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Quality of Life in 650 Lung Cancer Survivors 6 Months to 4 Years After Diagnosis
ORIGINAL ARTICLE QUALITY OF LIFE IN LUNG CANCER PATIENTS
Quality of Life in 650 Lung Cancer Survivors 6 Months to 4 Years After Diagnosis ADAM SVOBODNÍK, MS; PING YANG, MD, PHD; PAUL J. NOVOTNY, MS; ERIC BASS, BS; YOLANDA I. GARCES, MD; JAMES R. JETT, MD; JAMES A. BONNER, MD; AND JEFF A. SLOAN, PHD OBJECTIVE: To present the results of a quality-of-life (QOL) assessment performed with the current version of the Lung Cancer Symptom Scale (LCSS) questionnaire in a large single-institutional data set of 650 patients with lung cancer. PATIENTS AND METHODS: The study group included 650 patients with pathologically confirmed primary lung cancer whose conditions were diagnosed and/or treated at the Mayo Clinic in Rochester, Minn, between January 1, 1997, and December 31, 2001. The QOL assessment was performed using the self-administered LCSS questionnaire (version 2) 6 months to 4 years after the diagnosis of lung cancer. RESULTS: The item response rate for all 9 LCSS questions was 94.2% with a minimum of 92.9%. Significant differences in overall QOL by sex (P=.04), Karnofsky scale (P<.001), weight loss (P<.001), disease stage (P<.001), and histology (P=.001) were found, but no significant differences in overall QOL by age (P=.17) or marital status (P=.06) were observed. CONCLUSION: Our data suggest that QOL in patients with lung cancer at varying times after diagnosis highly correlates with baseline prognostic factors (disease stage, histology, Karnofsky scale, weight loss, and sex).
Mayo Clin Proc. 2004;79(8):1024-1030 LCSS = Lung Cancer Symptom Scale; NSCLC = non–small cell lung carcinoma; QOL = quality of life; SCLC = small cell lung carcinoma
T
he shift from primary reliance on clinical indicators to broader definitions of health outcomes resulted in assessment of measures for health status and quality of life (QOL). Evaluation of patients’ self-reported QOL is particularly important in the study of chronic diseases such as advanced lung cancer, for which short-term survival does not need to be a primary outcome of interest. In addition, patients with advanced lung cancer can be treated by numerous regimens that have similar therapeutic efficacy. Therefore, the QOL perspective is increasingly gaining favor as a priority. More than 50 different instruments have been developed and used for assessment of QOL in patients with lung cancer,1 3 of which are used most frequently: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) with a lung cancer module (EORTC QLQ-LC13),2,3 the Lung Cancer Symptom Scale (LCSS),4 and the Functional Assessment of Cancer Therapy-Lung (FACT-L).5 Patients’ self-reported QOL has become an important end point for treatment comparisons, and clinical investigators are increasingly inter1024
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ested in assessing QOL in lung cancer clinical trials. However, until recently, QOL in patients with lung cancer has been assessed rarely outside of clinical trial settings. We present the results of the LCSS questionnaire based on 650 patients with primary lung cancer at a typical tertiary referral medical center. We verified performance of the LCSS questionnaire and assessed whether the LCSS is correlated with known prognostic factors for short-term survival. PATIENTS AND METHODS Patients in this study were enrolled by the Epidemiology and Genetics of Lung Cancer Research Program at the Mayo Clinic in Rochester, Minn. Since January 1, 1997, all patients at our institution who were diagnosed pathologically as having lung cancer have been asked to participate in a prospective cohort study. At enrollment, each patient was informed about a 6-step follow-up (at 6 months, 1 year, and annually thereafter) in the upcoming 5 years and received mailed follow-up materials. All patients were enrolled with informed consent, and the study was approved by the Mayo Foundation Institutional Review Board. As of December 31, 2001, 4537 patients have been enrolled in this cohort with a participation rate of more than 95%. After a patient was enrolled, his or her clinical record was reviewed and abstracted by trained personnel to obtain data on demographics, comorbid conditions, tobacco exposure, tumor staging, location of primary tumor within the thorax, and treatment. Tumor type and stage were classified using the World Health Organization’s Histological Typing of Lung and Pleural Tumours and the revisions in the International System for Staging Lung Cancer, respectively.6,7 Treatment decisions were made by the patient’s team of surgical, radiaFrom the Department of Health Sciences Research (A.S., P.Y., P.J.N., E.B., J.A.S.), Department of Oncology (Y.I.G., J.A.B.), and Division of Pulmonary and Critical Care Medicine and Internal Medicine (J.R.J.), Mayo Clinic College of Medicine, Rochester, Minn. Mr Svobodník is now with the Center of Biostatistics and Analyses, Masaryk University Brno, Czech Republic. Dr Bonner is now with the University of Alabama at Birmingham. This work was supported in part by National Institutes of Health grants CA80127 and CA84354 (P.Y.). Individual reprints of this article are not available. Address correspondence to Ping Yang, MD, PhD, Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: yang [email protected]). © 2004 Mayo Foundation for Medical Education and Research
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QUALITY OF LIFE IN LUNG CANCER PATIENTS
tion, and medical oncologists and were not influenced by enrollment in the study. Patients were treated with surgical resection, radiation, chemotherapy, and/or the best supportive care on the basis of tumor stage, comorbid conditions, and overall health status to maximize the potential for cure, improved survival, and QOL. Beginning in 1999, the LCSS has been implemented with follow-up materials, hereafter referred to as the LCSS follow-up assessment. Of note, this may not have been the patient’s first follow-up as a patient in the entire cohort. A total of 791 patients were eligible for follow-up and were sent the LCSS questionnaire; 650 patients (82%) responded, were monitored for 6 months to 4 years, and were included in our LCSS analysis. We did not include the treatment variable because the standard treatment modalities are driven primarily by disease stage, and the latter was included in the analysis.8 Specific drugs and dosages were not available for every patient because some patients had been treated (partially or entirely) outside of our institution. Patients who did not speak English and/or were not US citizens or residents were excluded from this study. FOLLOW-UP On enrollment, each patient was informed about the 6-step follow-up in the upcoming 5 years.9,10 Only patients who consented were included in the study. Before recontacting study subjects, we attempted to learn their vital status. Multiple sources of vital status information ensured virtually 100% completeness and accuracy and included the Mayo Clinic registration database, next-of-kin reports, death certificates and obituary documents filed in the patients’ medical records, and the Mayo Tumor Registry. The vital status of a patient was also verified via the Internet and the Social Security Death Index Web site. The Internet site requires either the social security number or the patient’s name and date of birth. In January of each year since 1998, we have confirmed the vital status of every patient known to be alive during the previous years via these multiple sources. Thus, vital status data of all patients are current for analysis. QOL INSTRUMENT The QOL assessment was performed by analyzing the LCSS questionnaire, version 2.4,11 The questionnaire consists of 2 parts, 1 for patients and 1 for health professionals as observers; only the patient scale was used in this study. This scale consists of 9 items, 6 that measure major symptoms of lung cancer (appetite, fatigue, cough, dyspnea, hemoptysis, and pain) and 3 that assess total symptomatic distress, activity status, and overall QOL. The intensity of patient responses is measured by visual analog scales. The LCSS questionnaire was developed in the mid1980s at Memorial Sloan-Kettering Cancer Center as a Mayo Clin Proc.
