The Impact of Smoking Status on the Behavior and Survival Outcome of Patients With Advanced Non-small Cell Lung Cancer

The Impact of Smoking Status on the Behavior and Survival Outcome of Patients With Advanced Non-small Cell Lung Cancer

The Impact of Smoking Status on the Behavior and Survival Outcome of Patients With Advanced Non-small Cell Lung Cancer* A Retrospective Analysis Chee-...

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The Impact of Smoking Status on the Behavior and Survival Outcome of Patients With Advanced Non-small Cell Lung Cancer* A Retrospective Analysis Chee-Keong Toh, MD; Ee-Hwee Wong, MSc; Wan-Teck Lim, MD; Swan-Swan Leong, MD; Kam-Weng Fong, MD; Joseph Wee, MD; and Eng-Huat Tan, MD

Study objectives: There are fundamental differences in characteristics between smokers and nonsmokers with non-small cell lung cancer (NSCLC). We aim to study the impact of smoking status on the behavior of the disease, and to identify differences in outcome between the two groups. Design: A retrospective analysis was done of patients with NSCLC seen during the period from January 1999 to August 2002. Clinical characteristics, survival outcome, and response to treatment were reviewed and compared between the smokers and nonsmokers. Setting: Department of Medical Oncology, National Cancer Center. Results: Of 317 patients analyzed, 117 patients (36.3%) were nonsmokers. Among the nonsmokers, 74.5% had adenocarcinoma and 73.9% were women. The smokers had poorer performance status, reported more weight loss, and had a higher mean age at diagnosis of almost 8 years than nonsmokers. One hundred eighty-seven patients (59%) had died as of December 31, 2002. The nonsmokers had a longer median survival, although this was not statistically significant. There were no statistically significant differences in survival and response to chemotherapy between the two groups after adjusting for known prognostic factors. Conclusions: Despite the known differences in mutational spectra and clinical characteristics between smokers and nonsmokers with NSCLC, no differences in terms of response to chemotherapy and survival outcome were observed. This could imply that this disease is equally aggressive in these two groups. More research is needed to further delineate and characterize the differences between these two etiologically different forms of NSCLC. (CHEST 2004; 126:1750 –1756) Key words: chemotherapy; non-small cell lung cancer; smoking; survival Abbreviations: AJCC ⫽ American Joint Committee on Cancer; CI ⫽ confidence interval; ECOG ⫽ Eastern Cooperative Oncology Group; NSCLC ⫽ non-small cell lung cancer

cancer is one of the most common maligL ung nancies in the world. In Singapore, it is the most 1

frequent cancer in men, and ranks third most com*From the Department of Medical Oncology (Drs. Toh, Lim, and Leong), Department of Therapeutic Radiology (Drs. Fong and Wee), Division of Clinical Trials and Epidemiological Sciences (Drs. Wong and Tan), National Cancer Center, Singapore. Manuscript received January 23, 2004; revision accepted May 5, 2004. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Eng-Huat Tan, MD, Department of Medical Oncology, National Cancer Center, 11 Hospital Drive, Singapore 169610, Tel: 65– 64368171, Fax: 65– 62272759, e-mail: dmoteh@ nccs.com.sg 1750

mon in women.2 The prognosis of lung cancer is poor, with a 5-year overall survival rate of approximately 15%.3 The combination of high incidence with high lethality makes lung cancer the leading cause of cancer deaths in both men and women in many countries, including United States4 and Singapore.2 Smoking is the most important risk factor for lung cancer, as supported by epidemiologic evidence since the 1950s.5,6 It was estimated that approximately 85% of lung cancer cases were attributed to smoking.7,8 Most of these studies were done in Western countries and among male patients with lung cancer worldwide. Data from Asian populaClinical Investigations

