completed fully, TSDS, PHS and PSS were calculated as follows, provided that a minimum of 50% of items in the respective category were answered: sum of answered items number of possible items in category/number of answered items. TTD was defined as the time interval between the date of last ESAS assessment and the date of death. Descriptive statistics were used to summarize patient demographics, disease characteristics, TTD, and distribution of ESAS scores. Multiple
299
linear regression analyses were then conducted to determine the association of symptom burden with TTD and other patient- and disease-related variables. Specific covariates entered into the multivariate model included TTD, age, gender, and disease site. Age and TTD were included as continuous measures, whereas disease site was included as a categorical variable. To control for the effects of multiple testing, Bonferroni adjustment was used. All statistical analyses were performed with SASÒ (V9.1; SAS Institute, Cary, NC). To further determine the association of specific symptoms and time to death, patients were grouped according to time from assessment to death in the following categories: <1 month, 1 to <2 months, 2 to <3 months, and 3e4 months. Symptom scores were compared among patients in these four categories.
Results A total of 198 outpatients who satisfied our study inclusion criteria were identified from the PMH palliative care symptoms database. Baseline patient demographics and disease characteristics of study participants and nonparticipants were similar and are summarized in Table 1. The median age of patients included in the study was 65 years (range 25e98 years), and 108 (55%) were men. All patients had stage IV cancer at the time of their initial consultation in the OPOC. The majority (77%) had advanced solid tumors, with gastrointestinal and lung cancers being the most common disease sites. The mean TSDS, PHS, PSS, and individual symptom scores are listed in Table 2. Of the nine symptoms, fatigue, poor general well-being, and decreased appetite were most prominent during the last four months of life. In contrast, nausea appeared to be relatively well controlled. The median TTD from the date of the last ESAS assessment was 36 days (range 0e120). In multivariate analyses, a significant correlation with TSDS was observed only for TTD (P ¼ 0.001), where patients who were closer to death displayed a higher symptom severity. No significant association was found between TSDS and age, gender, or disease site (P ¼ 1.0). When the ESAS subscores were examined separately, the association between
300
Cheung et al.
Table 1 Baseline Patient and Disease Characteristics
Variable Age Mean (SD) Median (range) Gender Male Female Disease site Breast Gastrointestinal Genitourinary Gynecological Head and neck Hematological Lung Others
No. (%) of Patients Excluded from Study n ¼ 788
63.8 (12.9) 65.0 (24.9e89.3)
64.3 (14.3) 65.3 (54.7e74.9)
108 (54.6) 80 (45.4)
410 (52.0) 378 (48.0)
13 72 19 15 10 16 24 29
(6.6) (36.4) (9.6) (7.6) (5.0) (8.1) (12.1) (14.6)
57 221 64 76 53 74 125 118
Pain Fatigue Nausea Drowsiness Appetite Dyspnea
9 8 7 6 5 4 3 2
(7.2) (28.0) (8.1) (9.6) (6.7) (9.4) (15.9) (15.1)
1 0 -4
Our study differed from previous investigations in that we evaluated symptoms at the last assessment in the palliative care clinic rather than at the first visit. We chose this sampling method because the first visit to the palliative care clinic may occur as long as several years before death; for the purpose of the present study, we wished to describe the symptomatology of patients whose time from assessment to death was four months or less. The symptom burden 10
Anxiety Depression Well-being
9
90 60 20
190 191 194 194 195 192
5.2 4.6 6.1 2.9 6.9 5.1
(3.2) (3.4) (3.1) (3.1) (2.4) (3.1)
10 10 10 10 10 10
190 190
4.4 (3.1) 4.3 (3.1)
10 10
186
6.4 (2.6)
10
ESAS ¼ Edmonton Symptom Assessment Scale.
ESAS Scores
Individual ESAS scores Physical domain Pain Dyspnea Appetite Nausea Fatigue Drowsiness Psychological domain Anxiety Depression Other Well-being
0
Discussion
8
46.0 (17.9) 30.8 (12.3) 8.6 (5.6)
-1
association between these symptoms and age, gender, or disease site.
No. of Mean Score Possible Responses (SD) Score 195 196 186
-2
Fig. 1. Relationship of individual symptoms to time to death.
Table 2 Mean Scores of the Last ESAS Assessment Before Death
Total ESAS scores Total symptom distress Physical subscore Psychological subscore
-3
Months before Death
TTD and symptom intensity remained true for the PHS (P ¼ 0.001) only, and not the PSS (P ¼ 1.0). Among the physical symptoms, appetite (P ¼ 0.001), drowsiness (P ¼ 0.006), dyspnea (P ¼ 0.009), and fatigue (P ¼ 0.01) were correlated with TTD (Fig. 1), but not with age, gender, or disease site. The same trend of association with TTD was also evident for the patient’s sense of general well-being (P ¼ 0.07). In the psychological symptom domain, however, neither anxiety nor depression were significantly associated with TTD (P ¼ 1.0; Fig. 2), and there was also no
Variable
10
ESAS Scores
No. (%) of Patients Included in Study n ¼ 198
Vol. 37 No. 3 March 2009
7 6 5 4 3 2 1 0 -4
-3
-2
-1
0
Months before Death
Fig. 2. Relationship of anxiety, depression, and well-being to time to death.
(3.02) (3.54) (3.02) (3.02) (2.15) (3.23) (2.95) (3.15) (2.82) 4.88 4.00 6.83 2.94 7.67 5.49 3.67 3.71 6.40 2.92 3.26 5.78 2.00 7.06 4.77 2.95 3.28 5.37 (2.8) (2.9) (3.1) (2.8) (2.6) (3.1) (2.7) (2.9) (2.9) 3.4 2.7 6.0 2.3 6.4 3.9 2.8 2.9 4.8
Nekolaichuk et al.9,b (n ¼ 49)
(2.66) (3.33) (3.31) (2.99) (2.57) (2.81) (2.75) (2.58) (2.34) 5.38 4.16 6.24 2.27 6.44 4.84 3.05 2.97 5.97 (2.74) (2.95) (3.28) (2.94) (2.68) (3.08) (3.01) (3.04) (2.92) 5.40 2.80 5.25 2.53 5.40 4.39 3.27 3.57 5.41 (3.2) (3.4) (3.1) (3.1) (2.4) (3.1) (3.1) (3.1) (2.6) 5.2 4.6 6.1 2.9 6.9 5.1 4.3 4.4 6.4 Pain Dyspnea Appetite Nausea Fatigue Drowsiness Depression Anxiety Well-being
Stromgren et al. (n ¼ 34) Bruera et al. (n ¼ 166) Current study (n ¼ 198) Symptom
Values are mean (SD). ESAS ¼ Edmonton Symptom Assessment Scale; SD ¼ standard deviation. a For these studies, symptoms were scored on a 0e100 scale and were converted to 0e10 scale for easier comparison. b Fatigue item in these studies was recorded as ‘‘activity.’’ c SD is not given.