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disease-specific and site-specific QOL instrument that focuses primarily on the physical and functional dimensions of patients with lung cancer. The original version of the questionnaire (version 1) included only 7 items, omitting measurements of fatigue and overall symptomatic distress. Psychometric properties (feasibility, reliability, and validity) of the LCSS questionnaire have been tested thoroughly for years.11,12 Also, a comparison of key features and psychometric properties of the LCSS and other available QOL instruments was published by Hollen and Gralla.12 Until recently, the LCSS questionnaire was used in numerous studies assessing QOL in patients with lung cancer.4,11,13-20 The LCSS measures symptoms specifically and therefore is focused somewhat differently than other QOL tools. The definitions of QOL relative to the more global term of patient-reported outcomes are still evolving.21 For this article, we refer to the LCSS as a QOL measure, recognizing that it also can be identified as a patient-reported outcome. STATISTICAL ANALYSES Cronbach α for the 650 patients included in this study was 0.89. Kruskal-Wallis analysis of variance or MannWhitney U tests were used to compare differences in QOL between patients with different age, sex, Karnofsky scale, weight loss, marital status, disease stage, and histology. The Mann-Whitney U tests were used to compare the QOL scores between patients who were alive at the 6-month follow-up and those who had died. This nonparametric test was used because the distributions of QOL scores were skewed. Survival was measured from the date that the first QOL questionnaire was completed. P<.05 was considered statistically significant, and all statistical tests were 2-sided. RESULTS Clinical and demographic characteristics of the 650 patients included in this study are shown in Table 1. The item response rate for all 9 LCSS questions was 94.2% with a minimum of 92.9%. Approximately one half of the patients (52%) were men, and age ranged from 35 to 91 years with a mean of 66.8 years. Of the 650 patients, 580 (89%) were diagnosed as having non–small cell lung carcinoma (NSCLC) (49% stage I, 10% stage II, 20% stage III, and 10% stage IV), and 42 patients (6%) were diagnosed as having small cell lung carcinoma (SCLC) (5% limited and 1% extensive stage). In 28 patients (4%), disease stage was unknown. A total of 508 patients (78%) had a Karnofsky scale score of 80% or more. Most of the patients were white (82%); only 2% were Alaska native/American Indian. Less than 1% of the patients were black, Hispanic, or Asian/ Pacific Islander. Race was unknown in 15% of patients. All
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TABLE 1. Clinical and Demographic Characteristics of Patients (N=650) Variables*
No. (%)
Mean (SD) age (y) Sex Women Men Race White Alaska native/American Indian Black Hispanic Asian/Pacific Islander Other Unknown Marital status Married Widowed Divorced Single Unknown Education completed (y) <12 12 >12 Unknown Histology Adenocarcinoma Squamous Carcinoid Small cell Other Unknown Lung cancer stage Small cell lung carcinoma Limited Extensive Non–small cell lung carcinoma IA IB IIA IIB IIIA IIIB IV Unknown Karnofsky scale (%)* 90 80 70 60 50 Unknown Weight loss >5% in previous 6 mo* Yes No Unknown Comorbidities†‡ Lung disease (other than cancer) Cancer (other than lung) Cardiovascular Diabetes mellitus Cerebrovascular accident
66.8 (10.5) 311 (47.8) 339 (52.2) 531 15 1 2 1 1 99
(81.7) (2.3) (0.2) (0.3) (0.2) (0.2) (15.2)
471 66 44 25 44
(72.5) (10.2) (6.8) (3.8) (6.8)
96 220 298 36
(14.8) (33.8) (45.8) (5.5)
316 151 55 45 80 3
(48.6) (23.2) (8.5) (6.9) (12.3) (0.5)
34 (5.2) 8 (1.2) 196 123 18 49 74 53 67 28
(30.2) (18.9) (2.8) (7.5) (11.4) (8.2) (10.3) (4.3)
268 240 78 26 11 27
(41.2) (36.9) (12.0) (4.0) (1.7) (4.2)
101 (15.5) 525 (80.7) 24 (3.7) 308 198 134 42 26
(55.0) (35.4) (23.9) (7.5) (4.6)
*All but 2 variables were measured or collected at diagnosis. Karnofsky scale and weight loss variables were collected at administration of Lung Cancer Symptom Scale questionnaire. †Comorbid conditions data were collected both at diagnosis and at each follow-up. ‡Patients with missing data were excluded from percentage estimation.
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patients received standard therapeutic regimens (surgery, radiotherapy, and/or chemotherapy) as indicated by their attending clinicians. LCSS SCORES Descriptive statistics for the LCSS are presented in Table 2; to compare our results with previously published LCSS scores, normative data are shown. Because no normative data were published for patients with stage I-II NSCLC or for patients with SCLC, only comparisons for advanced stages are possible. The presented normative data were derived from 2 large randomized trials with new chemotherapeutic regimens.11 To show changes in QOL during treatment, these normative data represent QOL scores at baseline (after diagnosis but before initiation of treatment) and at day 71 (important therapeutic responses and toxicity assessment point). The mean LCSS score for patients with stage III-IV NSCLC in our study was 27.38 (SD, 17.23) compared with the mean of 28.77 (SD, 18.06) for normative data at baseline and the mean of 25.97 (SD, 16.50) for normative data at day 71. As Table 2 shows, except for symptomatic distress, QOL scores measured in our study conform well to normative data for individual items of the LCSS. To represent the differences in QOL between stages, the relative frequencies of our patients presenting with particular symptoms are shown in Figure 1. To prevent artificial overestimation of symptom frequencies and to adhere to our analysis of the distribution of QOL scores, we used 2 definitions of symptom presence: (1) any value greater than 2 (represents 2 units on a 100-unit [mm] visual analog scale) is treated as a symptom occurrence (Figure 1, top); (2) relative frequencies of patients with symptom intensity greater than 50 (theoretical middle value of the visual analog scale) further define symptom presence (Figure 1, bottom). RELATIONSHIP BETWEEN QOL AND CLINICAL AND DEMOGRAPHIC CHARACTERISTICS The relationships between QOL and age, sex, Karnofsky scale, weight loss, marital status, histology, and disease stage are presented in Table 3. There were no significant differences in QOL by marital status for all items. However, significant differences for particular LCSS items were found for the rest of the variables. A lower QOL for appetite (P=.004), coughing (P=.02), and hemoptysis (P<.001) was observed in older patients. In women, a better QOL compared with men was observed for coughing (P=.003), dyspnea (P<.001), symptomatic distress (P=.05), effect on activities (P=.001), and overall QOL (P=.04). No statistically significant differences in the distribution of stages between men and women were observed. Significant positive correlations between Karnof-
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QUALITY OF LIFE IN LUNG CANCER PATIENTS
TABLE 2. Mean LCSS Scores From 650 Patients, by Disease Stage*
LCSS item
Our data (≤12 mo after diagnosis)
Our data (>12 mo after diagnosis)
Normative data, NSCLC (III-IV)†
