Small cell lung carcinoma (SCLC) is characterized by early

ORIGINAL ARTICLE The Prognostic Value of the Simplified Comorbidity Score in the Treatment of Small Cell Lung Carcinoma Yao-Wen Kuo, MD,* Jih-Shuin Jerng, MD, PhD, Jin-Yuan Shih, MD, PhD, Kuan-Yu Chen, MD, PhD, Chong-Jen Yu, MD, PhD, and Pan-Chyr Yang, MD, PhD Introduction: Comorbidity may be an important prognostic factor in the treatment of small cell lung carcinoma (SCLC). This study aimed to investigate the prognostic values of simplified comorbidity score (SCS) in the treatment of patients with SCLC. Methods: The patients with SCLC admitted to the National Taiwan University Hospital during the period from January 2000 to December 2006 were included. The medical records were reviewed and analyzed. The SCS was used to evaluate comorbidities of the patients. A Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% confidence intervals (CIs) for age, gender, and factors significantly associated with survival identified in univariate analyses. Results: A total of 172 patients were included; 56 patients had limited-stage disease and 116 had extensive-stage disease. Patients with an SCS more than 9 had shorter overall survival than those with SCS 9 both in limited-stage (372 days versus 581 days, p 0.01) and extensive-stage disease (215 days versus 324 days, p 0.001). Multivariate analysis indicated that SCS more than 9 was associated with a worse prognosis in patients with limited-stage disease (HR: 2.17, 95% CI: 1.12 4.21) and extensive-stage disease (HR: 1.74, 95% CI: 1.12 2.72), respectively. For patients with extensive-stage disease, SCS more than 9 was associated with poor treatment response ( 9 versus 9, disease response rate: 60.0% versus 82.4%, p 0.02). Conclusions: The SCS may be an independent prognostic factor for patients with SCLC. Large-scale prospective studies may be required to validate the prognostic value of the SCS for SCLC. Key Words: Small cell lung carcinoma, Comorbidity, Prognostic factor. (J Thorac Oncol. 2011;6: 378 383) *Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin; and Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Kuan-Yu Chen, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. E-mail: tuff.chen@msa.hinet.net Copyright 2011 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/11/0602-0378 Small cell lung carcinoma (SCLC) is characterized by early dissemination, good initial treatment response, early relapse, and a more aggressive nature than non-small cell lung carcinoma (NSCLC). 1 SCLC accounts for approximately 13% and 8.1% of all lung cancer subtypes in the United States and Taiwan, respectively. 2,3 The median survival time for limited-stage SCLC is 12 to 17 months and that for extensive-stage SCLC is 7 to 9 months. 4,5 The incidence of SCLC has decreased and a modest improvement in survival has been observed between 1973 and 2002 2 ; however, the long-term outlook remains poor. For patients with SCLC, good performance status, limited-stage disease, and female gender are associated with a better prognosis than the converse. Elevated lactate dehydrogenase (LDH) levels also carry an unfavorable outcome. 6 12 Patients with old age, low serum sodium levels, or reduced hemoglobin levels were also reported to have a worse prognosis. 6,7,12,13 The factors associated with treatment response in SCLC include disease extent, performance status, gender, blood leukocyte count, and hemoglobin level. 11,14 The impact of comorbidity has been emphasized in the treatment of patients with NSCLC. Scoring systems using weighted items to quantify patients comorbidity burden have been used to predict treatment outcomes. 15 18 The Charlson comorbidity index score (CCIS) predicts surgical risk in patients operated on for NSCLC. 18 The presence of comorbidity (CCIS 1) is also related to a poor survival in patients with NSCLC receiving systemic chemotherapy. 15 Multivariate analysis performed in a previous study did not show prognostic value of the CCIS for patients with limited-stage SCLC. 19 Recent studies have validated simplified comorbidity score (SCS) as an independent prognostic factor in the treatment of NSCLC. 16,17 Nevertheless, the prognostic value of SCS has not been investigated in SCLC. Therefore, we investigated the prognostic value of comorbidity determined using the SCS in the treatment of patients with SCLC. PATIENTS AND METHODS Patients We included patients who were newly diagnosed with SCLC and received platinum-based chemotherapy between January 2000 and December 2006 at the National Taiwan University Hospital, a 2150-bed tertiary teaching hospital in northern Taiwan. The patients were identified using a com- 378

