Effects of symptom clusters and depression on the quality of life in patients with advanced lung cancer

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1 Original Article Effects of symptom clusters and depression on the quality of life in patients with advanced lung cancer S. CHOI, MSN, ONP, RN, Department of Nursing, National Cancer Center, Kyunggi-do & E. RYU, PHD, RN, Department of Nursing, Chung-Ang University, Seoul, South Korea CHOI S. & RYU E. (2018) European Journal of Cancer Care 27, e12508, doi: /ecc Effects of symptom clusters and depression on the quality of life in patients with advanced lung cancer People with advanced lung cancer experience later symptoms after treatment that is related to poorer psychosocial and quality of life (QOL) outcomes. The purpose of this study was to identify the effect of symptom clusters and depression on the QOL of patients with advanced lung cancer. A sample of 178 patients with advanced lung cancer at the National Cancer Center in Korea completed a demographic questionnaire, the M.D. Anderson Symptom Inventory Lung Cancer, the Center for Epidemiological Studies Depression Scale, and the Functional Assessment of Cancer Therapy General scale. The most frequently experienced symptom was fatigue, anguish was the most severe symptom-associated distress, and 28.9% of participants were clinically depressed. Factor analysis was used to identify symptom clusters based on the severity of patients symptom experiences. Three symptom clusters were identified: treatment-associated, lung cancer and psychological symptom clusters. The regression model found a significant negative impact on QOL for depression and lung cancer symptom cluster. Age as the control variable was found to be significant impact on QOL. Therefore, psychological screening and appropriate intervention is an essential part of advanced cancer care. Both pharmacological and non-pharmacological approaches for alleviating depression may help to improve the QOL of lung cancer patients. Keywords: lung cancer, quality of life, symptoms. INTRODUCTION Lung cancer is the fourth most common cancer and the leading cause of death in Korea, with more than cases being diagnosed each year, accounting for 10.3% of all new cancer cases (National Cancer Center 2014). Patients with advanced non-small-cell lung cancer (NSCLC) experience multiple distressing symptoms, which collectively impose a symptom burden that is highly disruptive to their physical and emotional Correspondence address: Eunjung Ryu, Department of Nursing, Chung- Ang University, 84 Heukuk-ro, Dongjak-gu, Seoul 06974, South Korea ( go2ryu@cau.ac.kr). Accepted 25 March 2016 DOI: /ecc European Journal of Cancer Care, 2018, 27, e12508, DOI: / ecc functioning (Cleeland 2007). Since patients with NSCLC have a low survival rate, a reasonable treatment goal is to reduce pain and other symptoms while increasing the quality of life (QOL) and functioning (National Cancer Center 2014). Unlike other cancers, lung cancer has no special subjective symptoms and has no appropriate early screening methods, such that fewer than 20% of lung cancer patients are diagnosed with early-stage lung cancer (i.e. stage I or II), and thus multimodality treatment is the only way to prolong patient survival for patients with advanced lung cancer (National Comprehensive Cancer Network 2014). The extremely poor prognosis of lung cancer is further demonstrated by its 5-year survival rate, which is reported only 23.5% (National Cancer Center 2014). In addition, the physiological and emotional pain suffered by these patients increases manifold with disease progression (Baker et al. 2005) John Wiley & Sons Ltd 1of8

2 CHOI & RYU In the first year after the initial diagnosis, early-stage lung cancer patients experience an mean of 4.9 symptoms, whereas patients with advanced lung cancer experience an mean of 5.7 symptoms (Given et al. 2001), confirming the phenomenon of symptom clusters among lung cancer patients (Dodd et al. 2001). Studying symptom clusters may not only provide the foundation for identifying and diagnosing the symptoms and the disease conditions during the treatment process (Barsevick 2007), but may also reveal the relationship among different symptoms within the same symptom cluster, and identify influential symptoms (Honea et al. 2007). In summary, investigating the symptom clusters of lung cancer patients is very important for identifying and managing both the most influential symptoms and the secondary symptoms that accompany the disease. With respect to treating advanced cancer, the recent development of therapy targeted against the biomolecular characteristics of the tumour led to the hope of easing the symptoms and extending the survival time of the patient. In fact, the median survival time has increased from approximately 6 months in the 1970s to approximately 12 months in the current era (Lee & Han 2011). Consequently, the focus of medical professionals should shift from how long