NSCLC (III-IV)
No. of patients
Mean (SD)
No. of patients
Mean (SD)
No. of patients
Mean (SD)
No. of patients
Mean (SD)
144
26.63 (28.58) 39.53 (27.28) 21.11 (24.79) 31.76 (26.83) 2.33 (5.93) 19.00 (23.01) 27.14 (24.34) 34.48 (24.43) 31.59 (26.27) 25.97 (16.50)
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27.06 (26.88) 41.57 (27.63) 23.13 (23.78) 36.98 (30.50) 6.07 (14.40) 18.37 (23.46) 18.52 (22.73) 32.44 (29.16) 33.67 (26.41) 26.82 (19.07)
72
16.90 (14.53) 32.58 (22.61) 19.13 (20.38) 31.00 (23.47) 2.58 (4.18) 11.26 (14.88) 10.89 (17.61) 18.19 (20.75) 17.82 (20.10) 17.80 (12.51)
12
37.83 (25.24) 52.08 (25.26) 24.67 (27.10) 32.83 (23.78) 9.33 (11.87) 16.50 (25.81) 21.75 (21.38) 29.91 (26.82) 46.91 (29.48) 30.77 (17.19)
Loss of appetite Fatigue
144
Cough
144
Dyspnea
144
Hemoptysis
144
Pain
144
Symptomatic distress Effect on activities Quality of life Mean LCSS
143 144 144 143
46 47 47 46 45 46 45 46 43
NSCLC (I-II)
72 71 71 71 70 70 70 71 68
SCLC
12 12 12 12 12 12 11 11 11
NSCLC (III-IV)
NSCLC (I-II)
No. of Mean patients (SD)
No. of Mean patients (SD)
142 141 143 140 137 137 138 138 139 126
26.79 (22.50) 43.90 (23.75) 27.64 (24.78) 38.82 (25.57) 4.07 (7.97) 19.64 (22.79) 21.55 (21.96) 32.68 (25.41) 34.78 (26.14) 27.16 (16.41)
302 300 302 298 301 298 295 297 297 277
21.60 (20.00) 35.33 (23.95) 21.54 (21.78) 34.08 (25.17) 4.27 (7.03) 15.24 (19.81) 14.36 (18.60) 21.37 (21.25) 23.54 (21.09) 20.98 (14.78)
SCLC No. of patients
Mean (SD)
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22.77 (16.61) 43.43 (22.96) 23.47 (21.25) 41.97 (22.05) 5.71 (7.60) 17.74 (22.72) 16.30 (15.45) 37.15 (24.59) 35.86 (24.19) 27.53 (12.61)
30 30 30 28 27 27 27 28 26
*Rating: best (lowest symptom intensity) = 0; worst (highest symptom intensity) = 100. LCSS = Lung Cancer Symptom Scale; NSCLC = non–small cell lung carcinoma; SCLC = small cell lung carcinoma. †Day 71: important therapeutic responses and toxicity assessment point. Normative data from Hollen et al.11
sky scale and QOL were found for all items (P<.001) except for hemoptysis (P=.12). In patients with more than 5% weight loss in the previous 6 months, significantly lower QOL scores were observed for appetite (P<.001), fatigue (P<.001), dyspnea (P=.02), pain (P=.01), symptomatic distress (P<.001), effect on activities (P<.001), and overall QOL (P<.001). Significantly lower QOL for hemoptysis (P=.04), effect on activities (P=.001), and overall QOL (P=.001) was observed in patients with SCLC compared with patients with NSCLC. In patients with stage I-II NSCLC, a better QOL for appetite (P=.008), fatigue (P<.001), pain (P=.05), symptomatic distress (P<.001), effect on activities (P<.001), and overall QOL (P<.001) was observed compared with patients in stage III-IV of NSCLC. RELATIONSHIP BETWEEN QOL AND SURVIVAL To analyze the relationship between QOL and survival, patients were divided into 2 subgroups according to the length of overall survival (cutoff was 12 months, measured from the date of LCSS administration). Differences in QOL scores between patients who survived more than 12 months and those who did not are presented in Table 4. Significant differences were found for appetite loss (P<.001), fatigue (P<.001), cough (P=.01), dyspnea (P<.001), pain (P=.001), total symptomatic distress (P<.001), activity status (P<.001), overall Mayo Clin Proc.
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QOL (P<.001), and mean LCSS score (P<.001). However, no significant differences were found for hemoptysis (P=.09). DISCUSSION Several instruments have been developed for measuring QOL in patients with lung cancer,1 and the LCSS is one of the most frequently used.13,14,22-24 Until recently, self-reported QOL was assessed rarely in patients with lung cancer. The feasibility, reliability, and validity of the LCSS questionnaire have been shown in studies of patients with advanced NSCLC.4,12,25 In the current study, internal consistency was high (Cronbach α = 0.89), and the lowest response rate for particular items was 92.9%. All individual items of the LCSS were correlated with overall QOL, confirming their nonredundancy. However, we encountered a problem with assessing the exact frequencies of patients presenting with individual symptoms. Symptom intensity is measured by visual analog scales in the LCSS. The score for each item is equal to the length of the line marked by the patient divided by the total length of the scale times 100. Zero corresponds to the lowest possible rating, and 100 represents the highest rating. Any value above zero was considered a symptom occurrence in previous studies.11 We suggest that this may result in artificial
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QUALITY OF LIFE IN LUNG CANCER PATIENTS
SCLC NSCLC (I-II) NSCLC (III-IV)
100
Patients (%)
80
60
40
20
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100
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80
60 SCLC NSCLC (I-II) NSCLC (III-IV)
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FIGURE 1. Major presenting symptoms of patients with Lung Cancer Symptom Scale scores >2 (top) and >50 (bottom). (Numbers represent distance in millimeters on a 100-mm visual analog scale.) NSCLC = non–small cell lung carcinoma; SCLC = small cell lung carcinoma.
overestimation in symptom frequencies because patients without particular symptoms (especially those with poor performance status) do not mark exactly the beginning of the visual analog scale. Adhering to our analysis of the distribution of QOL scores, we used 2 definitions of symptom presence in our study: (1) any value greater than 2 is treated as a symptom occurrence and (2) relative frequencies of patients with symptom intensity greater than 50 1028
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(theoretical middle value of the visual analog scale) further define the presence of symptoms. RELATIONSHIP BETWEEN QOL AND CLINICAL AND DEMOGRAPHIC CHARACTERISTICS The interpretation of QOL data from clinical trials should be based on the knowledge of the relationship between QOL and patient clinical and demographic characteris-
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QUALITY OF LIFE IN LUNG CANCER PATIENTS
TABLE 3. Relationship Between Quality of Life and Clinical and Demographic Characteristics* LCSS item
No. of patients
Age†
Sex‡
Karnofsky scale†
Weight loss >5% in previous 6 mo‡
Marital status†
Histology‡ (NSCLC/SCLC)
Stage‡ (I+II/III+IV)
Loss of appetite Fatigue Cough Dyspnea Hemoptysis Pain Symptomatic distress Effect on activities Quality of life
622 619 622 615 611 605 605 604 608
.004 .55 .02 .57 <.001 .36 .89 .47 .17
.10 .12 .003 <.001 .61 .72 .05 .001 .04
<.001 <.001 <.001 <.001 .12 <.001 <.001 <.001 <.001
<.001 <.001 .24 .02 .20 .01 <.001 <.001 <.001
.59 .09 .59 .10 .40 .15 .86 .16 .06
.14 .06 .45 .12 .04 .97 .13 .001 .001
.008 <.001 .06 .05 .77 .05 <.001 <.001 <.001
*Numbers represent P values. Bold numbers indicate significantly lower quality of life in older patients, men, patients with a lower Karnofsky scale, patients with weight loss >5% in previous 6 mo, stage of small cell lung carcinoma (SCLC) or stage III/IV of non-SCLC (NSCLC). LCSS = Lung Cancer Symptom Scale. †Kruskal-Wallis analysis of variance test. ‡Mann-Whitney U test.
