Med Oncol (2015) 32:339 DOI 10.1007/s12032-014-0339-3
ORIGINAL PAPER
Effect of smoking on survival from non-small cell lung cancer: a retrospective Veterans’ Affairs Central Cancer Registry (VACCR) cohort analysis Vijaya Raj Bhatt • Rishi Batra • Peter T. Silberstein Fausto R. Loberiza Jr. • Apar Kishor Ganti
•
Received: 4 September 2014 / Accepted: 7 November 2014 / Published online: 28 November 2014 Ó Springer Science+Business Media New York 2014
Abstract Although a well-established risk factor for lung cancer, the impact of smoking on the survival of non-small cell lung cancer (NSCLC) is not well known. We performed a retrospective analysis of the Veteran’s Affairs Comprehensive Cancer Registry of NSCLC patients. Smoking status was categorized as never smoker, past smoker and current smoker based on self-reported history. Multivariate analysis was performed to evaluate the impact of smoking on overall survival (OS) from NSCLC. The study population (n = 61,440) comprised predominantly of males (98 %) and Caucasians (81 %). The median age at diagnosis was 68 years (range 22–108 years). Current smokers were diagnosed with NSCLC at a younger age (65 years) compared to never smokers (71 years) and past smokers (72 years) (p \ 0.001). On multivariate analysis, current smokers (n = 34,613) [Hazard ratio (HR) 1.059; 95 % confidence interval (CI) 1.012–1.108], but not past smokers (n = 23,864) (HR 1.008; 95 % CI 0.962–1.056), had worse OS for Stage III and IV NSCLC, compared to
V. R. Bhatt F. R. Loberiza Jr. A. K. Ganti (&) Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, USA e-mail: [email protected] R. Batra Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA P. T. Silberstein A. K. Ganti Department of Internal Medicine, Veteran’s Affairs NebraskaWestern Iowa Health Care System, Omaha, NE, USA P. T. Silberstein Department of Internal Medicine, Creighton University Medical Center, Omaha, NE, USA
never smokers (n = 2,963). Smoking status was not prognostic in stages I and II NSCLC. Current smokers were diagnosed with NSCLC at a younger age than never smokers. Although current smoking was associated with worse prognosis, especially in stages III and IV, the impact of smoking status on OS was modest. Keywords Non-small cell lung cancer Tobacco Smoking Outcomes Survival
Introduction Lung cancer is the most common cause of cancer-related deaths worldwide and in the USA with an estimated death of 159,480 people in the USA in 2013 [1]. Despite progress in our understanding of the biology and advances in therapeutic options, long-term survival for non-small cell lung cancer (NSCLC) still remains poor. A well-established risk factor, smoking, is associated with several genetic alterations in NSCLC [2, 3]; proliferative activity (Ki-67 antigen expression) of the tumor [4] and can potentially influence outcomes in NSCLC. Correlative studies have shown that in NSCLC, the duration of smoking is associated with loss of p53 expression [5] and initiation of smoking at an early age is associated with hypermethylation of the RASSF1A promoter [6]; both of which may influence the prognosis [5, 6]. Smoking cessation prior to the diagnosis [7], smoking status at the time of diagnosis [8–10] and smoking cessation after the diagnosis [9, 11] have been shown to influence the prognosis of early-stage NSCLC. The improvement in survival also seems to correlate with the duration of smoking cessation prior to the diagnosis [7]. In both early and advanced stage NSCLC, smoking cessation after the diagnosis also has beneficial effects on
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performance status [12] and quality of life [13]. Although smoking status at the time of diagnosis has been shown to influence outcomes in advanced NSCLC in some studies [14–16], the results are inconsistent [17–21]. These disparities could be the result of sex-related and histologyrelated differences in the extent of benefit from smoking cessation [7, 22–27]. There may be several gender-related differences in intensity of smoking and the risk of lung cancer as well as the biology of lung cancer, response to therapy and outcomes [28–30]. Studies have shown that there are gender-related differences in susceptibility to smoking [31] and benefits from smoking cessation [32]. Despite this, studies focused on the smoking status and outcomes with advanced NSCLC are largely lacking. Additionally, many of the aforementioned studies are also limited by relatively small size of patient population. This study was conducted to analyze the association, if any, between smoking history and outcomes from NSCLC.
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Staging, 6th edition. Histological classification of lung cancer was based on World Health Organization classification. Overall survival was calculated from the date of diagnosis to the date of death or last follow-up. Statistical analysis Comparison of patient characteristics was performed using Kruskal–Wallis test or Chi-square test. Estimates of survival probabilities were done using Kaplan–Meier estimate. Multivariate Cox proportional hazard regression analysis using SAS version 10.2 was performed to evaluate association of smoking status and overall survival (death from any causes) while adjusting from other prognostic factors. Covariates with a p value of B0.05 were accounted for in the final model. Separate models were built for patients with stage I/II and stage III/IV.