Prognostic Values of SCS in the Treatment of SCLC puter registration database by using the International Classification of Diseases, Ninth Revision, coding system. SCLC was diagnosed on the basis of histologic examination of biopsy specimens or by fine-needle aspiration cytology examination. Exclusion criteria included patients receiving palliative care and patients with a histologic type that indicated combined SCLC and NSCLC. The hospital s Institutional Review Board approved the study protocol and waived the need to obtain informed consent because of the retrospective design of the study. Data Collection The medical records of the patients were reviewed and analyzed for clinical characteristics, including age, gender, tobacco consumption, disease stage, Eastern Cooperative Oncology Group (ECOG) performance status, comorbid conditions, laboratory data, treatment modalities and response, and dates of death or last visit. Disease staging was performed using the Veterans Administration Lung Study Group system, 20 and the stage was determined by examining the computed tomography scan of the thorax and upper part of the abdomen, brain computed tomography scan, and radionuclide scan of the bone system. Comorbid conditions before chemotherapy were assessed by using the SCS. 16 Briefly, seven comorbid conditions were included in the SCS: tobacco consumption (weighting 7; total lifelong consumption of at least 100 cigarettes); diabetes mellitus (weighting 5; under medication control), renal insufficiency (weighting 4; creatinine clearance 60 ml/min by the Cockroft formula), respiratory conditions (weighting 1; history of tuberculosis, pleural effusion, pneumonia, asthma, pulmonary embolism, chronic hypoxemia 60 mm Hg, and chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV 1 ) 1.5 liter), cardiovascular conditions (weighting 1; congestive heart failure, ischemic cardiopathy, severe valvular cardiopathy, arrhythmia under chronic treatment, history of cardiovascular disease, and peripheral vascular disease), neoplastic conditions (weighting 1; previous cancer history), and alcoholism (weighting 1; daily consumption of 80gof alcohol in men and 40 g in women). Patients comorbidities were also assessed by using CCIS for comparison. 21 The cutoff point at which the patient is considered to have a high comorbidity score was set at 9 for the SCS and at 2 for the CCIS. 15 17 The patients were divided into two groups: 70 years and less than 70 years according to previous elderly specific analyses for oncology patients. 16,22 25 Anemia was defined as hemoglobin level less than 12. 11 In the study hospital, the lower normal limit of serum sodium level was 135 mmol/liter. Low sodium level was defined as below 135 mmol/liter. The following laboratory parameters were divided into high and normal groups by using the upper normal limits as the cutoff point: serum LDH level, 460 U/liter; serum carcinoembryonic antigen, 5.0 ng/ml; and platelet count, 320 10 3 / l. Treatment response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 26 for patients who received at least two cycles of platinum-based chemotherapy. Disease response rate was defined as the percentage of patients who achieved complete remission or partial response. Overall survival was defined as the period from the date of diagnosis to the date of all-cause death. The patients were followed up until December 31, 2008, or until the date of their death. Statistics Exploratory analyses were performed, and the results were expressed as mean, standard deviation, or percentage. The 2 test or Fisher s exact test were used to compare categorical data between two patient groups. The independent-samples t test was used to compare continuous variables. The concordance of the two comorbidity scores was tested by using coefficient of reliability and McNemar test of symmetry. The correlation of the two comorbidity scores was also tested by correlations of Spearman (Rho). A p value 0.05 was considered to be significant. Survival functions were analyzed by the Kaplan-Meier method. Log-rank tests were performed to compare the difference in survival between patients groups in terms of different variables. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Univariate analyses were conducted to examine unadjusted associations between patient groups with each individual independent variable. Factors significantly associated with survival in univariate analyses (p 0.05), plus age and gender, were included in the multivariate analysis. RESULTS Clinical Characteristics Between January 2000 and December 2006, 229 patients were diagnosed with SCLC at National Taiwan University Hospital. A total of 172 patients were included. Among the 57 patients excluded, 47 patients received palliative care, seven had a histologic diagnosis of combined SCLC and NSCLC, and three received chemotherapy consisting of a nonplatinum-based regimen (cyclophosphamide, adriamycin, and vincristine). The clinical characteristics of patients included in the study are presented in Table 1. The median age was 68 years (range: 40 92 years). Most were current smokers or exsmokers (94.8%), men (89.5%), had an ECOG performance status of 0 to 1 (71.5%), and had extensive-stage disease (67.4%) at diagnosis. The median value of the SCS was 8 (range: 0 17). The median value of the CCIS was 1 (range: 0 5). The most common comorbidity was cardiovascular disease (42.4%). Mean value of hemoglobin levels was 12.6 1.8 g/dl; platelet count, 266.8 96.1 10 3 / l; serum sodium level, 135.6 6.7 mmol/liter; and serum LDH level, 866.0 1051.0 U/liter. Body weight measurements were missing from the available medical records in seven patients, and creatinine clearance could not be calculated. CCIS was calculated for 172 patients, whereas SCS was calculated for 165 patients. A statistical concordance and a statistically significant asymmetry were shown on Table 2 ( coefficient of reliability 0.378; p 0.0001; McNemar test of sym- Copyright 2011 by the International Association for the Study of Lung Cancer 379

Kuo et al. TABLE 1. The Clinical Characteristics of 172 Patients with Small Cell Lung Carcinoma Clinical Characteristics No. (%) Age 70 yr 99 (57.6) 70 yr 73 (42.4) Gender Male 154 (89.5) Female 18 (10.5) Stage Limited 56 (32.6) Extensive 116 (67.4) ECOG performance status 0 1 123 (71.5) 2 4 49 (28.5) CCIS 2 117 (68.0) 2 55 (32.0) SCS (n 165) 9 84 (50.9) 9 81 (49.1) Smoking Current/exsmoker 163 (94.8) Nonsmoker 9 (5.2) Comorbidity Diabetes mellitus 33 (19.2) Renal insufficiency (n 165) 72 (43.6) Cardiovascular 73 (42.4) Respiratory 47 (27.3) Alcoholism 11 (6.4) Neoplastic a 6 (3.5) LDH (n 156; U/liter) 460 113 (72.4) 460 43 (27.6) Serum sodium level (n 169; mmol/liter) 135 117 (69.2) 135 52 (30.8) Serum CEA level (n 140; ng/ml) 5 82 (58.6) 5 58 (41.4) Hemoglobin level (g/dl) 12 113 (65.7) 12 59 (34.3) Platelet count ( 10 3 / l) 320 129 (75.0) 320 43 (25.0) a Two patients had prostate cancer, and the other four had nasopharyngeal cancer, bladder cancer, laryngeal cancer, and esophageal cancer, respectively. ECOG, Eastern Cooperative Oncology Group; CCIS, Charlson comorbidity index score; SCS, simplified comorbidity score; LDH, lactate dehydrogenase; CEA, carcinoembryonic antigen. metry; p 0.0002). The correlation between the two scores was positive and significant (Rho 0.55; p 0.0001). TABLE 2. The Concordance of SCS and CCIS in the 165 Patients with Small Cell Lung Carcinoma CCIS SCS <9 >9 Total 2 72 39 111 2 12 42 54 Total 84 81 165 coefficient of reliability 0.378; p 0.0001, and McNemar test of symmetry; p 0.0002. SCS, simplified comorbidity score; CCIS, Charlson comorbidity index score. Treatment Distribution and Response A total of 147 patients (85.5%) received at least two cycles of platinum-based chemotherapy. Among the 25 patients receiving less than two cycles of chemotherapy, 22 had extensive-stage disease, 17 were aged 70 years or older, and 17 had a SCS more than 9. Of the 56 patients with limitedstage disease, 40 patients (71.4%) received concurrent chemoradiotherapy and 16 received only systemic chemotherapy. Eleven patients (19.6%) received prophylactic cranial irradiation. Of the 116 patients with extensive-stage disease, four patients (3.4%) received prophylactic cranial irradiation. Of the 53 evaluable patients with limited-stage disease, the disease response rate was 86.8%. An ECOG performance status of 2 to 4 (0 1 versus 2 4, disease response rate: 92.7% versus 66.7%, p 0.04) and hemoglobin level less than 12 g/dl ( 12 versus 12, disease response rate: 64.3% versus 94.9%, p 0.01) were associated with poor treatment response, whereas CCIS 2, SCS more than 9, age 70 years, sodium level less than 135 mmol/liter, and LDH level more than 460 U/liter were not. Of