tics.26-30 The association between QOL, treatment toxicity, and tumor response is a key issue in QOL research. Kaasa and Mastekaasa31 found significant relationships between disease-related symptoms and psychosocial well-being of patients with advanced NSCLC; however, the treatmentrelated adverse effects and the psychosocial well-being of the patients were not correlated. In a study by Wolf et al,27 an association between tumor response and QOL in patients with SCLC was documented. In patients with advanced NSCLC, Fernandez et al24 observed improvement of symptoms after tumor response. In the study by Langendijk et al,28 dyspnea and social functioning significantly improved in patients with objective tumor response. In our study, significant differences in QOL by age, sex, Karnofsky scale, weight loss, disease stage, and histology were found. A QOL association with performance status has been shown by many other researchers,32 and our results confirm these findings. In the study by Finkelstein et al,26 a higher QOL was seen in men, and no significant differences in QOL by race, education, or marital status
were observed. In our study, no significant differences in QOL by marital status were found; however, a better QOL was observed in women. Herndon et al29 reported a significant relationship between weight loss and QOL, and these findings correspond to our results. The analysis of relationships among treatment adverse effects, therapeutic response, and QOL was not the objective of this study and will be presented separately. QOL AND PROGNOSTIC FACTORS The relationship between survival and QOL in patients with lung cancer has been investigated by several authors.30,32,33 Montazeri et al32 suggested that prediagnosis QOL is an important and independent prognostic factor in patients with lung cancer. However, Herndon et al29 showed that after adjustment for clinical factors (performance status, histology, presence of dyspnea, weight loss, albumin level, and adrenal metastases), the only QOL predictor is pain. In lung cancer, treatments are invasive and symptoms are severe; therefore, the lack of a study relationship is not
TABLE 4. Comparison of LCSS Scores for Patients Who Survived More Than 12 Months and Those Who Did Not* Survival ≤12 mo
Survival >12 mo
LCSS item
No. of patients
Mean (SD)
No. of patients
Mean (SD)
P value
Loss of appetite Fatigue Cough Dyspnea Hemoptysis Pain Symptomatic distress Effect on activities Quality of life Mean LCSS
124 121 123 122 118 117 119 119 121 107
32.08 (24.58) 49.41 (24.86) 28.90 (26.47) 43.87 (25.68) 6.38 (12.15) 21.41 (23.70) 26.64 (24.59) 40.00 (26.60) 42.83 (24.85) 24.65 (12.69)
447 445 446 441 441 435 434 436 437 413
20.32 (18.59) 35.04 (23.00) 21.63 (21.44) 33.06 (24.71) 3.87 (6.52) 14.42 (19.20) 13.43 (17.44) 21.35 (21.29) 23.00 (21.71) 15.31 (10.70)
<.001 <.001 .01 <.001 .09 .001 <.001 <.001 <.001 <.001
*Total number of patients was 650. Rating: best (lowest symptom intensity) = 0; worst (highest symptom intensity) = 100. Bold numbers indicate significantly lower quality of life in patients who died within 12 mo after completion of Lung Cancer Symptom Scale (LCSS) questionnaire.
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unexpected. Responses shift, and patient coping could also be a factor.21,34 LIMITATIONS OF THE STUDY Patients seen at the Mayo Clinic do not necessarily represent a normative population as a result of referral bias that is commonly observed in most tertiary medical centers. Results may not be totally generalizable to all patients with lung cancer in other settings. Additional biases could be caused by the differences between the responders and nonresponders to our study follow-up, eg, age at diagnosis, disease stage, and smoking status; analyses of these potential biases are presented in our subsequent work with a much larger sample size.35 In particular, our patient population had a greater preponderance of patients with stage I cancer (surgical patients) than might be seen at other institutions. The QOL of these patients may have been more negatively influenced by the invasive nature of their therapy. In contrast, the QOL of patients with late-stage cancer might also be altered severely by the disease. Our analysis of early- vs late-stage cancer indicates a notable effect of disease stage on patients’ QOL. CONCLUSION Our data suggest that QOL in patients with lung cancer at varying times after diagnosis correlates highly with baseline prognostic factors (disease stage, histology, Karnofsky scale, weight loss, and sex). Because our data are not mature from the view of survival, multivariate regression analysis of potential predictors will be our future objective, once sufficient follow-up has been achieved. REFERENCES 1. Montazeri A, Gillis CR, McEwen J. Quality of life in patients with lung cancer: a review of literature from 1970 to 1995. Chest. 1998;113:467-481. 2. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365-376. 3. Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M, EORTC Study Group on Quality of Life. The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer. 1994;30A:635-642. 4. Hollen PJ, Gralla RJ, Kris MG, Potanovich LM. Quality of life assessment in individuals with lung cancer: testing the Lung Cancer Symptom Scale (LCSS). Eur J Cancer. 1993;29A(suppl 1):S51-S58. 5. Cella DF, Bonomi AE, Lloyd SR, Tulsky DS, Kaplan E, Bonomi P. Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer. 1995;12:199-220. 6. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Histological Typing of Lung and Pleural Tumours. 3rd ed. New York, NY: SpringerVerlag; 1999:21-47. 7. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest. 1997;111:1710-1717. 8. Visbal AL, Williams BA, Nichols FC III, et al. Gender differences in non–small-cell lung cancer survival: an analysis of 4,618 patients diagnosed between 1997 and 2002. Ann Thorac Surg. 2004;78:209-215. 9. Yang P, Yokomizo A, Tazelaar HD, et al. Genetic determinants of lung cancer short-term survival: the role of glutathione-related genes. Lung Cancer. 2002;35:221-229.
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10. Yang P, Wentzlaff KA, Katzmann JA, et al. Alpha1-antitrypsin deficiency allele carriers in lung cancer patients. Cancer Epidemiol Biomarkers Prev. 1999;8:461-465. 11. Hollen PJ, Gralla RJ, Kris MG, Eberly SW, Cox C. Normative data and trends in quality of life from the Lung Cancer Symptom Scale (LCSS). Support Care Cancer. 1999;7:140-148. 12. Hollen PJ, Gralla RJ. Comparison of instruments for measuring quality of life in patients with lung cancer. Semin Oncol. 1996;23(2, suppl 5):31-40. 13. Hollen PJ, Gralla RJ, Kris MG, et al. Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies: psychometric assessment of the Lung Cancer Symptom Scale. Cancer. 1994;73:2087-2098. 14. Klastersky J, Paesmans M. Response to chemotherapy, quality of life benefits and survival in advanced non-small cell lung cancer: review of literature results. Lung Cancer. 2001;34(suppl 4):S95-S101. 15. Hollen PJ, Gralla RJ, Cox C, Eberly SW, Kris MG. A dilemma in analysis: issues in the serial measurement of quality of life in patients with advanced lung cancer. Lung Cancer. 1997;18:119-136. 16. Miller VA, Rigas JR, Francis PA, et al. Phase II trial of a 75 mg/m2 dose of docetaxel with prednisone premedication for patients with advanced nonsmall cell lung cancer. Cancer. 1995;75:968-972. 17. Lutz ST, Huang DT, Ferguson CL, Kavanagh BD, Tercilla OF, Lu J. A retrospective quality of life analysis using the Lung Cancer Symptom Scale in patients treated with palliative radiotherapy for advanced nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys. 1997;37:117-122. 18. Comella P, Frasci G, Panza N, et al. Cisplatin, gemcitabine, and vinorelbine combination therapy in advanced non-small-cell lung cancer: a phase II randomized study of the Southern Italy Cooperative Oncology Group. J Clin Oncol. 1999;17:1526-1534. 19. Frasci G, Lorusso V, Panza N, et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000;18:2529-2536. 20. Comella P, Frasci G, Panza N, et al. Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol. 2000;18:1451-1457. 21. Sloan JA, Cella D, Frost M, Guyatt GH, Sprangers M, Symonds T, Clinical Significance Consensus Meeting Group. Assessing clinical significance in measuring oncology patient quality of life: introduction to the symposium, content overview, and definition of terms. Mayo Clin Proc. 2002;77:367-370. 22. Nunnally JC, Bernstein IH. Psychometric Theory. 3rd ed. New York, NY: McGraw-Hill; 1994. 23. Gridelli C, Perrone F, Nelli F, Ramponi S, De Marinis F. Quality of life in lung cancer patients. Ann Oncol. 2001;12(suppl 3):S21-S25. 24. Fernandez C, Rosell R, Abad-Esteve A, et al. Quality of life during chemotherapy in non-small cell lung cancer patients. Acta Oncol. 1989;28:2933. 25. Shepherd FA, Dancey D, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18:2095-2103. 26. Finkelstein DM, Cassileth BR, Bonomi PD, Ruckdeschel JC, Ezdinli EZ, Wolter JM. A pilot study of the Functional Living Index-Cancer (FLIC) Scale for the assessment of quality of life for metastatic lung cancer patients: an Eastern Cooperative Oncology Group study. Am J Clin Oncol. 1988;11:630-633. 27. Wolf M, Pritsch M, Drings P, et al. Cyclic-alternating versus responseoriented chemotherapy in small-cell lung cancer: a German multicenter randomized trial of 321 patients. J Clin Oncol. 1991;9:614-624. 28. Langendijk JA, Aaronson NK, ten Velde GP, de Jong JM, Muller MJ, Wouters EF. Pretreatment quality of life of inoperable non-small cell lung cancer patients referred for primary radiotherapy. Acta Oncol. 2000;39:949-958. 29. Herndon JE II, Fleishman S, Kornblith AB, Kosty M, Green MR, Holland J. Is quality of life predictive of the survival of patients with advanced nonsmall cell lung carcinoma? Cancer. 1999;85:333-340. 30. Herndon JE II, Fleishman S, Kosty MP, Green MR. A longitudinal study of quality of life in advanced non-small cell lung cancer: Cancer and Leukemia Group B (CALGB) 8931. Control Clin Trials. 1997;18:286-300. 31. Kaasa S, Mastekaasa A. Psychosocial well-being of patients with inoperable non-small cell lung cancer: the importance of treatment- and diseaserelated factors. Acta Oncol. 1988;27(6b):829-835. 32. Montazeri A, Milroy R, Hole D, McEwen J, Gillis CR. Quality of life in lung cancer patients: as an important prognostic factor. Lung Cancer. 2001;31: 233-240. 33. Ruckdeschel JC, Piantadosi S. Quality of life in lung cancer surgical adjuvant trials. Chest. 1994;106(6, suppl):324S-328S. 34. Schwartz CE, Sendor M. Helping others helps oneself: response shift effects in peer support. Social Sci Med. 1999;48:1563-1575. 35. Garces YI, Yang P, Parkinison J, et al. Does cigarette smoking have an impact on quality of life after diagnosis of lung cancer? Chest. In press.