Results Materials and methods Patient characteristics This is a retrospective analysis of Veteran’s Affairs Comprehensive Cancer Registry (VACCR) of NSCLC patients diagnosed between 1995 and 2009. Veteran’s Affairs (VA) health care system, with over 1,700 sites of care, is the largest health care provider in USA and serves 8.3 million veterans annually [33]. The VA facilities, which share an electronic health record system, have maintained a comprehensive database of all cancer patients treated in the VA system. Many VA facilities started local cancer registry following a national directive in 1998. VACCR, formally recognized in 2003, retrospectively abstracted cases diagnosed on or after January 1, 1995 and continues to do the same. Approximately 3 % of all new cancers in USA are diagnosed at VA annually, of which an estimated *90 % are captured by VACCR. Cancer registrars at VA facilities use cancer registry software, OncoTraX, for case identification and abstraction, which is integrated with the electronic health records. Case abstraction conforms to the standards set by the North American Association of Central Cancer Registries. After ensuring data integrity, the data are subsequently aggregated into the national registry [34]. The institutional review board at the VA-Nebraska Western Iowa Health Care System approved the study. Data abstracted included age, gender, family history, stage at diagnosis, histology, tumor grade, smoking history, other exposures, treatment received and overall survival (OS). Smoking status was categorized as never smoker (defined as a person who had never smoked), past smoker and current smoker (regardless of the intensity of smoking) based on the self-reported history at diagnosis. Staging was based on the American Joint Committee on Cancer
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The study population (n = 61,440) comprised predominantly of males (98 %), of which Caucasians (81 %) formed the majority (Table 1). The median age at diagnosis within this cohort was 68 years (range 22–108 years), and median follow-up was 6 months (range \1–161 months). The majority were current smokers (56.4 %) or past smokers (38.8 %), whereas never smokers comprised of only 4.8 % of the study population. A significant proportion of the patients had a history of asbestos exposure (42.9 %) and a history of drinking alcohol at present (31.7 %) or in the past (22.5 %). Positive family history was identified in one third. Squamous cell carcinoma (35 %) and adenocarcinoma (30 %) were the most common histologies. The majority (71 %) presented with stage III or IV disease. Thirty-two percent received no therapy, whereas others received radiation alone (22 %), chemoradiation (15 %), surgery (14 %), chemotherapy (13 %) and chemoradiation and surgery (4 %). Outcomes by smoking status Current smokers were diagnosed with NSCLC at a younger age (65 years) compared to never smokers (71 years) and past smokers (72 years) (p \ 0.001). Median OS for never smokers, past smokers and current smokers was 1.56 (95 % CI 1.46–1.67), 1.51 (95 % CI 1.41–1.56) and 1.57 (95 % CI 1.53–1.62) years, respectively, for stage I/II disease. Corresponding values for stages III/IV disease were 0.38 (95 % CI 0.36–0.42), 0.44 (95 % CI 0.43–0.46) and 0.44 (95 % CI 0.43–0.45) years, respectively.
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Table 1 Baseline characteristics of the non-small cell lung carcinoma patients Variables
Never smoker (n = 2,963)
Past smoker (n = 23,864)
Current smoker (n = 34,613)
Total (n = 61,440)
\0.001
Gender Male
2,877 (97.1 %)
23,544 (98.7 %)
34,046 (98.3 %)
60,467 (98.4 %)
Female
86 (2.9 %)
320 (1.3 %)
567 (1.7 %)
973 (1.6 %)
White
2,357 (80.2 %)
19,852 (83.2 %)
27,743 (80.1 %)
49,970 (81.3 %)
African–American
547 (18.5 %)
3,842 (16.1 %)
6,648 (19.2 %)
11,037 (17.9 %)
Asian American Others
29 (0.9 %) 12 (0.4 %)
94 (0.4 %) 76 (0.3 %)
95 (0.3 %) 127 (0.4 %)
218 (0.4 %) 215 (0.4 %)
Median
71
72
65
68
Range
25–100
22–105
26–108
22–108
2,326 (78.5 %)
7,195 (30.2 %)
8,144 (23.5 %)
17,665 (28.7 %)
Past
100 (3.4 %)
7,361 (30.8 %)
6,360 (18.4 %)
13,821 (22.5 %)
Current
229 (7.7 %)
5,425 (22.7 %)
13,804 (39.9 %)
19,458 (31.7 %)
Unknown
308 (10.4 %)
3,883 (16.3 %)
6,305 (18.2 %)
10,496 (17.1 %)
\0.0001
Race
\0.001
Age at diagnosis
\0.0001
Alcohol use None
\0.0001
Asbestos exposure No
64 (2.2 %)
1,369 (5.7 %)
1,464 (4.2 %)