tions, especially among female patients with lung cancer, indicate that other risk factors are as important, as smoking alone cannot explain the epidemiologic characteristics of lung cancer seen in some For editorial comment see page 1718 Asian countries. In these countries, the incidence of smoking is low among women; yet, there is a relatively high incidence of lung cancer among them.9 –12 The contribution of other biological, environmental, occupational, and socioeconomic factors may be more important in a population with high lung cancer incidence but low attributable risk from smoking.13 Smoking increases the risk of all histologic subtypes of lung cancer, although the relative risk is greater for squamous cell and small cell carcinoma than for adenocarcinoma.14 There is an increasing rate of adenocarcinoma and decreasing incidence of squamous cell carcinoma reported in men in United States15 and Europe.16 Among the nonsmokers and the women, adenocarcinoma is most frequently observed.17 Based on the observation that there are differences in epidemiologic characteristics and histologic subtypes between smokers and nonsmokers with non-small cell lung cancer (NSCLC), it is reasonable to assume that there would be underlying biological differences between the two groups. In fact, studies18,19 have identified significant differences in the mutational frequencies and spectra in lung cancers between smokers and nonsmokers that suggest different molecular carcinogenic pathways are involved in their development. Since the tumor biology is different, it is possible that this could translate into differences in survival and response to chemotherapy between the two groups. We performed a retrospective analysis of patients with NSCLC seen during the period of January 1999 until August 2002, to investigate the impact of the smoking status of patients on the behavior of the disease with regards to survival outcome and response to chemotherapy. Materials and Methods This study was conducted at the Department of Medical Oncology, National Cancer Center, a tertiary referral center in Singapore that is accessible to patients from all socioeconomic status. The case records of patients with NSCLC diagnosed during the period of January 1999 until August 2002 were retrieved. Selected epidemiologic characteristics, treatment given, and response to chemotherapy were recorded. Smoking history was taken as recorded in the case records by the attending physician. Smoking status was classified as defined by the World Health Organization classification criteria for smoking.20 A nonsmoker was defined as one who had never smoked before or smoked too little in the past to be regarded as an ex-smoker. www.chestjournal.org

Overall survival for each patient was measured from the date of diagnosis until the date of death, or until the date the patient was last known to be alive for censored observation. The data were checked with the Singapore registry of births and deaths on December 31, 2002. It is mandatory for Singapore residents to register in the event of death; therefore, the mortality data for residents is complete and exhaustive. Response to chemotherapy was defined in accordance to World Health Organization criteria.21 Complete response refers to complete disappearance of all measurable and evaluable disease with no new lesions, and partial response refers to a ⱖ 50% decrease in the sum of the products of perpendicular diameters of measurable lesions. Stable disease is defined by ⬍ 50% reduction or ⬍ 25% increase in the measurable disease. Progressive disease refers to an increase in measurable disease by ⬎ 25% or the appearance of new lesions. The duration of response was measured from the time of first documentation of complete response, partial response, or stable disease until the first date that progressive disease was objectively documented. If progression was not observed or the patient was unavailable for follow-up, the duration was measured from the date of complete response, partial response, or stable disease until the date of last follow-up. Statistical Analysis ␹2 test was used to test for differences in gender, race, histologic subtype, performance status (as defined by Eastern Cooperative Oncology Group [ECOG] classification), American Joint Committee on Cancer (AJCC) stage, comorbidities, and weight loss between the smokers and nonsmokers. The difference in age at diagnosis between the two groups was compared using a t test. A log-rank test was used to compare the overall survival between smokers and nonsmokers, and Kaplan-Meier survival estimates and curves were obtained. A Cox proportional hazards model was later used to adjust for known prognostic factors including ECOG status, presence of weight loss, AJCC stage at diagnosis, and treatment received. The type of chemotherapy and response to first-line chemotherapy between smokers and nonsmokers among patients with AJCC stage IIIB or IV disease were compared using a ␹2 test. Kaplan-Meier estimates of response duration to first line chemotherapy were obtained and compared using a log-rank test.