a lung cancer patient will live to the patient s QOL. Therefore, the purposes of this study were to identify (1) the symptoms experienced by advanced lung cancer patients and classify them into symptom clusters, (2) the presence of depression in patients and compare to symptom and QOL and (3) the factors influencing the effects of depression and symptom clusters on the QOL of patients. METHODS Design and sample A multivariate approach with a cross-sectional design was used in this study. Patients were recruited consecutively at the lung cancer clinic of the National Cancer Center (NCC) in Korea. The patients were invited to participate in the study after approval for it was obtained from the Institutional Review Board. The study invitation was distributed to potential patients by the oncologist and nurse who cared for the patients. An oncology research nurse met with all patients who responded to the study, confirmed the study criteria with patients, and provided a detailed explanation of the study. Participants were informed that their participation was voluntary, anonymous and confidential, and that they had the right to withdraw from the study at any time without any penalty or effect on their current treatment. The eligibility criteria 2of8 for the patients were (1) having advanced (stage IV) NSCLC or extended stage of small-cell lung cancer, (2) being scheduled to receive intravenous chemotherapy at the outpatient clinic of the cancer centre and (3) being 18 years of age or older. All patients gave their informed consent to participate. Their medical records were reviewed by the oncology research nurse to validate their clinical and treatment data. Measures Demographic and clinical characteristics Patient demographic information (e.g. gender, age, marital status, education level and job status) was collected during the clinic visit using a general survey questionnaire. A study-specific clinician checklist was used to collect medical background information from their medical records, including the treatment received, time since diagnosis and cancer diagnosis, location and staging. The Eastern Cooperative Oncology Group performance status (ECOG PS) was used to estimate the disease severity in these cancer patients (Sørensen et al. 1993). The ECOG PS score is a single-item rating of the degree to which patients are able to participate in typical daily activities without the need for rest. This index is used widely in clinical trials to assess the functional capability of patients. The ECOG PS score ranges from 0 ( I have normal activity without symptoms ) to 4 ( I am unable to get out of bed ). The Center for Epidemiological Studies Depression Scale The Center for Epidemiological Studies Depression Scale (CES-D) contains 20 items selected from previously validated scales of depression (Radloff 1977). The scores for the 20 items are summed, resulting in the possible total score ranging from 0 to 60, with a cutoff of 16. The CES-D was validated in Korea and the score 25 was suggested as the optimal cutoff point in clinical setting and the score 21 in the community setting to screen DSM-III-R major depression (Cho & Kim 1998). This relatively high cut-off point was decided on after considering culturally influenced responses in the Korean version of CES-D. Cronbach s a was in this study. M.D. Anderson Symptom Inventory Lung Cancer questionnaire Korean version was used to assess severity and impact of symptoms (Mendoza et al. 2011). The M.D. Anderson Symptom Inventory Lung Cancer (MDASI-LC) questionnaire includes the 13 core MDASI symptom items (i.e. pain, fatigue, nausea, vomiting, dry mouth, shortness of breath, lack of appetite, difficulty 2016 John Wiley & Sons Ltd

3 Quality of life in patients with advanced lung cancer remembering, drowsiness, disturbed sleep, sadness, distress and numbness) and three lung-cancer-specific items: coughing, constipation and sore throat. Each symptom is rated on an 11-point scale, with 0 indicating not present and 10 indicating as bad as you can imagine. Interference items are rated on an 11-point scale, with 0 indicating did not interfere and 10 indicating interfered completely. The mean score for the items constitutes a composite interference score. The ratings in the MDASI- LC can be averaged into several subscale scores: mean severity (13 core symptom items plus the lung-cancerspecific items), mean core (13 core symptom items only) and mean interference (interference items only). In this study, Cronbach alpha was 0.91 for the core subscale, at least 0.81 for the severity subscale, 0.93 for the interference subscale and 0.94 for all subscale scores. Functional Assessment of Cancer Therapy General Functional Assessment of Cancer Therapy General (FACT-G) was used to measure QOL (Cella et al. 1993). The FACT-G instrument was developed specifically for patients with any type of cancer. The original FACT-G has been used widely in clinical trials; it is easy to complete and has demonstrated