Yes
1,201 (40.5 %)
9,945 (41.7 %)
15,230 (44.0 %)
26,376 (42.9 %)
Unknown
1,698 (57.3 %)
12,550 (52.6 %)
17,919 (51.8 %)
32,167 (52.4 %)
2,897 (4.7 %)
No Yes
1,348 (45.5 %) 349 (11.8 %)
8,772 (36.8 %) 8,072 (33.8 %)
12,216 (35.3 %) 10,844 (31.3 %)
22,336 (36.3 %) 19,265 (31.4 %)
Unknown
1,266 (42.7 %)
7,020 (29.4 %)
11,553 (33.4 %)
19,839 (32.3 %)
I
670 (22.6 %)
5,897 (24.7 %)
7,456 (21.5 %)
14,023 (22.8 %)
II
136 (4.6 %)
1,364 (5.7 %)
1,785 (5.2 %)
3,285 (5.4 %)
III
859 (29.0 %)
7,255 (30.4 %)
10,092 (29.2 %)
18,206 (29.6 %)
IV
1,298 (43.8 %)
9,348 (39.2 %)
15,280 (44.1 %)
25,926 (42.2 %)
846 (28.5 %)
8,338 (34.9 %)
12,316 (35.6 %)
21,500 (35.0 %)
\0.0001
Family history
\0.0001
Stage
\0.0001
Histology Squamous
p value
Adenocarcinoma
1,072 (36.2 %)
7,345 (30.8 %)
10,003 (28.9 %)
18,420 (30.0 %)
Large cell
169 (5.7 %)
935 (3.9 %)
1,529 (4.4 %)
2,633 (4.3 %)
Adenosquamous
41 (1.4 %)
249 (1.1 %)
379 (1.1 %)
669 (1.1 %)
NSCLC
835 (28.2 %)
6,997 (29.3 %)
10,386 (30.0 %)
18,218 (29.6 %)
NSCLC non-small cell lung cancer
After adjusting for age at diagnosis, histology, family history and treatment, current smoking status [Hazard ratio (HR) 1.059; 95 % confidence interval (CI) 1.012–1.108], but not a previous smoking history (HR 1.008; 95 % CI 0.962–1.056), were associated with worse OS for Stage III and IV NSCLC, compared to never smokers (Table 2). In patients with early-stage NSCLC (stage I and II), OS was not different for past smokers (HR 1.010; 95 % CI 0.943–1.083) or current smokers (HR 1.068; 95 % CI 0.997–1.143), when compared to never smokers. Smoking status was not prognostic for any specific histology.
Discussion This large VA Comprehensive Cancer registry-based study comprising predominantly of Caucasian men showed that current smokers, compared to never smokers and past smokers, were diagnosed with NSCLC at a younger age and had a slightly worse OS for advanced, but not for earlystage NSCLC. Outcomes for any specific histology did not differ based on smoking status at diagnosis. Studies have shown that the risk of lung cancer is related to the intensity of smoking (number of cigarettes smoked
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339 Page 4 of 6 Table 2 Multivariate analysis of overall survival in NSCLC
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Variables
Stage I–II Risk of death HR (95 % CI)
Stage III–IV p value
Risk of death HR (95 % CI)
p value
Smoking status Never smoker
1.00
1.00
Past smoker
1.01 (0.94–1.08)
0.77
1.01 (0.96–1.06)
0.75
Current Smoker
1.07 (1.00–1.14)
0.06
1.06 (1.01–1.11)
0.01
Age
1.01 (1.00–1.011)
\0.0001
1.00 (1.00–1.00)
0.0007
Treatment None
1.00
Chemotherapy
0.60 (0.57–0.63)
\0.0001
0.48 (0.47–0.50)
\0.0001
Radiation
0.73 (0.70–0.76)
\0.0001
0.79 (0.77–0.81)
\0.0001
Surgery
0.28 (0.27–0.31)
\0.0001
0.28 (0.26–0.30)
\0.0001
Chemoradiation
0.46 (0.44–0.48)
\0.0001
0.40 (0.39–0.41)
\0.0001
Surgery and chemoradiation
0.28 (0.26–0.30)
\0.0001
0.25 (0.24–0.27)
\0.0001
Other covariates
1.000
Family history None
1.00
Yes
0.94 (0.91–0.98)
0.0008
1.000 0.94 (0.92–0.97)
\0.0001
Unknown
1.00 (0.96–1.03)
0.84
0.98 (0.96–1.00)
0.08
Histology
HR hazard ratio, CI confidence interval, NSCLC non-small cell lung cancer
Squamous
1.00
Adenocarcinoma
1.09 (1.05–1.14)
\0.0001
1.18 (1.15–1.21)
\0.0001
Large cell
0.96 (0.89–1.04)
0.29
1.14 (1.08–1.20)
\0.0001
Adenosquamous NSCLC
0.98 (0.84–1.14) 1.00 (0.97–1.04)
0.75 0.87
1.19 (1.07–1.32) 1.17(1.14–1.20)
0.0014 \0.0001
per day), the duration of smoking, total pack years and the age of initiation of smoking [35, 36]. In many studies, the majority of patients with lung cancer presenting at a young age were smokers [35–37]. In a landmark study, it has been shown that heavy smokers present with lung cancer at an earlier age [38]. Our study results, which show that current smokers are diagnosed with NSCLC at a younger age, are consistent with the prior results. In the present study, current smokers had a slightly worse OS for advanced, but not for early-stage NSCLC. Smoking status was not associated with a difference in survival when individual histology was evaluated. In prior studies, smoking status at the time of diagnosis has been shown to influence the prognosis of early-stage NSCLC [8– 10], but the results for advanced stage NSCLC are inconsistent [14–21, 39]. In one study, relapse-free proportions among stage II and III NSCLC patients were higher in ever smokers compared to never smokers, whereas overall survival was not different [20]. In another study, among advanced NSCLC patients treated with chemotherapy, never smokers had better outcomes compared to former or current smokers; however, outcomes were not poor with active smoking during therapy (former versus current smokers). Similarly, smoking status did not influence
