Ann Thorac Surg 2006;81:1189-1193
© 2006 The Society of Thoracic Surgeons
Original article: General thoracic
Smoking Status as a Prognostic Factor in Patients with Stage I Pulmonary Adenocarcinoma
Ichiro Yoshino, MD, PhD
*
,
Daigo Kawano, MD,
Taro Oba, MD,
Koji Yamazaki, MD, PhD,
Takuro Kometani, MD,
Yoshihiko Maehara, MD, PhD
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Accepted for publication September 1, 2005.
* Address correspondence to Dr Yoshino, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan (Email: iyoshino{at}surg2.med.kyushu-u.ac.jp).
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Abstract
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BACKGROUND: Cigarette smoking is a well-known risk factor for lung carcinogenesis; however, its effect on tumor progression is still unclear. We herein investigated the influence of cigarette smoking on postoperative prognosis in patients with non-small cell lung cancer (NSCLC).
METHODS: The postoperative survival and pathologic stage of 999 patients with NSCLC who underwent a curative resection were retrospectively investigated in relation to the pack-year index (PYI).
RESULTS: Adenocarcinoma patients with a PYI of less than 20 showed a more favorable prognosis than those with a PYI of 20 or more, whereas no difference was observed among the subgroups of squamous cell carcinoma patients. In adenocarcinoma, stage I disease was a significantly larger population in never-smokers than in smokers. A multivariate analysis revealed that the smoking habit (yes or no) and stage (IA or IB), but not gender or histologic subtype (bronchioloalveolar type or not), are independent prognostic factors in stage I adenocarcinoma with hazard ratios of 1.8 and 2.3, respectively.
CONCLUSIONS: The smoking status is a significant prognostic factor for stage I pulmonary adenocarcinoma.
Lung cancer remains, in the world, a leading cause of cancer death. Tobacco smoke-derived toxic compounds such as aromatic hydrocarbons have been proved to cause lung carcinogenesis [1, 2], and the increasing mortality due to lung cancer is significantly associated with the increase in the number of smokers [3]. To decrease lung cancer mortality, preventing people from smoking is thought to be the best way [4] to address this problem; however, the population of smokers worldwide continues to increase [5]. Another important issue is whether tobacco smoking affects the progression of lung cancer. Benzo[a]pyrene (B[a]P) is known to induce ligands of the epidermal growth factor receptor [6] and to activate NF
B [7], which thus further activates various molecules concerning inflammation, proliferation, and migration [8]. Therefore, tobacco smoke-derived aromatic hydrocarbon compounds have been suggested to modulate cancer progression. We recently reported that several prognostic factors of non-small cell lung cancer (NSCLC), such as skp2 [9], macrophage migration inhibitory factor [10], and type II hexokinase [11] expression, were positively associated with the degree of tobacco smoking. We therefore speculate that the smoking status influences the survival of NSCLC patients.
Recently, Nordquist and colleagues [12] reported that smokers showed a significantly unfavorable prognosis with only 16% of 5-year cancer-free survival rate in comparison with a 23% 5-year cancer-free survival rate in never-smokers for lung adenocarcinoma. On the other hand, Toh and colleagues [13] reported no statistical difference in the survival between never-smokers and smokers with advanced NSCLC, although the therapeutic response was better in never-smokers than in smokers.
In this study, to clarify the effect of cigarette smoking on postoperative prognosis of NSCLC, we retrospectively investigated the relationship between cigarette smoking and survival after curative surgery.
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Material and Methods
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Patients
The medical records of 999 patients with NSCLC who underwent a curative resection in Kyushu University Hospital were thoroughly reviewed for gender, pack-year index (PYI), pathologic stage, and survival. The patients comprised 339 squamous cell carcinomas and 660 adenocarcinomas, which were classified according to World Health Organization criteria [14]. The stage of all patients was pathologically defined according to the revised international staging system [15]. The PYI was defined as the number of cigarette packs (20 cigarettes per pack) consumed a day multiplied by years. In this study, "smokers" was defined to include both current smokers and ex-smokers who had ceased within 10 years before surgery. Patients were classified to four subgroups according to the PYI as never-smoker, less than 20 (1
, <20), less than 50 (20, <50), and 50 or more (50).