sensitivity for the performance status and the extent of disease. The FACT-G scales include a 27-item compilation of general questions divided into four primary QOL domains: physical (7 items), social/family (7 items), emotional (6 items) and functional well-being (7 items). The subjects circle numbers on a scale from 0 ( not at all ) to 4 ( very much ) to indicate their reaction to each statement. Higher scores for the scales indicate a better QOL. The possible total scores ranges from 0 to 180. The Cronbach alpha for reliability for the physical (PWB), social/family (SWB), emotional (EWB) and functional well-being (FWB) subscales were 0.93, 0.88, 0.88 and 0.92, respectively, and that for the total scale was Data analysis Descriptive statistics and frequency distributions were computed for sample characteristics, CES-D, FACT-G and MDASI-LC. The Kolmogorov Smirnov test was used to evaluate the goodness of fit on the distribution of scores obtained from the measures. The results indicate that the scores approximated a normal distribution. The CES-D score cut point of 20 or less was used to categorise a no depression group and 21 or greater to categorise a depression group to determine the mean values and compare to symptoms and QOL in depressive versus non-depressive patients. Effect size estimates and their associated 95% confidence intervals (Cohen s d statistic) also were calculated to provide a measure of the magnitude of differences according to the criteria suggested by Cohen (small, d = 0.2; medium, d = 0.5; and large, d = 0.8). With a Kaiser Meyer Oklin value of 0.91 and a Bartlett s Test of Sphericity reaching statistical significance (P < 0.001), a principal axis factoring with varimax rotation was conducted on the 19 possible symptoms (13 symptoms from MDASI and 6 additional symptoms) to derive symptom clusters. Stepwise multiple regression analysis was conducted to identify predictors of QOL in patients with advanced lung cancer. Cases with missing values were excluded from the analyses. Sample size and power were calculated based on the formula proposed by Cohen (1988). Eighty-seven patients were required to achieve a power of 0.8 for regression analysis. All tests were twotailed and a value of P < 0.05 was considered statistically significant. RESULTS Sample characteristics A sample of 178 patients who were receiving active treatment with Gefitinib for lung cancer completed the study. The mean age of the participants was 54.0 years (SD = 8.8), and 57.9% were male. Most of the patients (73.6%) had a college education or graduate degree, were married (80.9%), were unemployed (24.7%) and 32.6% of them reported having no religious beliefs. Most of the study sample (91.0%) had NSCLC, had a history of smoking (55.6%), took antidepressive agents (2.8%) and 72.5% had an ECOG PS score of 1, indicating that they were able to carry about normal activities but in the presence of some symptoms. The majority of the patients were diagnosed as stage IV with adenocarcinoma (83.0%) (see Table 1). The prevalence of the symptoms and symptom clusters Almost all the participants (98%) presented with at least four concurrent symptoms; the median number of concurrent symptoms reported by each participant was 14. Descriptive statistics on symptom severity and prevalence are displayed in Table 2. Each symptom was experienced by more than 53% of the sample, and the severity score of each symptom was greater than 2 on the 0 10 point scale. The five most common symptoms, ranked in order, were fatigue, distressed, sad, drowsy and dry mouth. Distressed was perceived to have the most severity, followed by fatigue, sad, disturbed sleep and lack of appetite John Wiley & Sons Ltd 3of8

4 CHOI & RYU Table 1. Demographic and clinical characteristics of the sample (N = 178) Characteristic Mean SD Min Max (range) Age (years) (45) Time since diagnosis, months (55) Characteristic n % Gender Male Female Education High-school degree or less College graduate Greater than college Marital status Never married 10 5 Married Divorced or separated 12 7 Widowed 12 7 Religion Christian Catholic Buddhist None Others 4 2 Job status Homemaker Employed outside home Retired/unemployed Smoking status Former or current Never Antidepressive agents Yes 5 3 No ECOG PS (score) (0) Fully active 12 7 (1) Restricted but ambulatory (2) Ambulatory, capable of self-care (3) Capable of only limited self-care 11 6 Lung cancer type Non-small-cell Adenocarcinoma Squamous cell carcinoma 8 5 Other 6 3 Small cell 16 9 ECOG PS, Eastern Cooperative Oncology Group performance status. The comparison of symptoms and QOL To test our hypothesis, we divided the sample into two groups based on the level of depression with cutoff score 21. Table 3 summarises the results of the t-test. As expected, depressive group was significantly different from non-depressive patients on the FACT-G (t = 8.69, P < 0.001), except for social well-being subscale. The MDASI-LC revealed a significant difference between