Factors Correlated with Dyspnea in Advanced Lung Cancer Patients

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Journal of Pain and Symptom Management

Vol. 23 No. 6 June 2002

Original Article

Factors Correlated with Dyspnea in Advanced Lung Cancer Patients: Organic Causes and What Else? Keiko Tanaka, MD, Tatsuo Akechi, MD, PhD, Toru Okuyama, MD, PhD, Yutaka Nishiwaki, MD, and Yosuke Uchitomi, MD, PhD Psycho-Oncology Division (K.T., T.A., T.O., Y.U.), National Cancer Center Research Institute East, Kashiwa, Chiba; and Thoracic Oncology Division (K.T., Y.N.), Palliative Care Unit (K.T.), and Psychiatry Division (T.A.), National Cancer Center Hospital East, Kashiwa, Chiba, Japan

Abstract This study aimed to investigate factors correlated with dyspnea in cancer patients among a broad range of medico-psycho-social factors. A total of 171 consecutive outpatients with advanced lung cancer were recruited. Dyspnea was evaluated by using the Cancer Dyspnea Scale, a valid, reliable 12-item self-rating scale developed to assess the multidimensional nature of dyspnea in cancer patients. Possible correlates, including 1) medical (clinical stage, Performance Status, SpO2, organic causes of dyspnea, other symptoms, such as cough and pain, etc.), 2) psychological (anxiety and depression), and 3) social (education, marital status, existence of confidants, etc.), factors were collected from medical charts, interviews, and self-rating questionnaires. Multiple regression analysis revealed that psychological distress, presence of organic causes, cough, and pain were significantly correlated with dyspnea (P  0.05, multiple R2  0.303). The present study confirms that dyspnea is multifactorial and that a beneficial therapeutic strategy might include intervention for psychological distress and pain. J Pain Symptom Manage 2002;23:490–500. © U.S. Cancer Pain Relief Committee, 2002. Key Words Dyspnea, cancer, correlated factors, Cancer Dyspnea Scale, lung, symptom management

Introduction Dyspnea is defined as “an uncomfortable sensation of breathing”1 and is one of the most common symptoms of advanced cancer patients, regardless of cancer sites. Published prevalence rates for dyspnea in the terminal stage range from 29% to 74%, even when no

Address reprint requests to: Yosuke Uchitomi, MD, PhD, Psycho-Oncology Division, National Cancer Center Research Institute East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. Accepted for publication: September 22, 2001. © U.S. Cancer Pain Relief Committee, 2002 Published by Elsevier, New York, New York

tumor involvement of the lung has been demonstrated.2–4 In spite of its high prevalence, the pathophysiology of dyspnea is not well understood,2,4 and it therefore remains one of the most refractory symptoms of advanced and terminal cancer patients.5 Dyspnea should be distinguished from respiratory failure, which is defined as hypoxia and/or hypercapnia. It cannot always be explained by organic causes,2,4 and is thought to be influenced by activity at many levels of the nervous system, including the respiratory center in the medulla and the cortex, although it is very difficult to quantify the events at these 0885-3924/02/$–see front matter PII S0885-3924(02)00400-1

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Factors Correlating with Dyspnea

levels.6 The manifestations of subjective symptoms have recently come to be interpreted as resulting from the interaction of production, perception, and expression, not as a direct representation of the intensity of the production of the dyspnea at the mechano- and chemoreceptor level.4,7 Some modulators, such as psychological state, cultural background, environment, and life experiences, are thought to amplify or decrease the intensity of perceived dyspnea at the cortical level.4,7 Several studies have yielded data supporting this hypothesis: dyspnea has been found to be significantly correlated with psychological status such as anxiety in cancer patients,6 and anxiety and depression in non-cancer populations,8,9 and with demographic factors, such as sex and age in non-cancer populations.9–11 However, few systematic studies in cancer patients that have focused on correlating factors, including medico-psycho-social factors, have ever been reported,6,12 and thus the correlates with perception and expression of dyspnea in cancer patients have yet to be identified. The purpose of this study was to identify factors correlated with dyspnea in cancer patients among a broad range of medical, psychological, and sociodemographic factors. Identification of such factors might contribute to better understanding of the nature of dyspnea and to establishing a management strategy. Dyspnea was evaluated by using the Cancer Dyspnea Scale (CDS), which was developed to assess dyspnea in cancer patients and validated by the authors.13