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1.00
outcomes among patients treated with chemoradiation [39]. In a different study, although there was a difference in overall survival in early-stage NSCLC based on smoking status, there was no difference in Stage III NSCLC and no difference in cancer-specific survival in either stage NSCLC [19]. Previous studies indicate a significant interaction between smoking status and gender as well as smoking status and histology in terms of prognosis of NSCLC. Studies have shown smoking status to be a prognostic factor in lung adenocarcinoma [24, 25]. In one study, among early-stage lung adenocarcinoma patients, smoking status and male gender were associated with adenocarcinoma with little or no bronchioloalveolar carcinoma subtype. Multivariate analysis showed only histology, but not smoking status to be an independent prognostic factor [40]. More importantly, studies have indicated that the benefit of smoking cessation prior to or after the diagnosis of earlystage NSCLC may only be observed in women (but not in men) [7] and adenocarcinoma (but not in non-adenocarcinoma or squamous cell carcinoma) [23, 26, 27]. These can be explained by the gender-related differences in susceptibility to smoking [31] and benefits from smoking cessation [32]. In addition, there are differences in ethnic and
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genetic variability in susceptibility to smoking-related lung cancers [41, 42] and NSCLC-related outcomes [43, 44]. For example, in one study, Japanese ethnicity, compared to Caucasian ethnicity, was an independent favorable prognostic factor for overall survival in NSCLC. Further, never smoking status was associated with improved overall survival in Japanese, but not in Caucasian patients [44]. Unlike some of the aforementioned studies, our study did not show any benefit from smoking cessation in early stage, and only modest benefit in advanced stage NSCLC. The difference is likely because of the predominantly Caucasian, male population in our study as well as possibly related to the ethnic and genetic differences in the study population. Being a retrospective study, the smoking intensity and duration as well as time duration between cessation of smoking and the development of NSCLC could not be assessed. These differences in definition of smoking status could also account for the differences in the study results. Many patients did not receive any therapy in the present study, but the reason for this decision could not be ascertained. However, we do not believe that this could have affected our results as treatment was adjusted for in the final statistical model. Despite these limitations, this is a very large cohort of NSCLC patients, who were treated within a single payer system with equitable access to healthcare. The duration of smoking increased lung cancer death rate more strongly than the intensity of smoking [45]. Early onset of smoking increases the risk of lung cancer because of increased duration of smoking as well as possibly increased susceptibility during a critical period of development [46]. Previous studies have shown that the benefits of smoking cessation on lung cancer outcomes are greater when accomplished at a younger ages [47, 48]. Taken together with the results of our study, primary prevention of smoking cessation is more likely to be meaningful than efforts on smoking cessation after the diagnosis of NSCLC.
Conclusions In conclusion, our study shows that current smokers were 6 years younger than never smokers at diagnosis of NSCLC. Although current smoking was associated with worse prognosis, especially in stages III and IV, the impact of smoking status on overall survival was modest, at least in Caucasian men. Acknowledgments The facilities of the VA-Nebraska Western Iowa Health Care System were used during the course of this study. Conflict of interest There are no conflicts of interest associated with the contents of this manuscript.