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Quality of Life in 650 Lung Cancer Survivors 6 Months to 4 Years After Diagnosis ADAM SVOBODNÍK, MS; PING YANG, MD, PHD; PAUL J. NOVOTNY, MS; ERIC BASS, BS; YOLANDA I. GARCES, MD; JAMES R. JETT, MD; JAMES A. BONNER, MD; AND JEFF A. SLOAN, PHD OBJECTIVE: To present the results of a quality-of-life (QOL) assessment performed with the current version of the Lung Cancer Symptom Scale (LCSS) questionnaire in a large single-institutional data set of 650 patients with lung cancer. PATIENTS AND METHODS: The study group included 650 patients with pathologically confirmed primary lung cancer whose conditions were diagnosed and/or treated at the Mayo Clinic in Rochester, Minn, between January 1, 1997, and December 31, 2001. The QOL assessment was performed using the self-administered LCSS questionnaire (version 2) 6 months to 4 years after the diagnosis of lung cancer. RESULTS: The item response rate for all 9 LCSS questions was 94.2% with a minimum of 92.9%. Significant differences in overall QOL by sex (P=.04), Karnofsky scale (P<.001), weight loss (P<.001), disease stage (P<.001), and histology (P=.001) were found, but no significant differences in overall QOL by age (P=.17) or marital status (P=.06) were observed. CONCLUSION: Our data suggest that QOL in patients with lung cancer at varying times after diagnosis highly correlates with baseline prognostic factors (disease stage, histology, Karnofsky scale, weight loss, and sex).
Mayo Clin Proc. 2004;79(8):1024-1030 LCSS = Lung Cancer Symptom Scale; NSCLC = non–small cell lung carcinoma; QOL = quality of life; SCLC = small cell lung carcinoma
T
he shift from primary reliance on clinical indicators to broader definitions of health outcomes resulted in assessment of measures for health status and quality of life (QOL). Evaluation of patients’ self-reported QOL is particularly important in the study of chronic diseases such as advanced lung cancer, for which short-term survival does not need to be a primary outcome of interest. In addition, patients with advanced lung cancer can be treated by numerous regimens that have similar therapeutic efficacy. Therefore, the QOL perspective is increasingly gaining favor as a priority. More than 50 different instruments have been developed and used for assessment of QOL in patients with lung cancer,1 3 of which are used most frequently: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) with a lung cancer module (EORTC QLQ-LC13),2,3 the Lung Cancer Symptom Scale (LCSS),4 and the Functional Assessment of Cancer Therapy-Lung (FACT-L).5 Patients’ self-reported QOL has become an important end point for treatment comparisons, and clinical investigators are increasingly inter1024
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ested in assessing QOL in lung cancer clinical trials. However, until recently, QOL in patients with lung cancer has been assessed rarely outside of clinical trial settings. We present the results of the LCSS questionnaire based on 650 patients with primary lung cancer at a typical tertiary referral medical center. We verified performance of the LCSS questionnaire and assessed whether the LCSS is correlated with known prognostic factors for short-term survival. PATIENTS AND METHODS Patients in this study were enrolled by the Epidemiology and Genetics of Lung Cancer Research Program at the Mayo Clinic in Rochester, Minn. Since January 1, 1997, all patients at our institution who were diagnosed pathologically as having lung cancer have been asked to participate in a prospective cohort study. At enrollment, each patient was informed about a 6-step follow-up (at 6 months, 1 year, and annually thereafter) in the upcoming 5 years and received mailed follow-up materials. All patients were enrolled with informed consent, and the study was approved by the Mayo Foundation Institutional Review Board. As of December 31, 2001, 4537 patients have been enrolled in this cohort with a participation rate of more than 95%. After a patient was enrolled, his or her clinical record was reviewed and abstracted by trained personnel to obtain data on demographics, comorbid conditions, tobacco exposure, tumor staging, location of primary tumor within the thorax, and treatment. Tumor type and stage were classified using the World Health Organization’s Histological Typing of Lung and Pleural Tumours and the revisions in the International System for Staging Lung Cancer, respectively.6,7 Treatment decisions were made by the patient’s team of surgical, radiaFrom the Department of Health Sciences Research (A.S., P.Y., P.J.N., E.B., J.A.S.), Department of Oncology (Y.I.G., J.A.B.), and Division of Pulmonary and Critical Care Medicine and Internal Medicine (J.R.J.), Mayo Clinic College of Medicine, Rochester, Minn. Mr Svobodník is now with the Center of Biostatistics and Analyses, Masaryk University Brno, Czech Republic. Dr Bonner is now with the University of Alabama at Birmingham. This work was supported in part by National Institutes of Health grants CA80127 and CA84354 (P.Y.). Individual reprints of this article are not available. Address correspondence to Ping Yang, MD, PhD, Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: yang [email protected]). © 2004 Mayo Foundation for Medical Education and Research
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QUALITY OF LIFE IN LUNG CANCER PATIENTS
tion, and medical oncologists and were not influenced by enrollment in the study. Patients were treated with surgical resection, radiation, chemotherapy, and/or the best supportive care on the basis of tumor stage, comorbid conditions, and overall health status to maximize the potential for cure, improved survival, and QOL. Beginning in 1999, the LCSS has been implemented with follow-up materials, hereafter referred to as the LCSS follow-up assessment. Of note, this may not have been the patient’s first follow-up as a patient in the entire cohort. A total of 791 patients were eligible for follow-up and were sent the LCSS questionnaire; 650 patients (82%) responded, were monitored for 6 months to 4 years, and were included in our LCSS analysis. We did not include the treatment variable because the standard treatment modalities are driven primarily by disease stage, and the latter was included in the analysis.8 Specific drugs and dosages were not available for every patient because some patients had been treated (partially or entirely) outside of our institution. Patients who did not speak English and/or were not US citizens or residents were excluded from this study. FOLLOW-UP On enrollment, each patient was informed about the 6-step follow-up in the upcoming 5 years.9,10 Only patients who consented were included in the study. Before recontacting study subjects, we attempted to learn their vital status. Multiple sources of vital status information ensured virtually 100% completeness and accuracy and included the Mayo Clinic registration database, next-of-kin reports, death certificates and obituary documents filed in the patients’ medical records, and the Mayo Tumor Registry. The vital status of a patient was also verified via the Internet and the Social Security Death Index Web site. The Internet site requires either the social security number or the patient’s name and date of birth. In January of each year since 1998, we have confirmed the vital status of every patient known to be alive during the previous years via these multiple sources. Thus, vital status data of all patients are current for analysis. QOL INSTRUMENT The QOL assessment was performed by analyzing the LCSS questionnaire, version 2.4,11 The questionnaire consists of 2 parts, 1 for patients and 1 for health professionals as observers; only the patient scale was used in this study. This scale consists of 9 items, 6 that measure major symptoms of lung cancer (appetite, fatigue, cough, dyspnea, hemoptysis, and pain) and 3 that assess total symptomatic distress, activity status, and overall QOL. The intensity of patient responses is measured by visual analog scales. The LCSS questionnaire was developed in the mid1980s at Memorial Sloan-Kettering Cancer Center as a Mayo Clin Proc.