Results Patient Characteristics A total of 317 patients with NSCLC were identified and analyzed (Table 1). At the time of analysis, 187 patients (59.0%) had died. There were 202 smokers (63.7%) and 115 nonsmokers (36.3%). The majority of them had advanced disease, as expected in a population of patients referred to the Department of Medical Oncology. There were significantly more male patients and squamous cell carcinoma among the smokers, while the proportion of female patients and adenocarcinoma was higher among the nonsmokers. A higher percentage of smokers reported weight loss and had poorer performance status compared to the nonsmokers, although the difference was not statistically significant. Diagnoses were made in nonsmokers almost a decade earlier CHEST / 126 / 6 / DECEMBER, 2004

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Table 1—Characteristics of Smokers and Nonsmokers* Variables Gender Male Female Race Chinese Malay Indian Others Age at diagnosis, yr Mean (SD) Range Histologic subtype Squamous cell carcinoma Adenocarcinoma Others ECOG performance status 0 1 2 3 4 AJCC stage IA IB IIA IIB IIIA IIIB IV Unknown Comorbidities Yes No Weight loss Yes No Survival status Dead Alive Survival time, mo Median Range

Smoker (n ⫽ 202)

Nonsmoker (n ⫽ 115)

Total (n ⫽ 317)

p Value ⬍ 0.001

180 (89.1) 22 (10.9)

30 (26.1) 85 (73.9)

210 (66.2) 107 (33.8)

176 (87.1) 15 (7.4) 4 (2.0) 7 (3.5)

100 (87.0) 11 (9.6) 1 (0.9) 3 (2.6)

276 (87.1) 26 (8.2) 5 (1.6) 10 (3.2)

0.828

⬍ 0.001 65.4 (9.8) (39–93)

57.3 (13.1) (29–89)

62.4 (11.8) (29–93)

66 (32.7) 87 (43.1) 49 (24.3)

4 (3.5) 86 (74.8) 25 (21.7)

70 (22.1) 173 (54.6) 74 (23.3)

28 (14.0) 123 (61.5) 25 (12.5) 18 (9.0) 6 (3.0)

14 (12.4) 81 (71.7) 14 (12.4) 4 (3.5) 0 (0)

42 (13.4) 204 (65.2) 39 (12.5) 22 (7.0) 6 (1.9)

5 (2.5) 11 (5.5) 3 (1.5) 6 (3.0) 24 (12.1) 51 (25.6) 97 (48.7) 2 (1.0)

3 (2.6) 5 (4.4) 0 (0) 3 (2.6) 15 (13.2) 16 (14.0) 71 (62.3) 1 (0.9)

8 (2.6) 16 (5.1) 3 (1.0) 9 (2.9) 39 (12.5) 67 (21.4) 168 (53.7) 3 (1.0)

108 (53.5) 94 (46.5)

58 (50.9) 56 (49.1)

165 (52.1) 148 (46.7)

120 (59.7) 81 (40.3)

55 (48.2) 59 (51.8)

175 (55.6) 140 (44.4)

125 (61.9) 77 (38.1)

62 (53.9) 53 (46.1)

187 (59.0) 130 (41.0)

⬍ 0.001

0.101

0.234

0.558

0.059

0.141 13.50 (0.1–83.4)

18.53 (0.1–48.7)

15.21 (0.1–84.0)

*Data are presented as No. (%) unless otherwise indicated.

than the smokers (mean age difference, ⫺ 7.94 years; 95% confidence interval [CI], ⫺10.7 to ⫺5.18; p ⬍ 0.001). Survival Data The median survival for all patients was 15.2 months (95% CI, 12.1 to 18.2). Figure 1 shows the Kaplan-Meier survival curves for smokers and nonsmokers, log-rank p ⫽ 0.14. Nonsmokers had a median survival of 18.5 months, while smokers had a median survival of 13.6 months. When known prognostic factors including ECOG status, presence of weight loss, stage at diagnosis, and treatment re1752

ceived were taken into account using a Cox proportional hazards model (Table 2), there was no statistically significant difference between smokers and nonsmokers (hazards ratio, 0.98; p ⫽ 0.92). However, performance status, weight loss, stage at diagnosis, and treatment with chemotherapy were factors that independently predicted for survival outcome. These findings concur with previous studies.22,23 In addition to these prognostic factors, comorbidities, histologic subtype, gender, and age at diagnosis were later included in the model using a stepwise selection procedure. Only age at diagnosis was statistically significant. Every 10-year increase in age resulted Clinical Investigations