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ORIGINAL PAPER
Effect of smoking on survival from non-small cell lung cancer: a retrospective Veterans’ Affairs Central Cancer Registry (VACCR) cohort analysis Vijaya Raj Bhatt • Rishi Batra • Peter T. Silberstein Fausto R. Loberiza Jr. • Apar Kishor Ganti
•
Received: 4 September 2014 / Accepted: 7 November 2014 / Published online: 28 November 2014 Ó Springer Science+Business Media New York 2014
Abstract Although a well-established risk factor for lung cancer, the impact of smoking on the survival of non-small cell lung cancer (NSCLC) is not well known. We performed a retrospective analysis of the Veteran’s Affairs Comprehensive Cancer Registry of NSCLC patients. Smoking status was categorized as never smoker, past smoker and current smoker based on self-reported history. Multivariate analysis was performed to evaluate the impact of smoking on overall survival (OS) from NSCLC. The study population (n = 61,440) comprised predominantly of males (98 %) and Caucasians (81 %). The median age at diagnosis was 68 years (range 22–108 years). Current smokers were diagnosed with NSCLC at a younger age (65 years) compared to never smokers (71 years) and past smokers (72 years) (p \ 0.001). On multivariate analysis, current smokers (n = 34,613) [Hazard ratio (HR) 1.059; 95 % confidence interval (CI) 1.012–1.108], but not past smokers (n = 23,864) (HR 1.008; 95 % CI 0.962–1.056), had worse OS for Stage III and IV NSCLC, compared to
V. R. Bhatt F. R. Loberiza Jr. A. K. Ganti (&) Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, USA e-mail: [email protected] R. Batra Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA P. T. Silberstein A. K. Ganti Department of Internal Medicine, Veteran’s Affairs NebraskaWestern Iowa Health Care System, Omaha, NE, USA P. T. Silberstein Department of Internal Medicine, Creighton University Medical Center, Omaha, NE, USA
never smokers (n = 2,963). Smoking status was not prognostic in stages I and II NSCLC. Current smokers were diagnosed with NSCLC at a younger age than never smokers. Although current smoking was associated with worse prognosis, especially in stages III and IV, the impact of smoking status on OS was modest. Keywords Non-small cell lung cancer Tobacco Smoking Outcomes Survival
Introduction Lung cancer is the most common cause of cancer-related deaths worldwide and in the USA with an estimated death of 159,480 people in the USA in 2013 [1]. Despite progress in our understanding of the biology and advances in therapeutic options, long-term survival for non-small cell lung cancer (NSCLC) still remains poor. A well-established risk factor, smoking, is associated with several genetic alterations in NSCLC [2, 3]; proliferative activity (Ki-67 antigen expression) of the tumor [4] and can potentially influence outcomes in NSCLC. Correlative studies have shown that in NSCLC, the duration of smoking is associated with loss of p53 expression [5] and initiation of smoking at an early age is associated with hypermethylation of the RASSF1A promoter [6]; both of which may influence the prognosis [5, 6]. Smoking cessation prior to the diagnosis [7], smoking status at the time of diagnosis [8–10] and smoking cessation after the diagnosis [9, 11] have been shown to influence the prognosis of early-stage NSCLC. The improvement in survival also seems to correlate with the duration of smoking cessation prior to the diagnosis [7]. In both early and advanced stage NSCLC, smoking cessation after the diagnosis also has beneficial effects on
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performance status [12] and quality of life [13]. Although smoking status at the time of diagnosis has been shown to influence outcomes in advanced NSCLC in some studies [14–16], the results are inconsistent [17–21]. These disparities could be the result of sex-related and histologyrelated differences in the extent of benefit from smoking cessation [7, 22–27]. There may be several gender-related differences in intensity of smoking and the risk of lung cancer as well as the biology of lung cancer, response to therapy and outcomes [28–30]. Studies have shown that there are gender-related differences in susceptibility to smoking [31] and benefits from smoking cessation [32]. Despite this, studies focused on the smoking status and outcomes with advanced NSCLC are largely lacking. Additionally, many of the aforementioned studies are also limited by relatively small size of patient population. This study was conducted to analyze the association, if any, between smoking history and outcomes from NSCLC.
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Staging, 6th edition. Histological classification of lung cancer was based on World Health Organization classification. Overall survival was calculated from the date of diagnosis to the date of death or last follow-up. Statistical analysis Comparison of patient characteristics was performed using Kruskal–Wallis test or Chi-square test. Estimates of survival probabilities were done using Kaplan–Meier estimate. Multivariate Cox proportional hazard regression analysis using SAS version 10.2 was performed to evaluate association of smoking status and overall survival (death from any causes) while adjusting from other prognostic factors. Covariates with a p value of B0.05 were accounted for in the final model. Separate models were built for patients with stage I/II and stage III/IV.