(3.42) (3.03) (3.63) (2.68) (3.15) (3.40) (3.46) (3.36) (3.27) 3.85 2.17 4.52 1.57 5.46 4.38 4.17 4.33 3.39 (3.2) (3.0) (3.2) (3.0) (2.4) (3.0) (3.1) (3.1) (2.9) 4.0 3.1 6.0 2.2 7.2 4.1 3.6 3.8 5.0
Jenkins et al. (n ¼ 86)
22,a
Modonesi et al. (n ¼ 162)
23
Inpatient Studies
Cancer Symptom Burden and Time to Death
24a,b 12,b
Outpatient Studies
Table 3 Symptom Distress in Previous Palliative Care Studies Using the ESAS
Rees et al.10a,c (n ¼ 71)
Stromgren et al.24,26,38a,b (n ¼ 116)
Vol. 37 No. 3 March 2009
301
observed in the current study was high, but our results are, overall, consistent with those from previous investigations using the ESAS to assess palliative symptomatology of oncology inpatients9,10,22e24 and outpatients12,24 (Table 3). Comparing across these studies, the severity of most physical and psychological symptoms was similar in inpatient and outpatient settings. The one exception was pain, which tended to be more severe in outpatients than in patients assessed in palliative care units. This may be because palliative care clinics often also serve as pain clinics, and patients may be referred specifically for pain control. Pain in our sample was similar to the mean pain scores seen in other outpatient palliative care settings. Nausea was the best-controlled symptom in our study, which is a trend evident in all other studies using the ESAS to determine symptom prevalence and severity. The only symptom in our study that differed considerably in severity from previous investigations was dyspnea, which was higher in our sample than for other studies in inpatients and outpatients (range in other studies 2.17e4.16; mean in our study 4.6). This difference cannot be explained by a difference in the relative proportion of lung cancer patients; with the exception of two studies,9,10 there were more lung cancer patients in other studies than in ours. Of note, the study that had the highest mean dyspnea score (4.16) was also a study of patients assessed in a palliative care outpatient clinic,24 suggesting that this symptom may be particularly prominent in ambulatory patients who are attempting to be more active. Greater attention should be given to the assessment and treatment of this distressing symptom in the palliative care outpatient setting.25 It also may be that patients in our study were closer to death than those in other studies. The median survival time for patients assessed was not given in the other studies except for the study by Modonesi et al.,23 where it was 46 days for the 88% of patients who had died by the end of the study. In a separate study by Stromgren et al.,24 mean survival from symptom assessment was 81 days. In contrast to physical symptoms, anxiety and depression appeared to be better controlled in our study and their severity was not significantly related to TTD. Thus, it would appear that physical rather than psychological
302
Cheung et al.
symptoms contributed predominantly to the total symptom burden of patients at the end of life. However, caution is necessary in the interpretation of these findings. Although standardized symptom assessment forms are more sensitive in the elucidation of symptoms than are patient reports,7,26,27 it has been noted that symptom acknowledgement correlates strongly with social desirability28 and patients may be more reluctant to report psychological symptoms than physical ones. Perhaps partly for this reason, the ESAS has been found to have greater validity in the reporting of physical than psychological symptoms.20,29 Furthermore, a retrospective study comparing the ESAS with the Hospital Anxiety and Depression Scale30 found that the cut-off point on the ESAS for the screening of both depression and anxiety was two of 10;31 the cut-off point for severe depression and anxiety is as yet unknown. Thus, in our sample, the mean score for depression and anxiety of four of 10, although low compared with the scores for most physical symptoms, may belie the true incidence of depression and anxiety in these patients. Prospective longitudinal studies are needed to determine the clinical significance of numerical values of the ESAS for depression and anxiety. A significant correlation with TTD was seen only for physical rather than psychological symptoms, and particularly for fatigue, dyspnea, drowsiness, and appetite. These results are similar to other studies constructing survival models for cancer patients in their last few months of life. In their study of 519 patients who were no longer receiving chemotherapy, Maltoni et al.17 reported anorexia and dyspnea as the only symptoms that were independent prognostic indicators. Fatigue and drowsiness were not measured, but fever, dry mouth, dysphagia, and pain were not independent predictors of survival. The median survival time in this study was 32 days, which is similar to the 36-day median survival time in our study. Morita et al.,32 in an evaluation of symptoms that influenced whether patients lived longer than three or six weeks, found that oral intake and dyspnea at rest were significant predictors. Again, fatigue and somnolence were not among the symptoms assessed in their study. More recently, Chow et al.16 reported that fatigue, appetite, and shortness
Vol. 37 No. 3 March 2009
of breath (all assessed using the ESAS) predicted prognosis in a palliative radiotherapy clinic, where the median prognosis was 19.4 weeks. In addition, a survival analysis of outpatients in a palliative care cancer center revealed that, in univariate analyses, dyspnea, drowsiness, lack of appetite, and nausea were significantly associated with shorter survival. However, in multivariate analyses only dyspnea and drowsiness showed a significant association.33 In the latter study, the median followup was 1.9 years, with 65% of the patients still alive and, therefore, censored in the analysis. The purpose of the latter studies was to detect independent predictors of survival, rather than to provide a descriptive account of the epidemiology of certain symptoms at the end of life. In contrast, the objective of our study was to describe the symptomatology of palliative care outpatients during the last four months of life, and to reveal which of these symptoms were significantly related to TTD. Several studies have mused on the existence of a ‘‘terminal cancer syndrome’’ where certain symptoms are associated with closeness to death, regardless of the cancer primary.17,34,35 However, the only previous study that has ever attempted to empirically characterize this syndrome was a cross-sectional evaluation of cancer outpatients with a relatively long median survival of 15.3 weeks.34 The overall symptom burden in this study was very low, with fatigue, anorexia, and poor feeling of well-being showing the worst scores (mean score 4/10 for each of these symptoms) and the association between symptom intensity and time to death was not measured. A more recent study of symptom prevalence and control on a palliative care unit in Italy reported that patients who survived for less than 30 days had a significantly higher intensity of fatigue, drowsiness, dyspnea, and anorexia, similar to the findings in our study.23 Another recent study of symptom patterns of advanced cancer patients in a palliative care unit found that, whereas pain and depression typically decreased and stabilized after admission, symptoms associated with the anorexiae cachexia syndrome, as well as dyspnea, did not show improvement.36 Thus, the latter symptoms appear to be specifically associated with advancing illness, regardless of diagnosis or treatment setting, and may not be as amenable to treatment.