the 94 evaluable patients with extensive-stage disease, the disease response rate was 73.4%. An SCS more than 9( 9 versus 9, disease response rate: 60.0% versus 82.4%, p 0.02) and an ECOG performance status of 2 to 4 (0 1 versus 2 4, disease response rate: 78.7% versus 52.6%, p 0.02) were associated with poor treatment response, whereas a CCIS 2, age 70 years, sodium level less than 135 mmol/liter, LDH level more than 460 U/liter, and hemoglobin less than 12 g/dl were not. Survival and Prognostic Factors During the follow-up period, a total of 153 deaths occurred (89.0%). Eleven patients were lost to follow-up, and eight patients were still alive at the end of the follow-up period. In limited-stage disease, overall survival was significantly longer in patients with SCS 9 than those with SCS more than 9 (median survival: 581 days versus 372 days, p 0.01, Figure 1A). In extensive-stage disease, overall survival was significantly longer in patients with SCS 9 than those with SCS more than 9 (median survival: 324 days versus 215 days, p 0.001, Figure 1B). In limited-stage disease, factors associated with poor prognosis in univariate analyses are presented in Table 3, including SCS more than 9 and hemoglobin level less than 12 g/dl. In multivariate analyses, SCS more than 9 (HR: 2.17, 95% CI: 1.12 4.21) and hemoglobin level less than 12 g/dl (HR: 3.54, 95% CI: 1.56 8.03) were associated with poor prognosis (Table 3). 380 Copyright 2011 by the International Association for the Study of Lung Cancer

Prognostic Values of SCS in the Treatment of SCLC FIGURE 1. Kaplan-Meier survival curves showed that overall survival was better in patients with small cell lung carcinoma (SCLC) with SCS 9 than those with simplified comorbidity score (SCS) 9 both in limited-stage (A, p 0.01) and extensivestage (B, p 0.001). TABLE 3. Univariate and Multivariate Analyses of Factors Associated with Survival in Patients with Limited-Stage SCLC (n 56) Clinical Characteristics Univariate Multivariate HR (95% CI) p HR (95% CI) p Age 70 yr 1.26 (0.70 2.24) 0.44 0.81 (0.40 1.64) 0.56 Male gender 0.55 (0.21 1.40) 0.21 1.51 (0.45 5.00) 0.50 ECOG performance status 2 4 0.93 (0.48 1.81) 0.84 SCS 9 2.10 (1.15 3.84) 0.02 2.17 (1.12 4.21) 0.02 CCIS 2 1.52 (0.83 2.80) 0.18 Less than two cycles of chemotherapy 0.91 (0.22 3.78) 0.90 LDH 460 U/liter 1.66 (0.87 3.17) 0.12 Sodium level 135 mmol/liter 1.11 (0.58 2.11) 0.76 Hemoglobin level 12 g/dl 2.28 (1.20 4.32) 0.01 3.54 (1.56 8.03) 0.003 CEA level 5 ng/ml 1.08 (0.54 2.17) 0.82 Platelet count 320 10 3 / l 1.53 (0.78 2.99) 0.22 HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; CCIS, Charlson comorbidity index score; SCS, simplified comorbidity score; LDH, lactate dehydrogenase; CEA, carcinoembryonic antigen; SCLC, small cell lung carcinoma. In extensive-stage disease, factors associated with poor prognosis in univariate analyses are presented in Table 4, including age 70 years, ECOG performance status of 2 to 4, SCS more than 9, less than two cycles of chemotherapy, sodium level less than 135 mmol/liter, and hemoglobin level less than 12 g/dl. In multivariate analyses, SCS more than 9 was associated with poor prognosis (HR: 1.74, 95% CI: 1.12 2.72). Less than two cycles of chemotherapy (HR: 17.77, 95% CI: 7.65 41.27), sodium level less than 135 mmol/liter (HR: 2.77, 95% CI: 1.74 4.41), hemoglobin level less than 12 g/dl (HR: 1.84, 95% CI: 1.19 2.84), and male gender (HR: 2.28, 95% CI: 1.15 4.52) were significantly associated with poorer outcomes (Table 4). DISCUSSION This study showed that a high SCS ( 9) was an independent, negative prognostic factor for patients with SCLC both in limited-stage and extensive-stage. In addition, SCS 9 was also associated with a better treatment response in patients with SCLC with extensive-stage disease. The impact of comorbidity on the management of patients with cancer can be viewed in various ways. First, Copyright 2011 by the International Association for the Study of Lung Cancer 381