Figure 1. Kaplan-Meier estimates of overall survival time in smokers and nonsmokers.

in approximately a 30% increase in hazard. The hazard ratio estimates for the other prognostic factors remained similar (results not shown). Response to Chemotherapy Two hundred thirty-one patients had AJCC stage IIIB and IV disease. Eighty-five patients (36.8%) did

not receive chemotherapy, while 146 patients (63.2%) were treated with palliative intent. The percentage of smokers and nonsmokers who received palliative chemotherapy was 57.9% and 68.6%, respectively (Table 3). There was no statistically significant difference in the chemotherapy regimens administered between the two groups

Table 2—Cox Regression Model Fitted to NSCLC Patients Comparing Smokers vs Nonsmokers Adjusted for Known Prognostic Factors* Variables Smoker No Yes ECOG status 0 to 1 2 to 4 Weight loss No Yes Treatment No Yes AJCC stage at diagnosis I or II III IV

Regression Coefficient

Regression Coefficient, SE

Hazard Ratio

0.171

1 0.984

0.171

1 2.046

0.155

1 1.617

0.182

1 0.462

0.332 0.326

1 3.243 5.635

95% CI

p Value 0.923

0 ⫺ 0.016 0 0.716

0.704–1.375 ⬍ 0.001 1.465–2.858 0.002

0 0.481

1.193–2.192 ⬍ 0.001

0 ⫺ 0.773 0 1.176 1.729

0.323–0.659 ⬍ 0.001 1.690–6.221 2.972–10.685

*Three hundred two patients were included in the Cox regression analysis, as 15 patients had missing data on at least one variable. www.chestjournal.org

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Table 3—Response to First-Line Chemotherapy Among Smokers vs Nonsmokers in NSCLC Patients With AJCC Stage IIIB or IV Disease* Variables Types of chemotherapy† Platinum based Non-platinum based None Response to first-line chemotherapy Complete Partial Stable disease Progressive disease Not evaluable Duration of response in patients with complete response, partial response, or stable disease, mo Median 95% CI

Smoker (n ⫽ 145)

Nonsmoker (n ⫽ 86)

Total (n ⫽ 231)

50 (34.5) 34 (23.4) 61 (42.1)

34 (39.5) 25 (29.1) 27 (31.4)

88 (38.1) 59 (25.5) 84 (36.4)

1 (0.7) 15 (10.3) 26 (17.9) 30 (20.7) 12 (8.3) n ⫽ 72

1 (1.2) 11 (12.8) 19 (22.1) 22 (25.6) 6 (7.0) n ⫽ 53

2 (0.9) 26 (11.3) 45 (19.5) 52 (22.5) 18 (7.8) n ⫽ 125

12.3 1.8–22.8

7.0 4.6–9.3

7.4 5.5–9.4

p Value 0.254

1.0*

0.145

*Data are presented as No. (%) unless otherwise indicated. The 18 patients who had nonevaluable response were not included in the ␹2 test. †Platinum based includes combination of either gemcitabine, paclitaxel, vinorelbine, or docetaxel with a platinum (carboplatin or cisplatin), and non-platinum based includes single-agent gemcitabine, vinorelbine, paclitaxel, or docetaxel or combination of gemcitabine/vinorelbine.