Vol. 37 No. 3 March 2009
Cancer Symptom Burden and Time to Death
In terms of limitations, our results may not be generalizable to other palliative care centers, as the study consisted of a single institutional review of cancer patients. Nevertheless, our results are consistent with those from other studies. There is a high percentage of gastrointestinal and lung cancers in our study population; however, this is also true of other studies that have examined prognosis in cancer patients at the end of life17,32 and likely reflects the fact that these are the cancers with the highest mortality rate.37 We also excluded all outpatients who did not participate in an ESAS assessment in the OPOC. Although the completion rate for the ESAS in our clinic is high, some of the excluded patients may have been too frail or symptomatic to complete these assessments, resulting in a selection bias and an underestimation of the actual symptom burden. Finally, it would have been ideal to precisely characterize the evolution of patient symptoms prospectively and longitudinally from the time of advanced cancer diagnosis to death. However, such studies are also fraught with methodological difficulties, including low recruitment rates and high loss to follow-up, resulting in bias and reduced generalizability of the results.38,39 In conclusion, the significant correlation with time to death of lack of appetite, drowsiness, dyspnea, and fatigue suggests that this may constitute a cluster of symptoms that tend to intensify at the end of life. Further prospective research is necessary to determine to what extent the augmentation of these symptoms at the end of life can be prevented by proactive treatment. The lack of intensification of depression and anxiety in relation to time to death is also striking and needs to be further investigated using specific validated measures for these symptoms.
References 1. McCarthy EP, Phillips RS, Zhong Z, et al. Dying with cancer: patients’ function, symptoms, and care preferences as death approaches. J Am Geriatr Soc 2000;48:S110eS121. 2. Claessens MT, Lynn J, Zhong Z, et al. Dying with lung cancer or chronic obstructive pulmonary disease: insights from SUPPORT. Study to understand prognoses and preferences for outcomes and risks of treatments. J Am Geriatr Soc 2000;48:S146eS153.
303
3. WHO definition of palliative care. Available from. World Health Organization, 2002 www.who. int/cancer/palliative/definition/en. Accessed September 15, 2007. 4. Fitzsimons D, Mullan D, Wilson JS, et al. The challenge of patients’ unmet palliative care needs in the final stages of chronic illness. Palliat Med 2007;21:313e322. 5. Sullivan AM, Warren AG, Lakoma MD, et al. End-of-life care in the curriculum: a national study of medical education deans. Acad Med 2004;79: 760e768. 6. Buss MK, Lessen DS, Sullivan AM, et al. A study of oncology fellows’ training in end-of-life care. J Support Oncol 2007;5:237e242. 7. Teunissen SC, Wesker W, Kruitwagen C, et al. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain Symptom Manage 2007;34:94e104. 8. Elsayem A, Swint K, Fisch MJ, et al. Palliative care inpatient service in a comprehensive cancer center: clinical and financial outcomes. J Clin Oncol 2004;22:2008e2014. 9. Nekolaichuk CL, Bruera E, Spachynski K, et al. A comparison of patient and proxy symptom assessments in advanced cancer patients. Palliat Med 1999;13:311e323. 10. Rees E, Hardy J, Ling J, et al. The use of the Edmonton Symptom Assessment Scale (ESAS) within a palliative care unit in the UK. Palliat Med 1998; 12:75e82. 11. Riechelmann RP, Krzyzanowska MK, O’Carroll A, et al. Symptom and medication profiles among cancer patients attending a palliative care clinic. Support Care Cancer 2007;15(12): 1407e1412. 12. Bruera E, Michaud M, Vigano A, et al. Multidisciplinary symptom control clinic in a cancer center: a retrospective study. Support Care Cancer 2001;9: 162e168. 13. Lidstone V, Butters E, Seed PT, et al. Symptoms and concerns amongst cancer outpatients: identifying the need for specialist palliative care. Palliat Med 2003;17:588e595. 14. Jordhoy MS, Fayers P, Loge JH, et al. Quality of life in advanced cancer patients: the impact of sociodemographic and medical characteristics. Br J Cancer 2001;85:1478e1485. 15. Vigano A, Bruera E, Jhangri GS, et al. Clinical survival predictors in patients with advanced cancer. Arch Intern Med 2000;160:861e868. 16. Chow E, Fung K, Panzarella T, et al. A predictive model for survival in metastatic cancer patients attending an outpatient palliative radiotherapy clinic. Int J Radiat Oncol Biol Phys 2002;53:1291e1302. 17. Maltoni M, Pirovano M, Scarpi E, et al. Prediction of survival of patients terminally ill with cancer.
304
Cheung et al.
Results of an Italian prospective multicentric study. Cancer 1995;75:2613e2622. 18. Zimmermann C, Seccareccia D, Clarke A, et al. Bringing palliative care to a Canadian cancer center: the palliative care program at Princess Margaret Hospital. Support Care Cancer 2006;14(10): 982e987.
Vol. 37 No. 3 March 2009
28. Koller M, Heitmann K, Kussmann J, et al. Symptom reporting in cancer patients II: relations to social desirability, negative affect, and self-reported health behaviors. Cancer 1999;86:1609e1620. 29. Moro C, Brunelli C, Miccinesi G, et al. Edmonton symptom assessment scale: Italian validation in two palliative care settings. Support Care Cancer 2006;14:30e37.
19. Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 1991;7:6e9.
30. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67:361e370.
20. Chang VT, Hwang SS, Feuerman M. Validation of the Edmonton Symptom Assessment Scale. Cancer 2000;88:2164e2171.
31. Vignaroli E, Pace EA, Willey J, et al. The Edmonton Symptom Assessment System as a screening tool for depression and anxiety. J Palliat Med 2006; 9:296e303.
21. Dudgeon D, Vaitonis V, Seow H, et al. Using networks to integrate palliative care province-wide. J Pain Symptom Manage 2007;33:640e644.