depression and no depression group (t = 4.61, P < 0.001; t = 4.87, P < 0.001; t = 2.46, P = 0.015; and t = 5.31, P < respectively). Large effects were found on the FACT-G, including the PWB, the EWB and the FWB subscales, the CES-D, and interference subscale on the MDASI-LC, whereas moderate effects were found for core symptoms and symptom severity on the MDASI-LC. Factors influencing QOL The factors affecting QOL in this sample were identified using stepwise multiple regression analyses (see Table 4). The following demographic and clinical characteristics with meaningful disparities as verified by univariate analysis were input as independent variables: age, education, marital status, economic burden and performance status. The study variables such as the three symptoms clusters, depression and time since diagnosis were also included. Some of variables measured using a nominal scale were regarded as dummy variables during the analysis. No problems of multiple collinearity were identified. The range of tolerance was , which is more than 0.1. The variance inflation factor ranged between and 3.819, and hence did not pass the standard point of 10. The results showed the QOL in lung cancer patients was most influenced by depression, followed by cancer related symptoms and age. The regression model accounted for 55% of the variance (F = , P < 0.001; see Table 4). An exploratory factor analysis using principal factor analysis and a varimax rotation was employed to understand the latent constructs of the 16 symptoms in this sample (see Table 2). Three factors with eigenvalues greater than 1 were retained and the three derived symptom clusters were labelled treatment related, lung cancer related and psychological, all of which accounted for 61.7% of the total variance. The internal reliabilities were 0.86 for the treatment-related symptom cluster, 0.83 for the lung cancer related symptom cluster and 0.83 for the psychological symptom cluster. 4of8 DISCUSSION This study evaluated measures of depression, symptoms and QOL in patients receiving Gefitinib for advanced lung cancer. The symptoms experienced by advanced-cancer patients were investigated in this study, and classified into symptom clusters. Their experiences of depression and their QOL were then examined to determine the factors influencing the QOL of these patients. This study found that among the symptoms experienced by advanced-cancer patients, fatigue was experienced by almost all of the study participants, and more than 53% 2016 John Wiley & Sons Ltd

5 Quality of life in patients with advanced lung cancer Table 2. Symptom occurrence, severity and clusters (N = 178) Occurrence Severity Factor loading Table 3. Quality of life, depression and symptom scores in non-depression and depression groups determined by the centre for epidemiological studies depression scale Total (N = 178) Symptom n % X SD Factor 1 Factor 2 Factor 3 Nausea Vomiting Disturbed sleep Pain Lack of appetite Sore throat Shortness of breath Cough Constipation Dry mouth Drowsy Distressed Sad Remembering things Fatigue Numbness or tingling Cronbach s a Eigenvalue Variance explained Total variance explained Factor 1 treatment-associated symptom cluster; Factor 2 lung cancer symptom cluster; Factor 3 psychological symptom cluster. Nondepression group (N = 119) Depression group (N = 59) Variable X SD X SD X SD t P Effect size Functional assessment of cancer therapy general Physical well-being < Social well-being Emotional well-being < Functional well-being < FACT General < The Center for Epidemiological Studies Depression Scale Depression < M.D. Anderson Symptom Inventory Lung Cancer Symptom severity < Core symptoms < Lung cancer symptoms Interference < Table 4. Stepwise multiple regression model of quality of life (N = 178) Variable B SE b t P Adjusted R 2 Depression < Lung cancer symptom cluster < Age Model F = , P < 0.001; R 2 = 0.533, Adjusted R 2 = experienced all 16 of the investigated symptoms. These findings were corroborated in another study, which found that more than 90% of female lung cancer patients experienced fatigue and shortness of breath, and more than 80% experienced a lack of appetite, coughing and pain (Brown et al. 2011). Distress was the most severe 2016 John Wiley & Sons Ltd 5of8