(p ⫽ 0.254). Sixty-three percent of the patients who were administered chemotherapy received gemcitabine-based chemotherapy as first-line treatment. The median survival of patients receiving chemotherapy was 16.4 months (95% CI, 2.5 to 20.3), while those without treatment had a median survival of 4 months (95% CI, 2.4 to 5.5). There was no significant difference in the response to first-line chemotherapy in the two groups (p ⫽ 1.0). Association of histologic subtype, weight loss, gender, age, and stage at diagnosis with response to chemotherapy was investigated using a logistic regression model (results not shown). None of these were found to be significant. Response between smokers and nonsmokers remained similar after adjusting for these factors. The duration of response to chemotherapy was also similar between these two groups (p ⫽ 0.145). Discussion The smoking prevalence rates in our resident population are 26.9% for male subjects and 3.1% for female subjects,24 and this rate among the female subjects is much lower compared to that in the United States.25 The standardized adjusted rate for lung cancer in female subjects in Singapore is among the highest in the Southeast Asian countries,26 but paradoxically the smoking rate is among the lowest. This is confirmed in our study, in which the percentage of patients with NSCLC who were nonsmokers was 36.3%, which is higher than that seen in Western countries.8 In addition, among the nonsmokers, 1754

73.9% were women and 75% had adenocarcinoma. The high incidence of female nonsmokers with adenocarcinoma is often seen only in the Asian population.17 The possible etiologic factors and risk factors are still largely unknown, and this is a relatively unexplored area of research. Several studies27,28 in the Chinese population have suggested exposure to oil fumes during cooking as a significant factor among nonsmokers with lung cancer, but this remains to be proven. One can postulate that passive smoking may be a contributory factor. Exposure to environmental tobacco smoke is difficult to quantify objectively, and therefore is subject to self-reported estimates, which are not accurate.29 Similarly, we believed that the documentation of passive smoking was not adequately reflected in our data, and this aspect was thus not addressed. An important observation in our study that may argue against passive smoking as a significant factor is that the mean age at diagnosis for nonsmokers was almost a decade earlier compared to the smokers. It is known that there is a clear dose-response relation between smoking and lung cancer, in which the risk increases with the number of cigarettes smoked, years of smoking, and earlier age at onset of smoking.30 Patients exposed to passive smoke would have a lower amount of carcinogen compared to the active smokers and should, by inference, acquire lung cancer later. Our counterintuitive observation was also corroborated by a similar observation in one other epidemiologic study,17 in which the authors showed that the mean age at which nonsmokers succumb to lung cancer was younger than that among smokers in Asian countries Clinical Investigations

like Japan and Hong Kong. However, one could also postulate that this subset of the population is constitutionally more susceptible to environmental carcinogenic effects, including that from passive smoking that resulted in the earlier onset of the cancer manifestation. It is possible that the interplay of the genetic make-up controlling carcinogen-metabolizing enzymes and the DNA repair capability could play a significant part, and further research along this aspect may help to delineate those who are at risk. Chemotherapy has been shown to improve survival in advanced lung cancer compared to best supportive care.31 Our study shows that the use of chemotherapy is an independent predictor of improved survival, which is in line with previous studies.23,32 However, no significant differences in survival, response rate, and duration of response to chemotherapy between smokers and nonsmokers could be observed. Cytotoxics kill cancer cells in a nonselective manner, in that they do not target specific molecular pathway(s) driving and maintaining the carcinogenic process. Hence, it can be difficult to appreciate the impact of any mutational differences between these two groups of patients with the use of chemotherapy. In smokers with lung cancer, p53 mutations were detected more often compared to nonsmokers,33 and there is also a predominance of p53 G3 T transversion that reflects mutagenic changes in DNA caused by tobacco smoke. K-ras mutations in lung cancer are also reported to be more frequent in smokers than in nonsmokers.34 Comparative genomic hybridization analysis of adenocarcinoma from nonsmokers in one study35 identified a distinct aberration at chromosome 16p in these tumors. It is likely that a more targeted form of treatment that inhibit the predominant pathway(s) that initiate and maintain the carcinogenic process may make this biological difference between tobacco-induced and non–tobaccoinduced lung cancer more manifest. Gefitinib, a tyrosine kinase inhibitor, is one such possible example.36 Already, there are studies37,38 that show the subgroup of patients who were nonsmokers and had adenocarcinoma respond better to gefitinib. We had postulated that there could be differences in survival and response to chemotherapy between smokers and nonsmokers based on the well-established different mutational spectrum, but this was not borne out by our study. It is possible that the sample size is not large enough to show the difference. However, it is also likely that other clinical factors such as performance status, presence of weight loss, and the use of chemotherapy proved to be more significant, thereby masking the impact of smoking status. The other possible explanation is that lung cancers arising as a result of tobacco smoke www.chestjournal.org