32. Morita T, Tsunoda J, Inoue S, et al. The Palliative Prognostic Index: a scoring system for survival prediction of terminally ill cancer patients. Support Care Cancer 1999;7:128e133.
22. Jenkins CA, Schulz M, Hanson J, et al. Demographic, symptom, and medication profiles of cancer patients seen by a palliative care consult team in a tertiary referral hospital. J Pain Symptom Manage 2000;19:174e184. 23. Modonesi C, Scarpi E, Maltoni M, et al. Impact of palliative care unit admission on symptom control evaluated by the Edmonton symptom assessment system. J Pain Symptom Manage 2005;30: 367e373.
33. Palmer JL, Fisch MJ. Association between symptom distress and survival in outpatients seen in a palliative care cancer center. J Pain Symptom Manage 2005;29:565e571. 34. Vigano A, Bruera E, Suarez-Almazor ME. Terminal cancer syndrome: myth or reality? J Palliat Care 1999;15:32e39. 35. Wachtel T, Allen-Masterson S, Reuben D, et al. The end stage cancer patient: terminal common pathway. Hosp J 1988;4:43e80.
24. Stromgren AS, Goldschmidt D, Groenvold M, et al. Self-assessment in cancer patients referred to palliative care: a study of feasibility and symptom epidemiology. Cancer 2002;94:512e520.
36. Tsai JS, Wu CH, Chiu TY, et al. Symptom patterns of advanced cancer patients in a palliative care unit. Palliat Med 2006;20:617e622.
25. Ripamonti C. Management of dyspnea in advanced cancer patients. Support Care Cancer 1999;7:233e243.
37. National Cancer Institute of Canada. Canadian cancer statistics 2005. Toronto: National Cancer Institute of Canada, 2005.
26. Stromgren AS, Groenvold M, Sorensen A, et al. Symptom recognition in advanced cancer. A comparison of nursing records against patient self-rating. Acta Anaesthesiol Scand 2001;45:1080e1085.
38. Stromgren AS, Sjogren P, Goldschmidt D, et al. A longitudinal study of palliative care: patient-evaluated outcome and impact of attrition. Cancer 2005;103:1747e1755.
27. Homsi J, Walsh D, Rivera N, et al. Symptom evaluation in palliative medicine: patient report vs systematic assessment. Support Care Cancer 2006;14: 444e453.
39. Jordhoy MS, Kaasa S, Fayers P, et al. Challenges in palliative care research; recruitment, attrition and compliance: experience from a randomized controlled trial. Palliat Med 1999;13:299e310.
Journal of Pain and Symptom Management
297
Original Article
The Association of Physical and Psychological Symptom Burden with Time to Death Among Palliative Cancer Outpatients Winson Y. Cheung, MD, Niusha Barmala, BSc, Sanaz Zarinehbaf, BSc, Gary Rodin, MD, Lisa W. Le, MSc, and Camilla Zimmermann, MD, MSc Division of Medical Oncology and Hematology (W.Y.C., C.Z.), Department of Medicine and Department of Psychiatry (G.R., C.Z.), University of Toronto; and Department of Psychosocial Oncology and Palliative Care (N.B., S.Z., G.R., C.Z.) and Department of Biostatistics (L.W.L.), Princess Margaret Hospital, University Health Network, Toronto, Canada
Abstract Previous studies have reported on the symptom burden of cancer inpatients, but outpatient studies have been few and have not examined the association of symptoms with time to death (TTD). Cancer patients seen in an oncology palliative care clinic from January 2005 to June 2006 and who subsequently died were identified from a palliative care database. Data from the last outpatient Edmonton Symptom Assessment Scale (ESAS) score completed in clinic were analyzed among patients who were followed during the last four months of life. Multiple linear regression analyses with Bonferroni adjustment were used to determine the association of ESAS total symptom distress score (TSDS), physical subscore (PHS), psychological subscore (PSS), and individual symptom scores with demographic parameters, disease characteristics, and TTD. Data from 198 patients were analyzed. All had stage IV cancer, the median age was 65, and 55% were men. There was no significant association between symptom burden and age, gender, or cancer site. TTD was significantly associated with TSDS (P ¼ 0.001) and PHS (P ¼ 0.001) but not with PSS (P ¼ 1.0). Individual symptoms most strongly associated with TTD were lack of appetite (P ¼ 0.001), drowsiness (P ¼ 0.006), dyspnea (P ¼ 0.009), and fatigue (P ¼ 0.01). There was no significant association between TTD and anxiety (P ¼ 1.0) or depression (P ¼ 1.0). Lack of appetite, drowsiness, dyspnea and fatigue represent a cluster of symptoms that tend to intensify at the end of life. The lack of intensification of psychological symptoms in relation to time to death is striking and needs to be further investigated using specific validated measures for depression and anxiety. J Pain Symptom Manage 2009;37:297e304. Ó 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Palliative care, symptom, time to death, Edmonton Symptom Assessment Scale, cancer
Address correspondence to: Camilla Zimmermann, MD, MSc, Department of Psychosocial Oncology and Palliative Care, Princess Margaret Hospital, 610 Ó 2009 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
University Avenue, 16-712, Toronto, Ontario, Canada M5G 2M9. E-mail: camilla.zimmermann@ uhn.on.ca 0885-3924/09/$esee front matter doi:10.1016/j.jpainsymman.2008.03.008
298
Cheung et al.
Vol. 37 No. 3 March 2009
Introduction
Methods
Cancer patients who are approaching the end of life represent a vulnerable population. In addition to experiencing substantial psychological distress, many individuals continue to suffer physical symptoms from their underlying illness, as well as side effects related to their treatment.1,2 In the oncology community, there is a growing recognition that comprehensive cancer management should emphasize not only measures that sustain and prolong life but also strategies that adequately address pain and symptom control. Accordingly, one of the main goals of palliative care is to improve, or at least maintain, the quality of life of dying patients by optimizing their physical, psychological, and social well-being.3 However, the task of providing appropriate symptom palliation can be a challenging endeavor requiring coordinated interdisciplinary collaboration, an approach that has generally not been emphasized in oncology training programs.4e6 Many studies have examined the complex dynamics of symptoms in the advanced cancer population.7 In the past, patients with poorly controlled or debilitating end-of-life symptoms were typically admitted to hospital for prolonged stays. For this reason, much of our current understanding of end-of-life symptomatology has been derived from research studies of palliative care inpatients.8e10 Although there has been an increasing emphasis on outpatient delivery of specialized palliative care, there are few reports of the symptomatology of outpatients with advanced cancer.11e13 Moreover, with notable exceptions,1,14 most prior studies of symptoms in advanced cancer patients have not measured or controlled for the association of symptoms with time to death (TTD). Conversely, studies specifically examining survival have focused on the predictive capacity of certain symptoms,15e17 rather than on providing a descriptive account of symptom epidemiology at the end of life. In the current study, our objectives were 1) to determine the physical and psychological symptom burden faced by patients who are assessed and followed in an outpatient palliative oncology clinic (OPOC) during the last four months of life, and 2) to evaluate the relationship of symptom intensity to TTD and demographic variables such as age and gender.