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disease-specific and site-specific QOL instrument that focuses primarily on the physical and functional dimensions of patients with lung cancer. The original version of the questionnaire (version 1) included only 7 items, omitting measurements of fatigue and overall symptomatic distress. Psychometric properties (feasibility, reliability, and validity) of the LCSS questionnaire have been tested thoroughly for years.11,12 Also, a comparison of key features and psychometric properties of the LCSS and other available QOL instruments was published by Hollen and Gralla.12 Until recently, the LCSS questionnaire was used in numerous studies assessing QOL in patients with lung cancer.4,11,13-20 The LCSS measures symptoms specifically and therefore is focused somewhat differently than other QOL tools. The definitions of QOL relative to the more global term of patient-reported outcomes are still evolving.21 For this article, we refer to the LCSS as a QOL measure, recognizing that it also can be identified as a patient-reported outcome. STATISTICAL ANALYSES Cronbach α for the 650 patients included in this study was 0.89. Kruskal-Wallis analysis of variance or MannWhitney U tests were used to compare differences in QOL between patients with different age, sex, Karnofsky scale, weight loss, marital status, disease stage, and histology. The Mann-Whitney U tests were used to compare the QOL scores between patients who were alive at the 6-month follow-up and those who had died. This nonparametric test was used because the distributions of QOL scores were skewed. Survival was measured from the date that the first QOL questionnaire was completed. P<.05 was considered statistically significant, and all statistical tests were 2-sided. RESULTS Clinical and demographic characteristics of the 650 patients included in this study are shown in Table 1. The item response rate for all 9 LCSS questions was 94.2% with a minimum of 92.9%. Approximately one half of the patients (52%) were men, and age ranged from 35 to 91 years with a mean of 66.8 years. Of the 650 patients, 580 (89%) were diagnosed as having non–small cell lung carcinoma (NSCLC) (49% stage I, 10% stage II, 20% stage III, and 10% stage IV), and 42 patients (6%) were diagnosed as having small cell lung carcinoma (SCLC) (5% limited and 1% extensive stage). In 28 patients (4%), disease stage was unknown. A total of 508 patients (78%) had a Karnofsky scale score of 80% or more. Most of the patients were white (82%); only 2% were Alaska native/American Indian. Less than 1% of the patients were black, Hispanic, or Asian/ Pacific Islander. Race was unknown in 15% of patients. All
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QUALITY OF LIFE IN LUNG CANCER PATIENTS
TABLE 1. Clinical and Demographic Characteristics of Patients (N=650) Variables*
No. (%)
Mean (SD) age (y) Sex Women Men Race White Alaska native/American Indian Black Hispanic Asian/Pacific Islander Other Unknown Marital status Married Widowed Divorced Single Unknown Education completed (y) <12 12 >12 Unknown Histology Adenocarcinoma Squamous Carcinoid Small cell Other Unknown Lung cancer stage Small cell lung carcinoma Limited Extensive Non–small cell lung carcinoma IA IB IIA IIB IIIA IIIB IV Unknown Karnofsky scale (%)* 90 80 70 60 50 Unknown Weight loss >5% in previous 6 mo* Yes No Unknown Comorbidities†‡ Lung disease (other than cancer) Cancer (other than lung) Cardiovascular Diabetes mellitus Cerebrovascular accident
66.8 (10.5) 311 (47.8) 339 (52.2) 531 15 1 2 1 1 99
(81.7) (2.3) (0.2) (0.3) (0.2) (0.2) (15.2)
471 66 44 25 44
(72.5) (10.2) (6.8) (3.8) (6.8)
96 220 298 36
(14.8) (33.8) (45.8) (5.5)
316 151 55 45 80 3
(48.6) (23.2) (8.5) (6.9) (12.3) (0.5)
34 (5.2) 8 (1.2) 196 123 18 49 74 53 67 28
(30.2) (18.9) (2.8) (7.5) (11.4) (8.2) (10.3) (4.3)
268 240 78 26 11 27
(41.2) (36.9) (12.0) (4.0) (1.7) (4.2)
101 (15.5) 525 (80.7) 24 (3.7) 308 198 134 42 26
(55.0) (35.4) (23.9) (7.5) (4.6)
*All but 2 variables were measured or collected at diagnosis. Karnofsky scale and weight loss variables were collected at administration of Lung Cancer Symptom Scale questionnaire. †Comorbid conditions data were collected both at diagnosis and at each follow-up. ‡Patients with missing data were excluded from percentage estimation.