exposure or otherwise are equally aggressive in behavior, which is independent of the carcinogenesis pathways driving the process, and hence will have similar survival outcome.

Conclusion Our study has demonstrated that there are differences in epidemiologic characteristics and histologic subtypes between smokers and nonsmokers with NSCLC. The lack of observable differences in response to chemotherapy and survival outcome between these two groups may imply that currently available cytotoxics have no impact on the biological differences that may exist. The advent of targeted therapeutics may make this difference more obvious in future. It must be emphasized, however, that this study was limited mainly to patients with advanced disease who received palliative treatment. Hence, we recognize that the findings of this study may not reflect the situation in those with earlier stages and more curable disease. We hope to include all stages for our future studies, especially those subjected to surgery for curative intent. It is also imperative that more studies be conducted to further delineate and characterize the differences between these two etiologically different forms of NSCLC. A prospective study of genetic profiling of patients with lung cancer is currently underway that we hope will shed more light on this important issue. ACKNOWLEDGMENT: We thank the nurses, Gemma and Myra, for support with patient data management.

References 1 Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2:533–543; Erratum in: Lancet Oncol 2001; 2:596 2 Chia KS, Seow A, Lee HP, et al. Cancer incidence in Singapore 1993–1997. Cancer Registry Report No. 5. Singapore: Singapore Cancer Registry, 2000; 12–14 3 Janssen-Heijnen ML, Coebergh JW. Trends in incidence and prognosis of the histological subtypes of lung cancer in North America, Australia, New Zealand and Europe. Lung Cancer 2001; 31:123–137 4 Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003; 53:5–26 5 Wynder EL, Graham EA. Tobacco smoking as a possible etiological factor in bronchiogenic carcinoma. J Am Med Assoc 1950; 143:329 –336 6 Doll R, Hill AB. A study of the aetiology of carcinoma of the lung. BMJ 1952; 2:1271–1285 7 Parkin DM, Pisani P, Lopez AD, et al. At least one in seven cases of cancer is caused by smoking: global estimates for 1985. Int J Cancer 1994; 59:494 –504 8 Tyczynski JE, Bray F, Parkin DM. Lung cancer in Europe in 2000: epidemiology, prevention, and early detection. Lancet Oncol 2003; 4:45–55 CHEST / 126 / 6 / DECEMBER, 2004