Characteristics of Study Hospital and Symptom Assessment Tool Princess Margaret Hospital (PMH) is a large tertiary cancer center located in Toronto, Canada. The institution has a comprehensive, multidisciplinary psycho-oncology department and a palliative care program, which consists of a 12-bed acute palliative care inpatient unit, a consultation service that assesses urgent cases on a same-day basis, and a daily OPOC. Approximately 1000 new patients are seen by the PMH palliative care service yearly, of which 80% are outpatients.18 Patients are referred to the OPOC by their oncologists for pain management, control of other symptoms, and palliative care planning.11 Follow-up is carried out in the palliative care clinic and also by telephone, especially if there are severe symptoms requiring daily assessment and titration of medications. When the patient is too ill to continue to come to the clinic or desires home-based care, referral is made to a home palliative care team.18 Since 2005, all patients who have been referred to and seen by a palliative care physician in the OPOC are requested to complete the Edmonton Symptom Assessment Scale (ESAS) questionnaire as a routine component of the initial consultation and at each subsequent clinic visit. The ESAS is a standardized, validated assessment tool that is commonly used by palliative care teams to evaluate the severity of nine physical and psychological symptoms, namely pain, dyspnea, appetite, nausea, fatigue, drowsiness, anxiety, depression, and general wellbeing.19,20 Patients grade each of the nine items on a scale from 0 to 10, with a score of 10 indicating the highest symptom intensity. Serial ESAS scores can provide a longitudinal measure of an individual’s symptom profile and response to palliative interventions. Results of ESAS assessments for all patients in the OPOC are prospectively entered into the PMH palliative care clinical database. A recent random chart audit for a provincial palliative care project that includes our cancer center21 found that the completion rate of the ESAS in our palliative care clinic was more than 90%.
Patient Selection and Data Collection This study was conducted on obtaining full research ethics approval from the institutional
Vol. 37 No. 3 March 2009
Cancer Symptom Burden and Time to Death
review board at PMH. Consecutive advanced cancer patients who were seen in consultation in the OPOC between January 1, 2005 and June 31, 2006, who died within four months of their last clinic assessment, and who responded to more than 50% of the items in the ESAS questionnaire during the latter assessment, were considered for inclusion in the study. Patients with early cancers (stage I to III as per the American Joint Committee on Cancer system) and patients without reliable mortality data were excluded from the analyses. The PMH palliative cancer symptoms database was used to identify all eligible subjects. Corresponding records and database entries for these patients were reviewed to extract baseline patient demographics, tumor characteristics, symptom information based on ESAS scores, and date of death. Demographics were also recorded for patients who did not meet inclusion criteria but who were assessed in the OPOC during the study period.
Statistical Analyses The last ESAS assessment before death was used for all analyses, whether this was an initial visit or a follow-up visit. The ESAS total symptom distress score (TSDS) was defined as the sum of individual scores from each of the nine symptom items on the questionnaire.19 In addition, the ESAS was categorized into a physical subscore (PHS) and a psychological subscore (PSS). The individual scores from the physical symptom domain (pain, dyspnea, appetite, nausea, fatigue, drowsiness) and the psychological symptom domain (anxiety, depression) were summated to generate PHS and PSS, respectively. Because ‘‘general wellbeing’’ is a measure of both physical and psychological manifestations of disease, this item was excluded from the subscores. For cases in which the questionnaire was not completed fully, TSDS, PHS and PSS were calculated as follows, provided that a minimum of 50% of items in the respective category were answered: sum of answered items number of possible items in category/number of answered items. TTD was defined as the time interval between the date of last ESAS assessment and the date of death. Descriptive statistics were used to summarize patient demographics, disease characteristics, TTD, and distribution of ESAS scores. Multiple
299
linear regression analyses were then conducted to determine the association of symptom burden with TTD and other patient- and disease-related variables. Specific covariates entered into the multivariate model included TTD, age, gender, and disease site. Age and TTD were included as continuous measures, whereas disease site was included as a categorical variable. To control for the effects of multiple testing, Bonferroni adjustment was used. All statistical analyses were performed with SASÒ (V9.1; SAS Institute, Cary, NC). To further determine the association of specific symptoms and time to death, patients were grouped according to time from assessment to death in the following categories: <1 month, 1 to <2 months, 2 to <3 months, and 3e4 months. Symptom scores were compared among patients in these four categories.
Results A total of 198 outpatients who satisfied our study inclusion criteria were identified from the PMH palliative care symptoms database. Baseline patient demographics and disease characteristics of study participants and nonparticipants were similar and are summarized in Table 1. The median age of patients included in the study was 65 years (range 25e98 years), and 108 (55%) were men. All patients had stage IV cancer at the time of their initial consultation in the OPOC. The majority (77%) had advanced solid tumors, with gastrointestinal and lung cancers being the most common disease sites. The mean TSDS, PHS, PSS, and individual symptom scores are listed in Table 2. Of the nine symptoms, fatigue, poor general well-being, and decreased appetite were most prominent during the last four months of life. In contrast, nausea appeared to be relatively well controlled. The median TTD from the date of the last ESAS assessment was 36 days (range 0e120). In multivariate analyses, a significant correlation with TSDS was observed only for TTD (P ¼ 0.001), where patients who were closer to death displayed a higher symptom severity. No significant association was found between TSDS and age, gender, or disease site (P ¼ 1.0). When the ESAS subscores were examined separately, the association between
300
Cheung et al.