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patients received standard therapeutic regimens (surgery, radiotherapy, and/or chemotherapy) as indicated by their attending clinicians. LCSS SCORES Descriptive statistics for the LCSS are presented in Table 2; to compare our results with previously published LCSS scores, normative data are shown. Because no normative data were published for patients with stage I-II NSCLC or for patients with SCLC, only comparisons for advanced stages are possible. The presented normative data were derived from 2 large randomized trials with new chemotherapeutic regimens.11 To show changes in QOL during treatment, these normative data represent QOL scores at baseline (after diagnosis but before initiation of treatment) and at day 71 (important therapeutic responses and toxicity assessment point). The mean LCSS score for patients with stage III-IV NSCLC in our study was 27.38 (SD, 17.23) compared with the mean of 28.77 (SD, 18.06) for normative data at baseline and the mean of 25.97 (SD, 16.50) for normative data at day 71. As Table 2 shows, except for symptomatic distress, QOL scores measured in our study conform well to normative data for individual items of the LCSS. To represent the differences in QOL between stages, the relative frequencies of our patients presenting with particular symptoms are shown in Figure 1. To prevent artificial overestimation of symptom frequencies and to adhere to our analysis of the distribution of QOL scores, we used 2 definitions of symptom presence: (1) any value greater than 2 (represents 2 units on a 100-unit [mm] visual analog scale) is treated as a symptom occurrence (Figure 1, top); (2) relative frequencies of patients with symptom intensity greater than 50 (theoretical middle value of the visual analog scale) further define symptom presence (Figure 1, bottom). RELATIONSHIP BETWEEN QOL AND CLINICAL AND DEMOGRAPHIC CHARACTERISTICS The relationships between QOL and age, sex, Karnofsky scale, weight loss, marital status, histology, and disease stage are presented in Table 3. There were no significant differences in QOL by marital status for all items. However, significant differences for particular LCSS items were found for the rest of the variables. A lower QOL for appetite (P=.004), coughing (P=.02), and hemoptysis (P<.001) was observed in older patients. In women, a better QOL compared with men was observed for coughing (P=.003), dyspnea (P<.001), symptomatic distress (P=.05), effect on activities (P=.001), and overall QOL (P=.04). No statistically significant differences in the distribution of stages between men and women were observed. Significant positive correlations between Karnof-
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QUALITY OF LIFE IN LUNG CANCER PATIENTS
TABLE 2. Mean LCSS Scores From 650 Patients, by Disease Stage*
LCSS item
Our data (≤12 mo after diagnosis)
Our data (>12 mo after diagnosis)
Normative data, NSCLC (III-IV)†
NSCLC (III-IV)
No. of patients
Mean (SD)
No. of patients
Mean (SD)
No. of patients
Mean (SD)
No. of patients
Mean (SD)
144
26.63 (28.58) 39.53 (27.28) 21.11 (24.79) 31.76 (26.83) 2.33 (5.93) 19.00 (23.01) 27.14 (24.34) 34.48 (24.43) 31.59 (26.27) 25.97 (16.50)
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27.06 (26.88) 41.57 (27.63) 23.13 (23.78) 36.98 (30.50) 6.07 (14.40) 18.37 (23.46) 18.52 (22.73) 32.44 (29.16) 33.67 (26.41) 26.82 (19.07)
72
16.90 (14.53) 32.58 (22.61) 19.13 (20.38) 31.00 (23.47) 2.58 (4.18) 11.26 (14.88) 10.89 (17.61) 18.19 (20.75) 17.82 (20.10) 17.80 (12.51)
12
37.83 (25.24) 52.08 (25.26) 24.67 (27.10) 32.83 (23.78) 9.33 (11.87) 16.50 (25.81) 21.75 (21.38) 29.91 (26.82) 46.91 (29.48) 30.77 (17.19)
Loss of appetite Fatigue
144
Cough
144
Dyspnea
144
Hemoptysis
144
Pain
144
Symptomatic distress Effect on activities Quality of life Mean LCSS
143 144 144 143
46 47 47 46 45 46 45 46 43
NSCLC (I-II)
72 71 71 71 70 70 70 71 68
SCLC
12 12 12 12 12 12 11 11 11
NSCLC (III-IV)
NSCLC (I-II)
No. of Mean patients (SD)
No. of Mean patients (SD)
142 141 143 140 137 137 138 138 139 126
26.79 (22.50) 43.90 (23.75) 27.64 (24.78) 38.82 (25.57) 4.07 (7.97) 19.64 (22.79) 21.55 (21.96) 32.68 (25.41) 34.78 (26.14) 27.16 (16.41)
302 300 302 298 301 298 295 297 297 277
21.60 (20.00) 35.33 (23.95) 21.54 (21.78) 34.08 (25.17) 4.27 (7.03) 15.24 (19.81) 14.36 (18.60) 21.37 (21.25) 23.54 (21.09) 20.98 (14.78)
SCLC No. of patients
Mean (SD)
30
22.77 (16.61) 43.43 (22.96) 23.47 (21.25) 41.97 (22.05) 5.71 (7.60) 17.74 (22.72) 16.30 (15.45) 37.15 (24.59) 35.86 (24.19) 27.53 (12.61)
30 30 30 28 27 27 27 28 26
*Rating: best (lowest symptom intensity) = 0; worst (highest symptom intensity) = 100. LCSS = Lung Cancer Symptom Scale; NSCLC = non–small cell lung carcinoma; SCLC = small cell lung carcinoma. †Day 71: important therapeutic responses and toxicity assessment point. Normative data from Hollen et al.11
sky scale and QOL were found for all items (P<.001) except for hemoptysis (P=.12). In patients with more than 5% weight loss in the previous 6 months, significantly lower QOL scores were observed for appetite (P<.001), fatigue (P<.001), dyspnea (P=.02), pain (P=.01), symptomatic distress (P<.001), effect on activities (P<.001), and overall QOL (P<.001). Significantly lower QOL for hemoptysis (P=.04), effect on activities (P=.001), and overall QOL (P=.001) was observed in patients with SCLC compared with patients with NSCLC. In patients with stage I-II NSCLC, a better QOL for appetite (P=.008), fatigue (P<.001), pain (P=.05), symptomatic distress (P<.001), effect on activities (P<.001), and overall QOL (P<.001) was observed compared with patients in stage III-IV of NSCLC. RELATIONSHIP BETWEEN QOL AND SURVIVAL To analyze the relationship between QOL and survival, patients were divided into 2 subgroups according to the length of overall survival (cutoff was 12 months, measured from the date of LCSS administration). Differences in QOL scores between patients who survived more than 12 months and those who did not are presented in Table 4. Significant differences were found for appetite loss (P<.001), fatigue (P<.001), cough (P=.01), dyspnea (P<.001), pain (P=.001), total symptomatic distress (P<.001), activity status (P<.001), overall Mayo Clin Proc.
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QOL (P<.001), and mean LCSS score (P<.001). However, no significant differences were found for hemoptysis (P=.09). DISCUSSION Several instruments have been developed for measuring QOL in patients with lung cancer,1 and the LCSS is one of the most frequently used.13,14,22-24 Until recently, self-reported QOL was assessed rarely in patients with lung cancer. The feasibility, reliability, and validity of the LCSS questionnaire have been shown in studies of patients with advanced NSCLC.4,12,25 In the current study, internal consistency was high (Cronbach α = 0.89), and the lowest response rate for particular items was 92.9%. All individual items of the LCSS were correlated with overall QOL, confirming their nonredundancy. However, we encountered a problem with assessing the exact frequencies of patients presenting with individual symptoms. Symptom intensity is measured by visual analog scales in the LCSS. The score for each item is equal to the length of the line marked by the patient divided by the total length of the scale times 100. Zero corresponds to the lowest possible rating, and 100 represents the highest rating. Any value above zero was considered a symptom occurrence in previous studies.11 We suggest that this may result in artificial
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QUALITY OF LIFE IN LUNG CANCER PATIENTS
SCLC NSCLC (I-II) NSCLC (III-IV)
100
Patients (%)
80
60
40
20
life ty ali Qu
na to Ef f
ec
tom Sy
mp
Lo
of
vit cti
ist cd ati
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ies
s res
Pa in
sis pty mo
Dy sp ne a
ug h Co
tig ue Fa
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ap
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tite
0
100
Patients (%)
80
60 SCLC NSCLC (I-II) NSCLC (III-IV)
40 20
life Qu
ali
ty
of
vit
Ef f
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FIGURE 1. Major presenting symptoms of patients with Lung Cancer Symptom Scale scores >2 (top) and >50 (bottom). (Numbers represent distance in millimeters on a 100-mm visual analog scale.) NSCLC = non–small cell lung carcinoma; SCLC = small cell lung carcinoma.