1755

9 Chen CJ, Wu HY, Chuang YC, et al. Epidemiologic characteristics and multiple risk factors of lung cancer in Taiwan. Anticancer Res 1990; 10:971–976 10 Koo LC, Ho JH, Lee N. An analysis of some risk factors for lung cancer in Hong Kong. Int J Cancer 1985; 35:149 –155 11 Maclennan R, Da Costa J, Day NE, et al. Risk factors for lung cancer in Singapore Chinese, a population with high female incidence rates. Int J Cancer 1977; 20:854 – 860 12 Gao YT, Blot WJ, Zheng W, et al. Lung cancer among Chinese women. Int J Cancer 1987; 40:604 – 609 13 Chan-Yeung M, Koo LC, Ho JC, et al. Risk factors associated with lung cancer in Hong Kong. Lung Cancer 2003; 40:131– 140 14 Simanato L, Agudo A, Ahrens W, et al. Lung cancer and cigarette smoking in Europe: an update of risk estimates and an assessment of inter-country heterogeneity. Int J Cancer 2001; 91:876 – 887 15 Travis WD, Lubin J, Ries L, et al. United States lung carcinoma incidence trends: declining for most histologic types among males, increasing among females. Cancer 1996; 77:2464 –2470 16 Charloux A, Quoix E, Wolkove N, et al. The increasing incidence of lung adenocarcinoma: reality or artifact? A review of the epidemiology of lung adenocarcinoma. Int J Epidemiol 1997; 26:14 –23 17 Koo LC, Ho JH. Worldwide epidemiological patterns of lung cancer in nonsmokers. Int J Epidemiol 1990; 19:S14 –S23 18 Hashimoto T, Tokuchi Y, Hayashi M, et al. Different subtypes of human lung adenocarcinoma caused by different etiological factors. Am J Pathol 2000; 157:2133–2141 19 Hainaut P, Pfeifer GP. Patterns of p53 G 3 T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke. Carcinogenesis 2001; 22: 367–374 20 WHO guidelines for controlling and monitoring the tobacco epidemic. Geneva, Switzerland: World Health Organization, 1998 21 WHO handbook for reporting results of cancer treatment. Geneva, Switzerland: World Health Organization, 1979; publication No. 48 22 Paesmans M, Sculier JP, Libert P, et al. Prognostic factors for survival in advanced non-small cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1052 patients. J Clin Oncol 1995; 13:1221–1230 23 Albain KS, Crowley JJ, LeBlanc M, et al. Survival determinants in extensive-stage non small cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991; 9:1618 –1626

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24 National Health Survey 1998, Singapore: Ministry of Health, Epidemiology and Disease Control Department, 1999 25 Centers for Disease Control and Prevention. Cigarette smoking among adults–United States, 2000. MMWR Morb Mortal Wkly Rep 2002; 51:642– 645 26 Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide. 2001; Lyon, France: International Agency for Research on Cancer, 2001 27 Ko YC, Lee CH, Chen MJ, et al. Risk factors for primary lung cancer among non-smoking women in Taiwan. Int J Epidemiol 1997; 26:24 –31 28 Wu-Williams AH, Da XD, Blot W, et al. Lung cancer among women in north-east China. Br J Cancer 1990; 62:982–987 29 Enstrom JE, Kabat GC. Environmental tobacco smoke and tobacco related mortality in a prospective study of Californians, 1960 –98. BMJ 2003; 326:1057–1061 30 Loeb LA, Ernster VL, Warner KE, et al. Smoking and lung cancer: an overview. Cancer Res 1984; 44: 5940 –5958; Erratum in: Cancer Res 1986; 46:5453 31 Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trial. BMJ 1995; 31:899 –909 32 Marino P, Pampallona S, Prestoni A, et al. Chemotherapy versus supportive care in advanced non-small cell lung cancer: results of a meta-analysis of the literature. Chest 1994; 106:861– 865 33 Ahrendt SA, Chow JT, Yang SC, et al. Alcohol consumption and cigarette smoking increase the frequency of p53 mutations in non-small cell lung cancer. Cancer Res 2000; 60: 3155–3159 34 Gealy R, Zhang L, Siegfried JM, et al. Comparison of mutations in the p53 and K-ras genes in lung carcinomas from smoking and nonsmoking women. Cancer Epidemiol Biomarkers Prev 1999; 8:297–302; Erratum in: Cancer Epidemiol Biomarkers Prev 2001; 10:1309 35 Wong MP, Fung LF, Wang E, et al. Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers. Cancer 2003; 97:1263–1270 36 Cohen MH, Williams GA, Sridhara R, et al. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8:303–306 37 Shah AT, Miller VA, Kris MG, et al. Bronchioalveolar histology and smoking history predict response to gefitinib [abstract]. Proc Am Soc Clin Oncol 2003; 22:628 38 Wong NS, Lim ST, Lim WT, et al. ZD1839 is more effective in patients (pts) with non-small cell lung cancer (NSCLC) who were lifetime non-tobacco users [abstract]. Proc Am Soc Clin Oncol 2003; 22:694

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