Methods Patients The subjects were consecutive ambulatory lung cancer patients in the Thoracic Oncology Division of the National Cancer Center Hospital East in Chiba and of the National Cancer Center Hospital in Tokyo, Japan. Eligible patients were required: a) to have been pathologically diagnosed as having lung cancer and to have been informed of their diagnosis, b) to be in the advanced stage clinically (i.e., in clinical stage IIIA [unresectable], IIIB, or IV) or recurrent stage, c) to be 18 years or older, d) to be well enough to complete the questionnaire, and e) not to be suffering from severe mental or cognitive disorders.

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This study was approved by the Institutional Review Board and the Ethics Committee of the National Cancer Center, Japan. Written consent was obtained after each patient had been fully informed of the purpose of the study.

Procedures The participants were interviewed and checked for vital signs, and they were asked to complete the questionnaires at home on the day of the hospital visit and mail it by the following day. If there were any blanks, telephone inquiry was used to obtain the missing answers, as agreed by the participants. Each participant was given a 500-yen prepaid telephone card for participating in the study.

Measures Cancer Dyspnea Scale (CDS). Dyspnea was measured by using the CDS, which was developed to evaluate the multidimensional nature of dyspnea in cancer patients.13 The reliability and validity of this scale in cancer patients were confirmed in the previous study.13 The CDS was revealed to consist of three factors by factor analysis in the previous study. They were named as 1) “sense of effort,” (five items: shortness of breath, panting, shallow breaths, airway narrowing, feeling of something stuck in the airway), 2) “sense of anxiety,” (four items: breathing difficulty accompanied by palpitations and sweating, breathing difficulty that the patient doesn’t know what to do about it, feeling as though breathing might stop or as though drowning), and 3) “sense of discomfort,” (three items: inhale easily, exhale easily, breathe slowly). Each item is rated from 1 (not at all) to 5 (very much). The maximal scores are: 20 for “sense of effort,” 16 for “sense of anxiety,” and 12 for “sense of discomfort.” The higher the score is, the more the severe the patient’s dyspnea. Hospital Anxiety and Depression Scale (HADS). HADS was applied to evaluate psychological distress. It is a 4-point, 14-item self-assessment scale that measures anxiety and depression separately.14 It does not include any physical symptoms to avoid unnecessary contamination. The full score is 21 points each for anxiety and depression. The Japanese version has also been

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validated, and its cut-off points for screening for adjustment disorder and major depression in cancer patients have been reported to be 10/11 and 19/20, respectively.15 Questionnaire on Symptoms. Patients were asked about common physical symptoms (cough, sputum, and pain) experienced within the past few days on a 4-point categorical scale, ranging from 1 (absent) to 4 (severe). Demographic, Medical, and Social Data. Patients’ demographic information, such as sex and age; and medical information, such as clinical stage, pathology, history of cancer treatments, number of days since the diagnosis of cancer, history of pulmonary disease (bronchial asthma, chronic obstructive pulmonary disease [COPD], tuberculosis), and current medication; were obtained from their medical records. Performance Status (PS) defined by Eastern Cooperative Oncology Group (ECOG) and organic causes of dyspnea were clinically judged on the day of the study by expert physicians who had practiced in thoracic oncology for over 5 years. The organic causes were classified as: tumor increasing in size, lymphangitis carcinomatosa, pleuritis and pleural effusion, atelectasis, pneumothorax, treatment-related pneumonitis, sputum, COPD, cardiac failure, carditis, superior vena cava syndrome, anemia, fever, pain, elevated diaphragm (due to ascites, liver swelling), others, and absence of any causes, referring to the literature.16 Pulmonary emboli, one of the frequent causes of dyspnea in this population, was to be grouped into others, since it was not included in the classification cited here and it is often difficult to diagnose clinically. Blood drawn in the clinical setting on the same day was also used in the analysis for reference: hemoglobin as an indicator of anemia and serum albumin as an indicator of disease progression and cachexia. Vital signs were taken after the patient sat at rest at least for five minutes, although the significant abnormalities only emerge with exertion, in order to evaluate their respiratory function in the same condition. The patient’s SpO2 (oxygen-saturated hemoglobin) and heart rate were measured with a finger pulse-oximeter. The number of respiration was counted for 20 seconds and multiplied by three to obtain the respiratory