6 CHOI & RYU symptom experienced by the participants. In a study by Wang et al. (2008), 74.1% of patients with stages I III lung cancer complained that fatigue was their most severe symptom, followed by disturbed sleep, lack of appetite, shortness of breath and distress, findings that differ slightly from those of this study. These differences may be attributable to the participants of this study spending a large amount of time at home with their families after chemotherapy or radiotherapy, despite them having metastasised lung cancer. They consequently reported that the symptoms of lung cancer disturbed their mood, joy in daily activities, work and the interpersonal relationships in their daily life. The patients recognition and fear that the treatment process might become more difficult and painful because of the high mortality rate of their disease, as well as uncertainty regarding the effectiveness of their treatment reflects that their psychological symptoms were more severe than their physiological symptoms. The 16 symptoms experienced in this study were categorised into three symptom clusters based on different symptom factors. Factor 1 consisted of five symptoms: nausea, vomiting, disturbed sleep, pain and lack of appetite. Gift et al. (2004) examined 32 symptoms of lung cancer patients receiving treatment, and identified fatigue, a sore throat, weakness, a lack of appetite, weight loss, a change in taste buds and vomiting as a single symptom cluster. In NSCLC patients who were receiving Gefitinib treatment, their symptoms were classified pain, constipation, sore throat and vomiting as a single symptom cluster (Lee & Park 2009). As demonstrated above, lung cancer patients exhibit similar symptoms during treatment. Factor 1 symptoms can be considered to arise from treatment. Consequently, factor 1 was named the treatment-associated symptom cluster. Factor 2 consisted of six symptoms: a sore throat, shortness of breath, coughing, constipation, dryness of mouth and drowsiness. Lee and Park (2009) considered shortness of breath, coughing and insomnia as a single symptom cluster in lung cancer patients. Sore throat, shortness of breath and coughing are characteristic symptoms of lung cancer, as per MDASI-LC, and so factor 2 of this study was named the lung-cancer-symptom cluster. Shortness of breath and coughing are symptoms of the presence of a tumour at a particular site, or the progression of the disease such that the fundamental treatment of the lung cancer is deemed the most important. In terms of nursing intervention, mucus drainage is important to regulate coughing, and this can be ameliorated by maintaining air humidity and ensuring postural drainage. In addition, caution should be taken 6of8 because the side effects of using pharmacological mucolytic agents include constipation and drowsiness. Furthermore, shortness of breath can be minimised by maintaining a correct posture, practicing breathing regulation and relaxation, and providing psychological support (Joyce et al. 2008). For factor 3, the symptom cluster consisted of five symptoms: distress, sadness, forgetfulness, fatigue and numbness or tingling. In a study of various types of cancer patients using MDASI assessment tools, distress and sadness constituted a symptom cluster, corroborating the results of this study (Chen & Tseng 2006). As such, factor 3 of this study was named psychological symptoms. Lung cancer patients receiving treatment have reported that only 43% of their symptoms were addressed by medical professionals (Hill et al. 2003). In addition, consulting with medical professionals regarding physiological symptoms occurred more frequently, despite there being a greater need to address the psychosocial symptoms of the patients. Medical professionals should therefore make efforts to try to understand patients by encouraging them to accurately describe various symptoms and experiences associated with their emotions. This study used the CES-D to measure the depression severity of the advanced-lung-cancer patients; 28.9% of the patients scored above 21 points, which is the threshold for depression on this scale. This percentage is higher than that for all lung cancer patients in Korea and the 5-year survivors of NSCLC, which are 16.3% and 22%, respectively, as assessed using the same instruments (Sarna et al. 2002; Lee & Kim 2011). A study that investigated depression in patients with various types of cancer, including breast cancer, prostate cancer, colon cancer and lung cancer, found that the proportion of patients with depression was highest among those with lung cancer, at 17.6% (Sellick & Edwardson 2007). The diverse tools and types of subjects addressed by previous research on depression make comparisons with the results of this study difficult; however, a common theme is that depression is more severe among lung cancer patients than among patients with other types of cancer. This indicates that medical professionals should make a concerted effort to become more aware of the depression experienced by lung cancer patients and respond to this appropriately. This study found that factors influencing the patients QOL were depression, the lung-cancer-characteristic symptoms cluster and age. The QOL increased with age. A poor prognosis of inoperability and high mortality rate due to the advanced nature of the cancer affected 2016 John Wiley & Sons Ltd