Results Materials and methods Patient characteristics This is a retrospective analysis of Veteran’s Affairs Comprehensive Cancer Registry (VACCR) of NSCLC patients diagnosed between 1995 and 2009. Veteran’s Affairs (VA) health care system, with over 1,700 sites of care, is the largest health care provider in USA and serves 8.3 million veterans annually [33]. The VA facilities, which share an electronic health record system, have maintained a comprehensive database of all cancer patients treated in the VA system. Many VA facilities started local cancer registry following a national directive in 1998. VACCR, formally recognized in 2003, retrospectively abstracted cases diagnosed on or after January 1, 1995 and continues to do the same. Approximately 3 % of all new cancers in USA are diagnosed at VA annually, of which an estimated *90 % are captured by VACCR. Cancer registrars at VA facilities use cancer registry software, OncoTraX, for case identification and abstraction, which is integrated with the electronic health records. Case abstraction conforms to the standards set by the North American Association of Central Cancer Registries. After ensuring data integrity, the data are subsequently aggregated into the national registry [34]. The institutional review board at the VA-Nebraska Western Iowa Health Care System approved the study. Data abstracted included age, gender, family history, stage at diagnosis, histology, tumor grade, smoking history, other exposures, treatment received and overall survival (OS). Smoking status was categorized as never smoker (defined as a person who had never smoked), past smoker and current smoker (regardless of the intensity of smoking) based on the self-reported history at diagnosis. Staging was based on the American Joint Committee on Cancer
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The study population (n = 61,440) comprised predominantly of males (98 %), of which Caucasians (81 %) formed the majority (Table 1). The median age at diagnosis within this cohort was 68 years (range 22–108 years), and median follow-up was 6 months (range \1–161 months). The majority were current smokers (56.4 %) or past smokers (38.8 %), whereas never smokers comprised of only 4.8 % of the study population. A significant proportion of the patients had a history of asbestos exposure (42.9 %) and a history of drinking alcohol at present (31.7 %) or in the past (22.5 %). Positive family history was identified in one third. Squamous cell carcinoma (35 %) and adenocarcinoma (30 %) were the most common histologies. The majority (71 %) presented with stage III or IV disease. Thirty-two percent received no therapy, whereas others received radiation alone (22 %), chemoradiation (15 %), surgery (14 %), chemotherapy (13 %) and chemoradiation and surgery (4 %). Outcomes by smoking status Current smokers were diagnosed with NSCLC at a younger age (65 years) compared to never smokers (71 years) and past smokers (72 years) (p \ 0.001). Median OS for never smokers, past smokers and current smokers was 1.56 (95 % CI 1.46–1.67), 1.51 (95 % CI 1.41–1.56) and 1.57 (95 % CI 1.53–1.62) years, respectively, for stage I/II disease. Corresponding values for stages III/IV disease were 0.38 (95 % CI 0.36–0.42), 0.44 (95 % CI 0.43–0.46) and 0.44 (95 % CI 0.43–0.45) years, respectively.
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Table 1 Baseline characteristics of the non-small cell lung carcinoma patients Variables
Never smoker (n = 2,963)
Past smoker (n = 23,864)
Current smoker (n = 34,613)
Total (n = 61,440)
\0.001
Gender Male
2,877 (97.1 %)
23,544 (98.7 %)
34,046 (98.3 %)
60,467 (98.4 %)
Female
86 (2.9 %)
320 (1.3 %)
567 (1.7 %)
973 (1.6 %)
White
2,357 (80.2 %)
19,852 (83.2 %)
27,743 (80.1 %)
49,970 (81.3 %)
African–American
547 (18.5 %)
3,842 (16.1 %)
6,648 (19.2 %)
11,037 (17.9 %)
Asian American Others
29 (0.9 %) 12 (0.4 %)
94 (0.4 %) 76 (0.3 %)
95 (0.3 %) 127 (0.4 %)
218 (0.4 %) 215 (0.4 %)
Median
71
72
65
68
Range
25–100
22–105
26–108
22–108
2,326 (78.5 %)
7,195 (30.2 %)
8,144 (23.5 %)
17,665 (28.7 %)
Past
100 (3.4 %)
7,361 (30.8 %)
6,360 (18.4 %)
13,821 (22.5 %)
Current
229 (7.7 %)
5,425 (22.7 %)
13,804 (39.9 %)
19,458 (31.7 %)
Unknown
308 (10.4 %)
3,883 (16.3 %)
6,305 (18.2 %)
10,496 (17.1 %)
\0.0001
Race
\0.001
Age at diagnosis
\0.0001
Alcohol use None
\0.0001
Asbestos exposure No
64 (2.2 %)
1,369 (5.7 %)
1,464 (4.2 %)
Yes
1,201 (40.5 %)