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rate. Body temperature was measured in the axilla in an air-conditioned room. Current smoking status and smoking index were confirmed in the interview. Current smokers were defined according to the criteria of substance dependence in Diagnostic and Substance Manual-IV17 as those who were currently smoking or who had quit less than one year before, and smoking index was calculated by multiplying the number of cigarettes smoked by the number of years. Social information, such as marital and employment status and education level, was also obtained in the interview. Patients’ utilization of a confidant was used as an indication of social support.18 The interview was conducted in a semistructured manner as follows:19 Patients were asked if there was anyone they confided in regarding their personal problems. They were also asked about their satisfaction with the confidants, or, if they had no confidants, about their satisfaction about not having a confidant.

Statistical Analysis Each subscore and the total score of the CDS were entered into the model as dependent variables. First, we performed univariate analysis between the CDS scores and the medicopsycho-social factors investigated to identify potential dyspnea-related factors by the chisquare test, Fisher’s exact method, unpaired Student’s t-test, Mann–Whitney U-test, and Pearson correlation coefficient, as appropriate. Associated factors (P  0.05) were retained, and correlations among the factors were checked to eliminate confounding factors. We then used backward stepwise multiple regression analysis to investigate these factors. Factors not having an association at P  0.05 were eliminated in this procedure. All P values reported are two-tailed. All statistical procedures were performed with Statistical Package for the Social Science ver. 10.0.J (SPSS Inc., 2000).

Results Patients One hundred seventy-six consecutive outpatients were asked to participate between May and July 1998. Two of them refused (1%) because of lack of time or feeling too ill, and three were excluded (2%) because of failure to

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Table 1 Demographic and Clinical Characteristics (n  171a) Characteristics Sociodemographic Factors Age (years) Sex male Education junior high school or less (9 yr) Married Presence of confidants Medical (Physical) Factors PS (ECOG)b 0 1 2–4 Clinical Stage III/IV recurrent Pathology non-small cell lung cancer Presence of organic causes of dyspnea History of anti-cancer treatment (multiple choice) surgery chemotherapy radiotherapy Current use of steroids opioids minor tranquilizer Current smoker Days after diagnosis of cancer CDSc total score sense of effort sense of anxiety sense of discomfort Coughd Sputumd Paind SpO2 Heart rate (/min) Respiratory rate (/min) Hemoglobin (g/dl)e Serum albumin (g/dl)f Psychological Factors Anxiety-HADSg Depression-HADSg Total-HADSh

Mean  SD (range) median 64

No. (%) 63.0  9.3 (27–80) 122 (70) 74 (43) 145 (85) 151 (88) 36 (21) 126 (74) 9 (6) 122 (71) 49 (29) 142 (83) 80 (47) 38 (22) 130 (76) 88 (52)

348 7 3 0 3 2 2 1 97 82 18 12.2 3.9 3 5 8

17 (10) 27 (16) 25 (15) 41 (24) 610  657 (15–3138) 8.0  6.7 (0–35) 3.6  3.3 (0–17) 1.0  2.1 (0–10) 3.4  2.8 (0–12) 2.0  0.7 (1–4) 1.9  0.7 (1–4) 1.5  0.7 (1–4) 96  2 (88–99) 83  13 (48–117) 18  3 (12–33) 11.9  2.1 (5.1–16.9) 3.9  0.5 (2.3–5.0) 4.0  3.2 (0–15) 5.4  3.7 (0–17) 9.4  6.2 (0–32)

aExcept

for laboratory data, which were obtained from 91 patients. Status by Eastern Cooperative Oncology Group. Dyspnea Scale. dGraded by patients on a 4-point scale: from 1 (none) to 4 (severe). eNormal range: 13–17 (male), 12–15 (female). f Normal range: 45–85. gNormal range: 4.0–5.2. hHospital Anxiety and Depression Scale. bPerformance cCancer

reply. The characteristics of the remaining 171 patients are shown in Table 1.

for sense of effort, sense of anxiety, and sense of discomfort were 8.0  6.7 (7), 3.6  3.3 (3), 1.0  2.1 (0), 3.4  2.8 (3), respectively.