overestimation in symptom frequencies because patients without particular symptoms (especially those with poor performance status) do not mark exactly the beginning of the visual analog scale. Adhering to our analysis of the distribution of QOL scores, we used 2 definitions of symptom presence in our study: (1) any value greater than 2 is treated as a symptom occurrence and (2) relative frequencies of patients with symptom intensity greater than 50 1028
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(theoretical middle value of the visual analog scale) further define the presence of symptoms. RELATIONSHIP BETWEEN QOL AND CLINICAL AND DEMOGRAPHIC CHARACTERISTICS The interpretation of QOL data from clinical trials should be based on the knowledge of the relationship between QOL and patient clinical and demographic characteris-
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QUALITY OF LIFE IN LUNG CANCER PATIENTS
TABLE 3. Relationship Between Quality of Life and Clinical and Demographic Characteristics* LCSS item
No. of patients
Age†
Sex‡
Karnofsky scale†
Weight loss >5% in previous 6 mo‡
Marital status†
Histology‡ (NSCLC/SCLC)
Stage‡ (I+II/III+IV)
Loss of appetite Fatigue Cough Dyspnea Hemoptysis Pain Symptomatic distress Effect on activities Quality of life
622 619 622 615 611 605 605 604 608
.004 .55 .02 .57 <.001 .36 .89 .47 .17
.10 .12 .003 <.001 .61 .72 .05 .001 .04
<.001 <.001 <.001 <.001 .12 <.001 <.001 <.001 <.001
<.001 <.001 .24 .02 .20 .01 <.001 <.001 <.001
.59 .09 .59 .10 .40 .15 .86 .16 .06
.14 .06 .45 .12 .04 .97 .13 .001 .001
.008 <.001 .06 .05 .77 .05 <.001 <.001 <.001
*Numbers represent P values. Bold numbers indicate significantly lower quality of life in older patients, men, patients with a lower Karnofsky scale, patients with weight loss >5% in previous 6 mo, stage of small cell lung carcinoma (SCLC) or stage III/IV of non-SCLC (NSCLC). LCSS = Lung Cancer Symptom Scale. †Kruskal-Wallis analysis of variance test. ‡Mann-Whitney U test.
tics.26-30 The association between QOL, treatment toxicity, and tumor response is a key issue in QOL research. Kaasa and Mastekaasa31 found significant relationships between disease-related symptoms and psychosocial well-being of patients with advanced NSCLC; however, the treatmentrelated adverse effects and the psychosocial well-being of the patients were not correlated. In a study by Wolf et al,27 an association between tumor response and QOL in patients with SCLC was documented. In patients with advanced NSCLC, Fernandez et al24 observed improvement of symptoms after tumor response. In the study by Langendijk et al,28 dyspnea and social functioning significantly improved in patients with objective tumor response. In our study, significant differences in QOL by age, sex, Karnofsky scale, weight loss, disease stage, and histology were found. A QOL association with performance status has been shown by many other researchers,32 and our results confirm these findings. In the study by Finkelstein et al,26 a higher QOL was seen in men, and no significant differences in QOL by race, education, or marital status
were observed. In our study, no significant differences in QOL by marital status were found; however, a better QOL was observed in women. Herndon et al29 reported a significant relationship between weight loss and QOL, and these findings correspond to our results. The analysis of relationships among treatment adverse effects, therapeutic response, and QOL was not the objective of this study and will be presented separately. QOL AND PROGNOSTIC FACTORS The relationship between survival and QOL in patients with lung cancer has been investigated by several authors.30,32,33 Montazeri et al32 suggested that prediagnosis QOL is an important and independent prognostic factor in patients with lung cancer. However, Herndon et al29 showed that after adjustment for clinical factors (performance status, histology, presence of dyspnea, weight loss, albumin level, and adrenal metastases), the only QOL predictor is pain. In lung cancer, treatments are invasive and symptoms are severe; therefore, the lack of a study relationship is not
TABLE 4. Comparison of LCSS Scores for Patients Who Survived More Than 12 Months and Those Who Did Not* Survival ≤12 mo
Survival >12 mo
LCSS item
No. of patients
Mean (SD)
No. of patients
Mean (SD)
P value
Loss of appetite Fatigue Cough Dyspnea Hemoptysis Pain Symptomatic distress Effect on activities Quality of life Mean LCSS
124 121 123 122 118 117 119 119 121 107
32.08 (24.58) 49.41 (24.86) 28.90 (26.47) 43.87 (25.68) 6.38 (12.15) 21.41 (23.70) 26.64 (24.59) 40.00 (26.60) 42.83 (24.85) 24.65 (12.69)
447 445 446 441 441 435 434 436 437 413
20.32 (18.59) 35.04 (23.00) 21.63 (21.44) 33.06 (24.71) 3.87 (6.52) 14.42 (19.20) 13.43 (17.44) 21.35 (21.29) 23.00 (21.71) 15.31 (10.70)
<.001 <.001 .01 <.001 .09 .001 <.001 <.001 <.001 <.001
*Total number of patients was 650. Rating: best (lowest symptom intensity) = 0; worst (highest symptom intensity) = 100. Bold numbers indicate significantly lower quality of life in patients who died within 12 mo after completion of Lung Cancer Symptom Scale (LCSS) questionnaire.
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unexpected. Responses shift, and patient coping could also be a factor.21,34 LIMITATIONS OF THE STUDY Patients seen at the Mayo Clinic do not necessarily represent a normative population as a result of referral bias that is commonly observed in most tertiary medical centers. Results may not be totally generalizable to all patients with lung cancer in other settings. Additional biases could be caused by the differences between the responders and nonresponders to our study follow-up, eg, age at diagnosis, disease stage, and smoking status; analyses of these potential biases are presented in our subsequent work with a much larger sample size.35 In particular, our patient population had a greater preponderance of patients with stage I cancer (surgical patients) than might be seen at other institutions. The QOL of these patients may have been more negatively influenced by the invasive nature of their therapy. In contrast, the QOL of patients with late-stage cancer might also be altered severely by the disease. Our analysis of early- vs late-stage cancer indicates a notable effect of disease stage on patients’ QOL. CONCLUSION Our data suggest that QOL in patients with lung cancer at varying times after diagnosis correlates highly with baseline prognostic factors (disease stage, histology, Karnofsky scale, weight loss, and sex). Because our data are not mature from the view of survival, multivariate regression analysis of potential predictors will be our future objective, once sufficient follow-up has been achieved. REFERENCES 1. Montazeri A, Gillis CR, McEwen J. Quality of life in patients with lung cancer: a review of literature from 1970 to 1995. Chest. 1998;113:467-481. 2. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365-376. 3. Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M, EORTC Study Group on Quality of Life. The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer. 1994;30A:635-642. 4. Hollen PJ, Gralla RJ, Kris MG, Potanovich LM. Quality of life assessment in individuals with lung cancer: testing the Lung Cancer Symptom Scale (LCSS). Eur J Cancer. 1993;29A(suppl 1):S51-S58. 5. Cella DF, Bonomi AE, Lloyd SR, Tulsky DS, Kaplan E, Bonomi P. Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer. 1995;12:199-220. 6. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Histological Typing of Lung and Pleural Tumours. 3rd ed. New York, NY: SpringerVerlag; 1999:21-47. 7. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest. 1997;111:1710-1717. 8. Visbal AL, Williams BA, Nichols FC III, et al. Gender differences in non–small-cell lung cancer survival: an analysis of 4,618 patients diagnosed between 1997 and 2002. Ann Thorac Surg. 2004;78:209-215. 9. Yang P, Yokomizo A, Tazelaar HD, et al. Genetic determinants of lung cancer short-term survival: the role of glutathione-related genes. Lung Cancer. 2002;35:221-229.
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