9,945 (41.7 %)
15,230 (44.0 %)
26,376 (42.9 %)
Unknown
1,698 (57.3 %)
12,550 (52.6 %)
17,919 (51.8 %)
32,167 (52.4 %)
2,897 (4.7 %)
No Yes
1,348 (45.5 %) 349 (11.8 %)
8,772 (36.8 %) 8,072 (33.8 %)
12,216 (35.3 %) 10,844 (31.3 %)
22,336 (36.3 %) 19,265 (31.4 %)
Unknown
1,266 (42.7 %)
7,020 (29.4 %)
11,553 (33.4 %)
19,839 (32.3 %)
I
670 (22.6 %)
5,897 (24.7 %)
7,456 (21.5 %)
14,023 (22.8 %)
II
136 (4.6 %)
1,364 (5.7 %)
1,785 (5.2 %)
3,285 (5.4 %)
III
859 (29.0 %)
7,255 (30.4 %)
10,092 (29.2 %)
18,206 (29.6 %)
IV
1,298 (43.8 %)
9,348 (39.2 %)
15,280 (44.1 %)
25,926 (42.2 %)
846 (28.5 %)
8,338 (34.9 %)
12,316 (35.6 %)
21,500 (35.0 %)
\0.0001
Family history
\0.0001
Stage
\0.0001
Histology Squamous
p value
Adenocarcinoma
1,072 (36.2 %)
7,345 (30.8 %)
10,003 (28.9 %)
18,420 (30.0 %)
Large cell
169 (5.7 %)
935 (3.9 %)
1,529 (4.4 %)
2,633 (4.3 %)
Adenosquamous
41 (1.4 %)
249 (1.1 %)
379 (1.1 %)
669 (1.1 %)
NSCLC
835 (28.2 %)
6,997 (29.3 %)
10,386 (30.0 %)
18,218 (29.6 %)
NSCLC non-small cell lung cancer
After adjusting for age at diagnosis, histology, family history and treatment, current smoking status [Hazard ratio (HR) 1.059; 95 % confidence interval (CI) 1.012–1.108], but not a previous smoking history (HR 1.008; 95 % CI 0.962–1.056), were associated with worse OS for Stage III and IV NSCLC, compared to never smokers (Table 2). In patients with early-stage NSCLC (stage I and II), OS was not different for past smokers (HR 1.010; 95 % CI 0.943–1.083) or current smokers (HR 1.068; 95 % CI 0.997–1.143), when compared to never smokers. Smoking status was not prognostic for any specific histology.
Discussion This large VA Comprehensive Cancer registry-based study comprising predominantly of Caucasian men showed that current smokers, compared to never smokers and past smokers, were diagnosed with NSCLC at a younger age and had a slightly worse OS for advanced, but not for earlystage NSCLC. Outcomes for any specific histology did not differ based on smoking status at diagnosis. Studies have shown that the risk of lung cancer is related to the intensity of smoking (number of cigarettes smoked
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339 Page 4 of 6 Table 2 Multivariate analysis of overall survival in NSCLC
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Variables
Stage I–II Risk of death HR (95 % CI)
Stage III–IV p value
Risk of death HR (95 % CI)
p value
Smoking status Never smoker
1.00
1.00
Past smoker
1.01 (0.94–1.08)
0.77
1.01 (0.96–1.06)
0.75
Current Smoker
1.07 (1.00–1.14)
0.06
1.06 (1.01–1.11)
0.01
Age
1.01 (1.00–1.011)
\0.0001
1.00 (1.00–1.00)
0.0007
Treatment None
1.00
Chemotherapy
0.60 (0.57–0.63)
\0.0001
0.48 (0.47–0.50)
\0.0001
Radiation
0.73 (0.70–0.76)
\0.0001
0.79 (0.77–0.81)
\0.0001
Surgery
0.28 (0.27–0.31)
\0.0001
0.28 (0.26–0.30)
\0.0001
Chemoradiation
0.46 (0.44–0.48)
\0.0001
0.40 (0.39–0.41)
\0.0001
Surgery and chemoradiation
0.28 (0.26–0.30)
\0.0001
0.25 (0.24–0.27)
\0.0001
Other covariates
1.000
Family history None
1.00
Yes
0.94 (0.91–0.98)
0.0008
1.000 0.94 (0.92–0.97)
\0.0001
Unknown
1.00 (0.96–1.03)
0.84
0.98 (0.96–1.00)
0.08
Histology
HR hazard ratio, CI confidence interval, NSCLC non-small cell lung cancer
Squamous
1.00
Adenocarcinoma
1.09 (1.05–1.14)
\0.0001
1.18 (1.15–1.21)
\0.0001
Large cell
0.96 (0.89–1.04)
0.29
1.14 (1.08–1.20)
\0.0001
Adenosquamous NSCLC
0.98 (0.84–1.14) 1.00 (0.97–1.04)
0.75 0.87
1.19 (1.07–1.32) 1.17(1.14–1.20)
0.0014 \0.0001
per day), the duration of smoking, total pack years and the age of initiation of smoking [35, 36]. In many studies, the majority of patients with lung cancer presenting at a young age were smokers [35–37]. In a landmark study, it has been shown that heavy smokers present with lung cancer at an earlier age [38]. Our study results, which show that current smokers are diagnosed with NSCLC at a younger age, are consistent with the prior results. In the present study, current smokers had a slightly worse OS for advanced, but not for early-stage NSCLC. Smoking status was not associated with a difference in survival when individual histology was evaluated. In prior studies, smoking status at the time of diagnosis has been shown to influence the prognosis of early-stage NSCLC [8– 10], but the results for advanced stage NSCLC are inconsistent [14–21, 39]. In one study, relapse-free proportions among stage II and III NSCLC patients were higher in ever smokers compared to never smokers, whereas overall survival was not different [20]. In another study, among advanced NSCLC patients treated with chemotherapy, never smokers had better outcomes compared to former or current smokers; however, outcomes were not poor with active smoking during therapy (former versus current smokers). Similarly, smoking status did not influence