Descriptive Data The total CDS scores ranged from 0 to 35, and the subscores for sense of effort, sense of anxiety, and sense of discomfort ranged from 0 to 17, 0 to 10, and 0 to 12, respectively. The means  SD (median) of the total CDS scores, the subscores

Univariate Analyses Among the sociodemographic factors, age and sex showed significant correlations with some of the subscores: aged people and females complained of more severe dyspnea (Table 2).

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Table 2 Univariate Analysis Between CDS Score and Sociodemographic Factors (n  171) Subscores Potential Factors

Total Score, mean

Age

Total Score 0.09

Effort

Anxiety

Correlation Coefficient 0.02 0.05

Discomfort 0.17a

t value Sex Male Female Education 9 years 9 years Marital status Married Other Working status Work outside Other Confidants Present Absent Satisfaction with confidants Yes No aP

7.3 9.7

2.09

2.14a

1.35

1.54

8.5 7.6

0.93

0.26

0.54

1.56

7.8 9.2

0.99

0.98

1.11

0.41

7.0 8.2

1.22

0.67

1.13

0.74

7.7 9.9

1.35

0.78

1.60

0.50

7.9 8.8

0.39

0.01

1.04

0.37

 0.05.

Among the medical factors, PS, cough, sputum, pain, and presence of organic causes were significantly associated with total dyspnea (Table 3). Although current smoking status was also significantly correlated with dyspnea, the correlation was negative; that is, current smokers experienced less dyspnea. Perhaps this can be explained by patients with severe dyspnea quitting smoking and those with mild or no dyspnea continuing to smoke. Because our goal was to identify factors correlated with dyspnea, current smoking status was omitted. Organic causes were reclassified into two simple categories: presence or absence of an organic cause, because the numbers for the individual causes were too small to analyze separately. Among the psychological factors, both anxiety and depression were strongly correlated with dyspnea. This was the case not only with the total score, but also with each of the subscores (Table 4). Two pairs of independent factors having P  0.05 associations with the CDS scores had correlation coefficients above .40: anxiety and depression (r  0.63, P  0.01) and cough and sputum (r  0.56, P  0.01). It was decided to apply the total HADS score as an indicator of psychological distress, rather than anxiety-

HADS and depression-HADS, in order to minimize confounding the analysis, because anxiety and depression often overlap and are difficult to clearly distinguish from each other.20 Both cough and sputum were considered important to include in this study, and it was decided to keep them for the multiple regression models.

Multiple Regression Analysis The results of multiple regression analysis of the factors that correlated with the dyspnea scores are shown in Table 5. Psychological distress, presence of organic causes, cough, and pain were significantly correlated with total dyspnea. This model accounted for 30.3% (multiple R2) of the variance in the total score of the CDS. In addition to these four factors, heart rate was also significantly correlated in the subscore for sense of effort, while psychological distress and pain were the significant correlating factors in sense of anxiety. The correlations between total dyspnea and its significant correlating factors are shown in Figure 1.