Table 1 Baseline Patient and Disease Characteristics
Variable Age Mean (SD) Median (range) Gender Male Female Disease site Breast Gastrointestinal Genitourinary Gynecological Head and neck Hematological Lung Others
No. (%) of Patients Excluded from Study n ¼ 788
63.8 (12.9) 65.0 (24.9e89.3)
64.3 (14.3) 65.3 (54.7e74.9)
108 (54.6) 80 (45.4)
410 (52.0) 378 (48.0)
13 72 19 15 10 16 24 29
(6.6) (36.4) (9.6) (7.6) (5.0) (8.1) (12.1) (14.6)
57 221 64 76 53 74 125 118
Pain Fatigue Nausea Drowsiness Appetite Dyspnea
9 8 7 6 5 4 3 2
(7.2) (28.0) (8.1) (9.6) (6.7) (9.4) (15.9) (15.1)
1 0 -4
Our study differed from previous investigations in that we evaluated symptoms at the last assessment in the palliative care clinic rather than at the first visit. We chose this sampling method because the first visit to the palliative care clinic may occur as long as several years before death; for the purpose of the present study, we wished to describe the symptomatology of patients whose time from assessment to death was four months or less. The symptom burden 10
Anxiety Depression Well-being
9
90 60 20
190 191 194 194 195 192
5.2 4.6 6.1 2.9 6.9 5.1
(3.2) (3.4) (3.1) (3.1) (2.4) (3.1)
10 10 10 10 10 10
190 190
4.4 (3.1) 4.3 (3.1)
10 10
186
6.4 (2.6)
10
ESAS ¼ Edmonton Symptom Assessment Scale.
ESAS Scores
Individual ESAS scores Physical domain Pain Dyspnea Appetite Nausea Fatigue Drowsiness Psychological domain Anxiety Depression Other Well-being
0
Discussion
8
46.0 (17.9) 30.8 (12.3) 8.6 (5.6)
-1
association between these symptoms and age, gender, or disease site.
No. of Mean Score Possible Responses (SD) Score 195 196 186
-2
Fig. 1. Relationship of individual symptoms to time to death.
Table 2 Mean Scores of the Last ESAS Assessment Before Death
Total ESAS scores Total symptom distress Physical subscore Psychological subscore
-3
Months before Death
TTD and symptom intensity remained true for the PHS (P ¼ 0.001) only, and not the PSS (P ¼ 1.0). Among the physical symptoms, appetite (P ¼ 0.001), drowsiness (P ¼ 0.006), dyspnea (P ¼ 0.009), and fatigue (P ¼ 0.01) were correlated with TTD (Fig. 1), but not with age, gender, or disease site. The same trend of association with TTD was also evident for the patient’s sense of general well-being (P ¼ 0.07). In the psychological symptom domain, however, neither anxiety nor depression were significantly associated with TTD (P ¼ 1.0; Fig. 2), and there was also no
Variable
10
ESAS Scores
No. (%) of Patients Included in Study n ¼ 198
Vol. 37 No. 3 March 2009
7 6 5 4 3 2 1 0 -4
-3
-2
-1
0
Months before Death
Fig. 2. Relationship of anxiety, depression, and well-being to time to death.
(3.02) (3.54) (3.02) (3.02) (2.15) (3.23) (2.95) (3.15) (2.82) 4.88 4.00 6.83 2.94 7.67 5.49 3.67 3.71 6.40 2.92 3.26 5.78 2.00 7.06 4.77 2.95 3.28 5.37 (2.8) (2.9) (3.1) (2.8) (2.6) (3.1) (2.7) (2.9) (2.9) 3.4 2.7 6.0 2.3 6.4 3.9 2.8 2.9 4.8
Nekolaichuk et al.9,b (n ¼ 49)
(2.66) (3.33) (3.31) (2.99) (2.57) (2.81) (2.75) (2.58) (2.34) 5.38 4.16 6.24 2.27 6.44 4.84 3.05 2.97 5.97 (2.74) (2.95) (3.28) (2.94) (2.68) (3.08) (3.01) (3.04) (2.92) 5.40 2.80 5.25 2.53 5.40 4.39 3.27 3.57 5.41 (3.2) (3.4) (3.1) (3.1) (2.4) (3.1) (3.1) (3.1) (2.6) 5.2 4.6 6.1 2.9 6.9 5.1 4.3 4.4 6.4 Pain Dyspnea Appetite Nausea Fatigue Drowsiness Depression Anxiety Well-being
Stromgren et al. (n ¼ 34) Bruera et al. (n ¼ 166) Current study (n ¼ 198) Symptom
Values are mean (SD). ESAS ¼ Edmonton Symptom Assessment Scale; SD ¼ standard deviation. a For these studies, symptoms were scored on a 0e100 scale and were converted to 0e10 scale for easier comparison. b Fatigue item in these studies was recorded as ‘‘activity.’’ c SD is not given.
(3.42) (3.03) (3.63) (2.68) (3.15) (3.40) (3.46) (3.36) (3.27) 3.85 2.17 4.52 1.57 5.46 4.38 4.17 4.33 3.39 (3.2) (3.0) (3.2) (3.0) (2.4) (3.0) (3.1) (3.1) (2.9) 4.0 3.1 6.0 2.2 7.2 4.1 3.6 3.8 5.0
Jenkins et al. (n ¼ 86)
22,a
Modonesi et al. (n ¼ 162)
23
Inpatient Studies
Cancer Symptom Burden and Time to Death
24a,b 12,b
Outpatient Studies
Table 3 Symptom Distress in Previous Palliative Care Studies Using the ESAS
Rees et al.10a,c (n ¼ 71)
Stromgren et al.24,26,38a,b (n ¼ 116)
Vol. 37 No. 3 March 2009
301
observed in the current study was high, but our results are, overall, consistent with those from previous investigations using the ESAS to assess palliative symptomatology of oncology inpatients9,10,22e24 and outpatients12,24 (Table 3). Comparing across these studies, the severity of most physical and psychological symptoms was similar in inpatient and outpatient settings. The one exception was pain, which tended to be more severe in outpatients than in patients assessed in palliative care units. This may be because palliative care clinics often also serve as pain clinics, and patients may be referred specifically for pain control. Pain in our sample was similar to the mean pain scores seen in other outpatient palliative care settings. Nausea was the best-controlled symptom in our study, which is a trend evident in all other studies using the ESAS to determine symptom prevalence and severity. The only symptom in our study that differed considerably in severity from previous investigations was dyspnea, which was higher in our sample than for other studies in inpatients and outpatients (range in other studies 2.17e4.16; mean in our study 4.6). This difference cannot be explained by a difference in the relative proportion of lung cancer patients; with the exception of two studies,9,10 there were more lung cancer patients in other studies than in ours. Of note, the study that had the highest mean dyspnea score (4.16) was also a study of patients assessed in a palliative care outpatient clinic,24 suggesting that this symptom may be particularly prominent in ambulatory patients who are attempting to be more active. Greater attention should be given to the assessment and treatment of this distressing symptom in the palliative care outpatient setting.25 It also may be that patients in our study were closer to death than those in other studies. The median survival time for patients assessed was not given in the other studies except for the study by Modonesi et al.,23 where it was 46 days for the 88% of patients who had died by the end of the study. In a separate study by Stromgren et al.,24 mean survival from symptom assessment was 81 days. In contrast to physical symptoms, anxiety and depression appeared to be better controlled in our study and their severity was not significantly related to TTD. Thus, it would appear that physical rather than psychological
302
Cheung et al.