Kuo et al. TABLE 4. Univariate and Multivariate Analyses of Factors Associated with Survival in Patients with Extensive-Stage SCLC (n 116) Clinical Characteristics Univariate Multivariate HR (95% CI) p HR (95% CI) p Age 70 yr 1.51 (1.02 2.25) 0.04 0.92 (0.58 1.46) 0.73 Male gender 1.47 (0.78 2.77) 0.23 2.28 (1.15 4.52) 0.02 ECOG performance status 2 4 2.51 (1.64 3.85) 0.001 1.53 (0.87 2.71) 0.14 SCS 9 1.92 (1.29 2.84) 0.001 1.74 (1.12 2.72) 0.01 CCIS 2 1.49 (0.99 2.24) 0.06 Less than two cycles of chemotherapy 21.23 (10.55 42.74) 0.001 17.77 (7.65 41.27) 0.001 LDH 460 U/liter 1.31 (0.78 2.19) 0.31 Sodium level 135 mmol/liter 2.25 (1.46 3.49) 0.001 2.77 (1.74 4.41) 0.001 Hemoglobin level 12 g/dl 1.57 (1.05 2.34) 0.03 1.84 (1.19 2.84) 0.006 CEA level 5 ng/ml 1.11 (0.70 1.74) 0.67 Platelet count 320 10 3 / l 0.82 (0.53 1.29) 0.39 HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; CCIS, Charlson comorbidity index score; SCS, simplified comorbidity score; LDH, lactate dehydrogenase; CEA, carcinoembryonic antigen; SCLC, small cell lung carcinoma. comorbidity may alter the treatment modality. 27 In patients with lung cancer, the use of cisplatin is of concern due to the unfavorable side effects of emesis and nephrotoxicity, 28 especially in patients with poor renal reserve. Second, comorbidity may worsen the physical condition and hinder the treatment process. 27 Similarly, in our study, patients with SCS 9 tended to receive more than two cycles of chemotherapy and were associated with a better disease response rate in patients with extensive-stage disease. The SCS may be helpful in predicting treatment course, response, and prognosis for patients with SCLC. In this study, SCS more than 9 was associated with shorted survival time in both limited-stage and extensivestage, whereas CCIS 2 was not. The CCIS, first described in 1987 in a longitudinal study, is the sum of 19 weighted comorbidities based on the 1-year mortality rates of 559 medical patients. 21 The CCIS had been used to predict survival in various cancers, including lung, head and neck, prostate, and colon cancer. 29 33 Nevertheless, the CCIS was not originally designed for patients with cancer. The SCS, first described in 2005, contains only seven weighted items 16 and may be of great convenience in routine clinical practice. The SCS was originally validated on the basis of heavysmoking patients with NSCLC, which is similar to the SCLC patient population. Compared with the CCIS, the SCS is more informative in the extended NSCLC validation population. 17 The SCS give much weight to renal insufficiency (weighting 4), whereas the CCIS give the less weight to renal insufficiency (weighting 2). Besides, the SCS may more accurately estimate the renal reserve in the elderly by using creatinine clearance rather than serum creatinine used by the CCIS. Because renal function plays an important role in the pharmacokinetics of chemotherapy regimens, the difference of weighting and measurements may lead to a better prognostic value of SCS for patients with SCLC. Advanced age remains a major concern in SCLC. 34 Because of concerns about poor tolerance to chemotherapy, attenuating the doses used in the chemotherapy regimen has been attempted. This practice may contribute to lower toxicity and to lower response rates and inferior survival. 25 Previous studies have demonstrated that advanced age is associated with a poor survival 6,7,12,13 ; nevertheless, the impact of comorbidity was not taken into consideration. In this study, after adjusting for other prognostic factors, advanced age was not associated with poor prognosis. Our findings are similar to results reported in patients with NSCLC by Asmis et al., 15 namely, that presence of comorbid conditions, rather than old age, correlates with poor outcomes. Because the elderly may still retain a fair amount of functional reserve in many organs, 35 treatment modalities in the elderly should be based on patients actual physical condition rather than on their chronological age. Our study has some limitations. First, this is a singleunit, hospital-based study that lacked the validation of SCS in another study population. Further multicenter study is warranted to validate the use of SCS in the treatment of SCLC. Second, the treatment response and the survival analyses were assessed separately for limited- and extensive-stage disease. The number of patients with limited-stage disease was relatively small. The findings should be interpreted carefully. Finally, the correlation of the toxicity profile with the dosage of chemotherapy could not be recorded thoroughly due to the retrospective nature of the study design. This study may have been more persuasive if tolerance and quality of life were also investigated and compared with comorbid conditions. In conclusion, the SCS may be an independent prognostic factor for patients with SCLC both in limited-stage and extensive-stage SCLC. 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