Discussion The present study revealed that the dyspnea in advanced lung cancer patients was signifi-

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Table 3 Univariate Analysis Between CDS Score and Medical Factors (n  171)a Potential Factors

Total Score, mean

Total Score 0.32b 0.01

PS (ECOG) Days after diagnosis of cancer Cough Sputum Pain SpO2 Heart rate Respiratory rate Body temperature Hemoglobin White blood cell count Serum albumin

0.29b 0.31b 0.26b 0.12 0.09 0.03 0.01 0.04 0.07 0.17

Subscores Effort

Anxiety

Correlation Coefficient 0.36b 0.22b 0.05 0.02 0.30b 0.30b 0.28b 0.12 0.17c 0.04 0.01 0.02 0.09 0.15

Discomfort 0.18c 0.04

0.19c 0.17c 0.28b 0.02 0.02 0.04 0.05 0.07 0.08 0.05

0.24b 0.23b 0.14 0.17c 0.04 0.01 0.04 0.02 0.00 0.16

t value Clinical Stage III/IV Recurrent Pathology Small cell Non-small cell Organic causes Present Absent History of: surgery no chemotherapy no radiotherapy no Current use of: steroids no opioids no minor tranquilizers no Current smoker yes no Smoking index 400 400

7.5 9.2

1.47

1.98c

1.42

0.06

7.3 8.1

0.63

0.92

0.41

0.14

10.4 5.9

4.71b

5.04b

2.01c

3.78b

8.8 7.8 8.1 7.6 8.1 7.9

0.80

0.66

0.81

0.56

0.49

0.64

0.65

0.01

0.13

0.77

1.31

0.37

9.7 7.8 9.5 7.7 9.5 7.7

1.07

0.75

1.81

0.18

1.29

1.39

1.31

0.15

1.20

0.37

1.36

1.08

8.6 6.2

2.01c

2.17c

2.43c

0.90

7.4 8.4

0.97

0.69

1.38

0.58

aExcept

for laboratory data, which were obtained from 91 patients.  0.01 cP  0.05. bP

cantly correlated with psychological distress, presence of organic causes, cough, and pain. The correlation between pain and dyspnea is a matter of controversy. There are three possible relationships: 1) pain worsens dyspnea, 2) dyspnea worsens pain, and 3) they coexist with no causal relation between the two. Dyspnea may be induced by pain because severe pain anywhere sometimes may lead to hyperventilation, or chest pain caused by rib metastasis, and these factors

may make it difficult for patients to breath adequately and result in dyspnea. Nishino and colleagues showed that experimental pain augments experimental dyspnea in human volunteers and explained that a pain stimulus may increase ventilatory drive and in turn increase the sense of dyspnea.21 Conversely, pain may be induced by dyspnea because dyspnea may prevent patients from relaxation and controlled breathing, which help them cope with pain,22 or dyspnea may di-

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Table 4 Univariate Analysis Between CDS Score and Psychological Factors (n  171) Subscores Potential Factors

Total

Anxiety-HADS Depression-HADS Total-HADS

0.30 0.34 0.35

Effort

Anxiety

Discomfort

Correlation Coefficient 0.30 0.22 0.21 0.32 0.21 0.30 0.34 0.24 0.28

P  0.01 for all values.

minish serotonergic function, which has been found to increase pain sensitivity and decrease pain tolerance in animal studies.23 It is also possible, however, that pain could be decreased, instead of being increased, by dyspnea with respiratory failure because of a mechanism involving the release of endogenous opioids due to hypercapnia.24 Finally, it is possible that pain and dyspnea coexist because both symptoms progress in the natural course of the disease. Such unpleasant sensations may be impossible to clearly distinguish, since dyspnea has been reported to be construed by lung cancer patients as synonymous with fatigue.25 Although causality remains to be determined by a longitudinal study design, there may be

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complicated bidirectional causal pathways between pain and dyspnea and they may to some degree interfere each other dynamically in each patient. The present findings suggested that pain management is important, whatever the cause-effect relationships may be, and it might be helpful in relieving dyspnea. An association between anxiety and dyspnea was reported by Bruera et al.6 and has been also indicated by numerous clinical anecdotes. It is easy to understand why patients perceive dyspnea as an indication of progression of their disease and that it can evoke anxiety.26 A few studies have also shown that anxiety tends to influence the perception and expression of dyspnea in non-cancer populations9,27 and in cancer patients.28 It is worth noting that HADS score as a gross indicator for psychological distress was significantly related with dyspnea in this study. The psychological distress of cancer patients is mainly characterized by anxiety and depression,15 and a consistent strong association has been found between them,20,29 the same as in the present study (r  0.63, P  0.01). Therefore, it is reasonable that not only anxiety as reported before, but also gross psychological distress, including depression, should be taken into consideration. It should