symptoms contributed predominantly to the total symptom burden of patients at the end of life. However, caution is necessary in the interpretation of these findings. Although standardized symptom assessment forms are more sensitive in the elucidation of symptoms than are patient reports,7,26,27 it has been noted that symptom acknowledgement correlates strongly with social desirability28 and patients may be more reluctant to report psychological symptoms than physical ones. Perhaps partly for this reason, the ESAS has been found to have greater validity in the reporting of physical than psychological symptoms.20,29 Furthermore, a retrospective study comparing the ESAS with the Hospital Anxiety and Depression Scale30 found that the cut-off point on the ESAS for the screening of both depression and anxiety was two of 10;31 the cut-off point for severe depression and anxiety is as yet unknown. Thus, in our sample, the mean score for depression and anxiety of four of 10, although low compared with the scores for most physical symptoms, may belie the true incidence of depression and anxiety in these patients. Prospective longitudinal studies are needed to determine the clinical significance of numerical values of the ESAS for depression and anxiety. A significant correlation with TTD was seen only for physical rather than psychological symptoms, and particularly for fatigue, dyspnea, drowsiness, and appetite. These results are similar to other studies constructing survival models for cancer patients in their last few months of life. In their study of 519 patients who were no longer receiving chemotherapy, Maltoni et al.17 reported anorexia and dyspnea as the only symptoms that were independent prognostic indicators. Fatigue and drowsiness were not measured, but fever, dry mouth, dysphagia, and pain were not independent predictors of survival. The median survival time in this study was 32 days, which is similar to the 36-day median survival time in our study. Morita et al.,32 in an evaluation of symptoms that influenced whether patients lived longer than three or six weeks, found that oral intake and dyspnea at rest were significant predictors. Again, fatigue and somnolence were not among the symptoms assessed in their study. More recently, Chow et al.16 reported that fatigue, appetite, and shortness
Vol. 37 No. 3 March 2009
of breath (all assessed using the ESAS) predicted prognosis in a palliative radiotherapy clinic, where the median prognosis was 19.4 weeks. In addition, a survival analysis of outpatients in a palliative care cancer center revealed that, in univariate analyses, dyspnea, drowsiness, lack of appetite, and nausea were significantly associated with shorter survival. However, in multivariate analyses only dyspnea and drowsiness showed a significant association.33 In the latter study, the median followup was 1.9 years, with 65% of the patients still alive and, therefore, censored in the analysis. The purpose of the latter studies was to detect independent predictors of survival, rather than to provide a descriptive account of the epidemiology of certain symptoms at the end of life. In contrast, the objective of our study was to describe the symptomatology of palliative care outpatients during the last four months of life, and to reveal which of these symptoms were significantly related to TTD. Several studies have mused on the existence of a ‘‘terminal cancer syndrome’’ where certain symptoms are associated with closeness to death, regardless of the cancer primary.17,34,35 However, the only previous study that has ever attempted to empirically characterize this syndrome was a cross-sectional evaluation of cancer outpatients with a relatively long median survival of 15.3 weeks.34 The overall symptom burden in this study was very low, with fatigue, anorexia, and poor feeling of well-being showing the worst scores (mean score 4/10 for each of these symptoms) and the association between symptom intensity and time to death was not measured. A more recent study of symptom prevalence and control on a palliative care unit in Italy reported that patients who survived for less than 30 days had a significantly higher intensity of fatigue, drowsiness, dyspnea, and anorexia, similar to the findings in our study.23 Another recent study of symptom patterns of advanced cancer patients in a palliative care unit found that, whereas pain and depression typically decreased and stabilized after admission, symptoms associated with the anorexiae cachexia syndrome, as well as dyspnea, did not show improvement.36 Thus, the latter symptoms appear to be specifically associated with advancing illness, regardless of diagnosis or treatment setting, and may not be as amenable to treatment.
Vol. 37 No. 3 March 2009
Cancer Symptom Burden and Time to Death
In terms of limitations, our results may not be generalizable to other palliative care centers, as the study consisted of a single institutional review of cancer patients. Nevertheless, our results are consistent with those from other studies. There is a high percentage of gastrointestinal and lung cancers in our study population; however, this is also true of other studies that have examined prognosis in cancer patients at the end of life17,32 and likely reflects the fact that these are the cancers with the highest mortality rate.37 We also excluded all outpatients who did not participate in an ESAS assessment in the OPOC. Although the completion rate for the ESAS in our clinic is high, some of the excluded patients may have been too frail or symptomatic to complete these assessments, resulting in a selection bias and an underestimation of the actual symptom burden. Finally, it would have been ideal to precisely characterize the evolution of patient symptoms prospectively and longitudinally from the time of advanced cancer diagnosis to death. However, such studies are also fraught with methodological difficulties, including low recruitment rates and high loss to follow-up, resulting in bias and reduced generalizability of the results.38,39 In conclusion, the significant correlation with time to death of lack of appetite, drowsiness, dyspnea, and fatigue suggests that this may constitute a cluster of symptoms that tend to intensify at the end of life. Further prospective research is necessary to determine to what extent the augmentation of these symptoms at the end of life can be prevented by proactive treatment. The lack of intensification of depression and anxiety in relation to time to death is also striking and needs to be further investigated using specific validated measures for these symptoms.
References 1. McCarthy EP, Phillips RS, Zhong Z, et al. Dying with cancer: patients’ function, symptoms, and care preferences as death approaches. J Am Geriatr Soc 2000;48:S110eS121. 2. Claessens MT, Lynn J, Zhong Z, et al. Dying with lung cancer or chronic obstructive pulmonary disease: insights from SUPPORT. Study to understand prognoses and preferences for outcomes and risks of treatments. J Am Geriatr Soc 2000;48:S146eS153.