7 Quality of life in patients with advanced lung cancer patients of younger age groups, who had higher hopes of survival. The lung cancer symptom cluster was shown to influence the QOL, indicating that symptom management and treatment effects are important influencing factors. Finally, depression was identified as the factor having the greatest influence on the patients QOL. Although 52 participants (28.9%) of this study were considered to be depressed, only five participants (2.8%) were taking antidepressant medications: two of these were receiving therapeutic counselling and pharmacological treatment from a psychiatric professional, and the other three individuals had their medications prescribed by the oncologist. Currently, the main almost only pathway by which cancer patients receive psychosocial interventions is a psychiatric referral by their oncologist in Korea. When we estimated the rate of psychiatric consultations at the NCC in Korea during 2006, about 1.3% of the patients had been referred for a psychiatric consultation (Kim 2007). This implies that an extremely low proportion of cancer patients experiencing various states of psychological distress actually receive psychosocial services in a clinical setting. Although there are various reasons for the discontinuity between the evaluation of psychological problems and their therapeutic intervention, the primary reasons include the lack of diverse psychosocial service resources, the stigma about receiving such services, and a lack of awareness by medical professionals. Yu et al. (2012) found that more than 80% of patients who were co-referred to the psychiatry department exhibited symptoms that indicated depression beyond a severe level, which suggests that the cancer patients were only referred to a psychiatric department if they exhibited visibly severe symptoms. That study also showed that the use of antidepressants led to an improvement in the depressive conditions of the participants. Similarly, the participants who were taking antidepressants in this study was lower depression and higher QOL score, demonstrating that appropriate treatment of their depression led to an improvement in their QOL. Given that virtually no studies have investigated the physiological symptoms and emotional pain of lung cancer sufferers, this study is valuable in that it confirms comprehensively the physiological symptoms of advanced-lung-cancer patients, the presence of depression in these patients and their QOL. The recently increased the survival rate of cancer patients has led to attempts by a diverse group of medical professionals to improve their QOL, by addressing their physical, emotional and social well-being. However, to provide more effective nursing, it is important to clearly identify the factors that influence QOL. To this end, the results of this study provide important information for healthcare professionals regarding the design of interventions to improve the QOL of cancer patients. In particular, if depression in lung cancer is assessed aggressively and managed with interventions, it is possible to improve the QOL of these patients. This study was subject to several limitations. First, all the participants were advanced-lung-cancer patients at a single specialised cancer treatment hospital, which limits the generalisability of the study results. This research should therefore be repeated with larger numbers of participants that accurately reflect the proportions among the different stages of cancers. Second, because the advanced-lung-cancer patients in this study were receiving outpatient treatments, the ECOG PS score was characteristically good and the severity of physiological symptoms associated with the disease was low. Comparative studies examining the physiological symptoms and emotional pain of patients with low ECOG PS scores are thus necessary. CONCLUSION This descriptive study identified the symptoms of advanced-lung-cancer patients and classified them into symptom clusters. The depression and QOL of the participants were also examined to investigate the factors influencing their QOL. The three symptom clusters classified in this study will be useful in managing the symptoms of advanced-lung-cancer patients in a clinical setting. Depressed patients with advanced lung cancer had lower QOL and higher symptoms. Medical professionals must approach the patient with the awareness that the patient is experiencing a considerable amount of emotional pain. In particular, depression should be assessed and comprehensive care should be provided so as to improve the QOL of advanced-lung-cancer patients. Among the subscales of the QOL of advancedlung-cancer patients, emotional well-being yielded the lowest score. Given that depression was confirmed as an influential variable in determining a patient s QOL, physiological symptoms associated with emotional pain, including fatigue, disturbed sleep and anxiety, must be investigated in a future study. The influencing factors confirmed in this study should be used as a basis for developing non-pharmacological intervention programmes that incorporate psychosocial elements, and applying them to improve the QOL of advancedlung-cancer patients John Wiley & Sons Ltd 7of8

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