Table 5 Multiple Regression Analysis of Factors Correlated with Dyspnea (n  171) CDSa Variable

Coefficient

Standardized Coefficient

Total Psychological distressb 0.29 0.27 Presence of organic causesc 3.55 0.26 Coughd 2.09 0.22 Paind 1.39 0.14 Intercept  2.791, Multiple R  0.550, Multiple R2  0.303, Adjusted R2  0.286 Sense of Effort 1.87 0.29 Presence of organic causesc Psychological distressb 0.13 0.24 Coughd 1.05 0.22 Paind 0.74 0.16 Heart rate 0.04 0.15 Intercept  4.716, Multiple R  0.586, Multiple R2  0.343, Adjusted R2  0.323 Sense of Anxiety Psychological distressb 0.06 0.17 Paind 0.49 0.16 Intercept  1.230, Multiple R  0.336, Multiple R2  0.113, Adjusted R2  0.097 Sense of discomfort Psychological distressb 0.11 0.24 Presence of organic causesc 1.24 0.23 Coughd 0.69 0.17 Intercept  0.437, Multiple R  0.420, Multiple R2  0.176, Adjusted R2  0.161 aCancer

Dyspnea Scale. by Hospital Anxiety and Depression Scale. cCoded 0 (absent), 1 (present). dGraded 1 (none) to 4 (severe). bAssessed

Multiple R2

t

P

0.101 0.098 0.063 0.036

4.02 3.95 3.10 2.05

0.01 0.01 0.01 0.04

0.113 0.102 0.067 0.042 0.029

4.40 3.72 3.30 2.31 2.34

0.01 0.01 0.01 0.02 0.02

0.058 0.045

2.26 2.11

0.03 0.04

0.073 0.066 0.041

3.36 3.11 2.36

0.01 0.01 0.02

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Fig. 1. Correlation between dyspnea and correlated factors in advanced lung cancer patients. aCancer Dyspnea Scale. b Hospital Anxiety and Depression Scale. c Judged by expert physicians. dGraded by patients on a 4-point scale from 1 (none) to 4 (severe).

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also be noted that psychological distress was correlated not only with the total scores of the CDS but to each of the subscores. Psychological distress is much more broadly and strongly associated with dyspnea than expected. Although causality could not be determined from the findings in this study, there may be causal relationships in either direction, and a vicious cycle may develop. According to the cutoff point for HADS,15 36% of the participants in this study had to have adjustment disorders or major depression. Previous reports also have noted the high prevalence of psychiatric disorders among cancer patients. According to Derogatis et al., almost half of the ambulatory cancer patients with a wide range of cancer disease and stages can be diagnosed as having a psychiatric disorder.30 Furthermore, it was reported that lung cancer patients had higher emotional distress than those with other cancers,31 and that patients with advanced disease were particularly emotionally vulnerable.32 When such high prevalence is considered, it is in the interest of patients not to overlook psychological distress, to detect it early, and to emphasize the therapeutically-appropriate intervention. In regard to organic causes, two points should be mentioned: 1) organic causes were significantly correlated with dyspnea, as previously reported,6 but 2) they accounted for only relatively small part of the total score of the CDS (multiple R2  0.098). The first point seems reasonable and logical, since organic abnormalities produce respiratory failure, which can easily lead to dyspnea. The second point, that organic causes do not contribute much to dyspnea, may be more informative, because it means that dyspnea cannot always be resolved by correcting organic abnormalities alone. The present findings suggest that management of organic causes, including treatment for cough, is a priority, but that other factors described should also be evaluated and managed to relieve dyspnea. Contrary to our expectations, some of the possible factors showed no correlation with dyspnea in the present study. Among the medical factors, surprisingly, laboratory data and respiratory rate showed no significant associations with dyspnea. History of treatment also showed no association with dyspnea, contrary to the previous study which showed the significant correlation of history of irradiation and dyspnea.12 This means