303
3. WHO definition of palliative care. Available from. World Health Organization, 2002 www.who. int/cancer/palliative/definition/en. Accessed September 15, 2007. 4. Fitzsimons D, Mullan D, Wilson JS, et al. The challenge of patients’ unmet palliative care needs in the final stages of chronic illness. Palliat Med 2007;21:313e322. 5. Sullivan AM, Warren AG, Lakoma MD, et al. End-of-life care in the curriculum: a national study of medical education deans. Acad Med 2004;79: 760e768. 6. Buss MK, Lessen DS, Sullivan AM, et al. A study of oncology fellows’ training in end-of-life care. J Support Oncol 2007;5:237e242. 7. Teunissen SC, Wesker W, Kruitwagen C, et al. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain Symptom Manage 2007;34:94e104. 8. Elsayem A, Swint K, Fisch MJ, et al. Palliative care inpatient service in a comprehensive cancer center: clinical and financial outcomes. J Clin Oncol 2004;22:2008e2014. 9. Nekolaichuk CL, Bruera E, Spachynski K, et al. A comparison of patient and proxy symptom assessments in advanced cancer patients. Palliat Med 1999;13:311e323. 10. Rees E, Hardy J, Ling J, et al. The use of the Edmonton Symptom Assessment Scale (ESAS) within a palliative care unit in the UK. Palliat Med 1998; 12:75e82. 11. Riechelmann RP, Krzyzanowska MK, O’Carroll A, et al. Symptom and medication profiles among cancer patients attending a palliative care clinic. Support Care Cancer 2007;15(12): 1407e1412. 12. Bruera E, Michaud M, Vigano A, et al. Multidisciplinary symptom control clinic in a cancer center: a retrospective study. Support Care Cancer 2001;9: 162e168. 13. Lidstone V, Butters E, Seed PT, et al. Symptoms and concerns amongst cancer outpatients: identifying the need for specialist palliative care. Palliat Med 2003;17:588e595. 14. Jordhoy MS, Fayers P, Loge JH, et al. Quality of life in advanced cancer patients: the impact of sociodemographic and medical characteristics. Br J Cancer 2001;85:1478e1485. 15. Vigano A, Bruera E, Jhangri GS, et al. Clinical survival predictors in patients with advanced cancer. Arch Intern Med 2000;160:861e868. 16. Chow E, Fung K, Panzarella T, et al. A predictive model for survival in metastatic cancer patients attending an outpatient palliative radiotherapy clinic. Int J Radiat Oncol Biol Phys 2002;53:1291e1302. 17. Maltoni M, Pirovano M, Scarpi E, et al. Prediction of survival of patients terminally ill with cancer.
304
Cheung et al.
Results of an Italian prospective multicentric study. Cancer 1995;75:2613e2622. 18. Zimmermann C, Seccareccia D, Clarke A, et al. Bringing palliative care to a Canadian cancer center: the palliative care program at Princess Margaret Hospital. Support Care Cancer 2006;14(10): 982e987.
Vol. 37 No. 3 March 2009
28. Koller M, Heitmann K, Kussmann J, et al. Symptom reporting in cancer patients II: relations to social desirability, negative affect, and self-reported health behaviors. Cancer 1999;86:1609e1620. 29. Moro C, Brunelli C, Miccinesi G, et al. Edmonton symptom assessment scale: Italian validation in two palliative care settings. Support Care Cancer 2006;14:30e37.
19. Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 1991;7:6e9.
30. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67:361e370.
20. Chang VT, Hwang SS, Feuerman M. Validation of the Edmonton Symptom Assessment Scale. Cancer 2000;88:2164e2171.
31. Vignaroli E, Pace EA, Willey J, et al. The Edmonton Symptom Assessment System as a screening tool for depression and anxiety. J Palliat Med 2006; 9:296e303.
21. Dudgeon D, Vaitonis V, Seow H, et al. Using networks to integrate palliative care province-wide. J Pain Symptom Manage 2007;33:640e644.
32. Morita T, Tsunoda J, Inoue S, et al. The Palliative Prognostic Index: a scoring system for survival prediction of terminally ill cancer patients. Support Care Cancer 1999;7:128e133.
22. Jenkins CA, Schulz M, Hanson J, et al. Demographic, symptom, and medication profiles of cancer patients seen by a palliative care consult team in a tertiary referral hospital. J Pain Symptom Manage 2000;19:174e184. 23. Modonesi C, Scarpi E, Maltoni M, et al. Impact of palliative care unit admission on symptom control evaluated by the Edmonton symptom assessment system. J Pain Symptom Manage 2005;30: 367e373.
33. Palmer JL, Fisch MJ. Association between symptom distress and survival in outpatients seen in a palliative care cancer center. J Pain Symptom Manage 2005;29:565e571. 34. Vigano A, Bruera E, Suarez-Almazor ME. Terminal cancer syndrome: myth or reality? J Palliat Care 1999;15:32e39. 35. Wachtel T, Allen-Masterson S, Reuben D, et al. The end stage cancer patient: terminal common pathway. Hosp J 1988;4:43e80.
24. Stromgren AS, Goldschmidt D, Groenvold M, et al. Self-assessment in cancer patients referred to palliative care: a study of feasibility and symptom epidemiology. Cancer 2002;94:512e520.
36. Tsai JS, Wu CH, Chiu TY, et al. Symptom patterns of advanced cancer patients in a palliative care unit. Palliat Med 2006;20:617e622.
25. Ripamonti C. Management of dyspnea in advanced cancer patients. Support Care Cancer 1999;7:233e243.
37. National Cancer Institute of Canada. Canadian cancer statistics 2005. Toronto: National Cancer Institute of Canada, 2005.
26. Stromgren AS, Groenvold M, Sorensen A, et al. Symptom recognition in advanced cancer. A comparison of nursing records against patient self-rating. Acta Anaesthesiol Scand 2001;45:1080e1085.
38. Stromgren AS, Sjogren P, Goldschmidt D, et al. A longitudinal study of palliative care: patient-evaluated outcome and impact of attrition. Cancer 2005;103:1747e1755.
27. Homsi J, Walsh D, Rivera N, et al. Symptom evaluation in palliative medicine: patient report vs systematic assessment. Support Care Cancer 2006;14: 444e453.
39. Jordhoy MS, Kaasa S, Fayers P, et al. Challenges in palliative care research; recruitment, attrition and compliance: experience from a randomized controlled trial. Palliat Med 1999;13:299e310.