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1.00
outcomes among patients treated with chemoradiation [39]. In a different study, although there was a difference in overall survival in early-stage NSCLC based on smoking status, there was no difference in Stage III NSCLC and no difference in cancer-specific survival in either stage NSCLC [19]. Previous studies indicate a significant interaction between smoking status and gender as well as smoking status and histology in terms of prognosis of NSCLC. Studies have shown smoking status to be a prognostic factor in lung adenocarcinoma [24, 25]. In one study, among early-stage lung adenocarcinoma patients, smoking status and male gender were associated with adenocarcinoma with little or no bronchioloalveolar carcinoma subtype. Multivariate analysis showed only histology, but not smoking status to be an independent prognostic factor [40]. More importantly, studies have indicated that the benefit of smoking cessation prior to or after the diagnosis of earlystage NSCLC may only be observed in women (but not in men) [7] and adenocarcinoma (but not in non-adenocarcinoma or squamous cell carcinoma) [23, 26, 27]. These can be explained by the gender-related differences in susceptibility to smoking [31] and benefits from smoking cessation [32]. In addition, there are differences in ethnic and
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genetic variability in susceptibility to smoking-related lung cancers [41, 42] and NSCLC-related outcomes [43, 44]. For example, in one study, Japanese ethnicity, compared to Caucasian ethnicity, was an independent favorable prognostic factor for overall survival in NSCLC. Further, never smoking status was associated with improved overall survival in Japanese, but not in Caucasian patients [44]. Unlike some of the aforementioned studies, our study did not show any benefit from smoking cessation in early stage, and only modest benefit in advanced stage NSCLC. The difference is likely because of the predominantly Caucasian, male population in our study as well as possibly related to the ethnic and genetic differences in the study population. Being a retrospective study, the smoking intensity and duration as well as time duration between cessation of smoking and the development of NSCLC could not be assessed. These differences in definition of smoking status could also account for the differences in the study results. Many patients did not receive any therapy in the present study, but the reason for this decision could not be ascertained. However, we do not believe that this could have affected our results as treatment was adjusted for in the final statistical model. Despite these limitations, this is a very large cohort of NSCLC patients, who were treated within a single payer system with equitable access to healthcare. The duration of smoking increased lung cancer death rate more strongly than the intensity of smoking [45]. Early onset of smoking increases the risk of lung cancer because of increased duration of smoking as well as possibly increased susceptibility during a critical period of development [46]. Previous studies have shown that the benefits of smoking cessation on lung cancer outcomes are greater when accomplished at a younger ages [47, 48]. Taken together with the results of our study, primary prevention of smoking cessation is more likely to be meaningful than efforts on smoking cessation after the diagnosis of NSCLC.
Conclusions In conclusion, our study shows that current smokers were 6 years younger than never smokers at diagnosis of NSCLC. Although current smoking was associated with worse prognosis, especially in stages III and IV, the impact of smoking status on overall survival was modest, at least in Caucasian men. Acknowledgments The facilities of the VA-Nebraska Western Iowa Health Care System were used during the course of this study. Conflict of interest There are no conflicts of interest associated with the contents of this manuscript.
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