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that simple indicators of respiratory dysfunction cannot predict dyspnea. There were no significant correlations among the demographic factors, although “female” and “advanced age” had previously been reported to be correlated with dyspnea in cancer31 and non-cancer populations.9–11 This difference in results may depend on the difference in the patient populations, because most of the participants in this study were older males, similar to the general prevalence of lung cancer. The results showed no significant correlations with social factors, while high education level, working full time, living alone,33 and unmarried status34 were pointed out as factors correlated with higher perception of symptoms such as fatigue and pain. The multidimensional nature of dyspnea in cancer patients was recently confirmed by factor analysis, which identified three dimensions.13 The three subscores were named according to the items included by the authors.13 One of them is sense of anxiety, the convergent validity of which was confirmed by significant correlations with state- and trait-anxiety evaluated by the State-Trait-Anxiety-Inventory.13 The present multiple regression analysis also showed that dyspnea was significantly correlated with anxiety and depression evaluated with HADS, and not with physical factors, such as presence of organic causes, cough and heart rate. The present finding reconfirms that dyspnea has a psychological dimension that is not directly related to respiratory dysfunction. On the other hand, a definite difference in characteristics between sense of effort and sense of discomfort could not be reconfirmed in this study. This may be explained if the major part of sense of effort was explained by physical factors, such as presence of organic causes, cough, pain, and heart rate (multiple R2  0.343), whereas sense of discomfort was not adequately explained in this model (multiple R2  0.176). Based on these findings, it can be proposed that sense of effort is mainly characterized by physical aspects associated with organic failure, whereas sense of discomfort is an unpleasant feeling associated with unknown triggers that were not entered into this model. Further research is needed to confirm the validity of aggregating item scores within each of these factors and to identify the differences in these characteristics among these three dimensions.

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This model accounted for 30.3% of the variance in the total CDS score. This multiple R2 value was lower than expected. The reason for this is either that our measures of important factors may not be sufficiently sensitive or that many other factors remain to be identified. We had picked as many potential correlating factors as possible, but other factors may remain to be considered. Recently, fatigue in cancer patients has been reported to be significantly correlated with dyspnea,35 and malnutrition has also been reported to be weakly correlated with maximum inspiratory pressure,36 which has been found to be correlated with dyspnea.6,28 Further study is needed to explain the complicated nature of dyspnea in cancer patients. The limitations of this study were: 1) causality remains to be determined, because it was a cross-sectional design, and 2) the participants were ambulatory outpatients, therefore the results of this study may not apply to more severe dyspnea. In summary, this study showed that the dyspnea experienced by ambulatory advanced cancer patients was correlated not only with medical factors, such as organic causes, cough, and pain, but also with multiple other factors, such as psychological distress. These findings should contribute to better understanding the nature of dyspnea in this population. Further research is needed in two directions. First, the causal relationships between pain, psychological distress, and dyspnea should be determined. Second, a prospective study is needed to determine whether management of pain and psychological distress, including psychotropics and psychological intervention such as relaxation, which have been reported to be effective in relieving depression and anxiety,36 is effective in relieving dyspnea.

Acknowledgments The authors are grateful to anonymous patients who gave their time so willingly. They also wish to thank the physicians of the Thoracic Oncology Division of the National Cancer Center Hospital East (Drs. R. Kakinuma, Y. Ohe, F. Hojo, T. Matsumoto, H. Ohmatsu), and of the National Cancer Center Hospital (Drs. N. Saijo, T. Kodama, T. Tamura, T. Shinkai, H. Kunitoh, I. Sekine) for enrollment of their patients onto this study, and Y. Kojima,

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Factors Correlating with Dyspnea

RN, K. Harada, RN, Y. Sugihara, BA, M. Sakai, and R. Katayama for their research assistance, and S. Sasaki, MD, PhD, for his helpful advice in the statistical analysis. The first author would like to acknowledge K. Kubota, MD, PhD, for his encouragement as a supervisor. This work was supported in part by Grants- in-Aid for Research (9-31) and the Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare, Japan. Toru Okuyama is an awardee of a Research Resident Fellowship from the Foundation for the Promotion of Cancer Research.

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