Follow-Up of Postoperative Patients
Just before or after surgery, almost all patients were directed to cease smoking. A routine check-up with a physical examination, blood cell counts, serum chemistry, serum tumor markers including carcinoembryonic antigen and cytokeratin fragment 19, and chest x-ray was performed in an outpatient clinic four times a year for the first 3 years, and thereafter twice a year. Computed tomography and bone scans were performed twice a year for the first 3 years, and thereafter at least once a year. When a relapse was diagnosed, radiation or systemic chemotherapy was performed if feasible.
Statistics
The relationship between the proportion of each stage and the subpopulation divided by PYI was analyzed by the 
2 test. The survival curves of subgroups were illustrated by the Kaplan-Meier test, and differences among the curves were analyzed by the log-rank test.
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Results
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Clinical Analysis of the Relationship Between the Pack-Year Index and the Prognosis-Proportion of Pathologic Stage in Squamous Cell Carcinoma
In squamous cell carcinomas, the survival curves showed there was no significant difference among the subgroups divided according to a PYI (Fig 1A). When the proportions of the various pathologic stages among the four subgroups according to the PYI were analyzed, no clear trends between the PYI levels and proportion of the various stages were observed (Fig 1B).
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Fig 1. The relationship between the pack-year index (PYI) and the prognosis-proportion of pathologic stage in squamous cell carcinoma. (A) Survival curves of subgroups classified by smoking status. Patients with squamous cell carcinoma were classified to four subgroups according to their PYI, and the respective survival curves were statistically analyzed. (B) The proportion and number of patients with squamous cell carcinoma in the subgroups according to PYI were shown.
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Clinical Analysis of the Relationship Between the Pack-Year Index and the Prognosis-Proportion of Pathologic Stage in Adenocarcinoma
In the case of adenocarcinomas, never-smokers and smokers with a PYI score of less than 20 showed a significantly more favorable survival than smokers with a PYI score of 20 or more (Fig 2A). Never-smokers demonstrated a larger proportion of stage I cases, and the proportion was lower for the smoker subgroups with a PYI score of 20 or more, and this tendency was statistically significant (p = 0.0273) (Fig 2B). Based on the results, the impact of cigarette smoking on the prognosis of adenocarcinomas was thus suggested to show a significant difference in the proportion of early stage cases.
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Fig 2. The relationship between the pack-year index (PYI) and the prognosis-proportion of pathologic stage in adenocarcinoma. (A) Survival curves of subgroups classified by smoking status. Patients with adenocarcinoma were classified to four subgroups according to their PYI, and the respective survival curves were statistically analyzed. (B) The proportion and number of patients with adenocarcinoma in the subgroups according to PYI score were shown.
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Further Analysis of the Significance of Smoking Habit on the Prognosis of Adenocarcinoma Cases
Next, the survival of the subgroups according to the PYI was compared at each stage of adenocarcinoma (Table 1). A difference among the various PYI subgroups was observed only for stage I (p = 0.0001, Fig 2B), whereas such difference was not observed in stage II and III/IV. Since the smoking status is suggested to be a prognostic factor for stage I adenocarcinoma, a multivariate analysis was performed. Since smoking is generally more popular for males than for females, gender as well as stage was also included in the analysis. According to these results, the smoking status (yes or no) and pathologic stage (IA or IB) but not gender or histologic subtype (bronchioloalveolar type or not) were revealed to be prognostic factors in stage I adenocarcinomas (Table 2). The hazard ratio of smokers to never-smokers was 1.8 (p = 0.0461) while that for stage IB to IA was 2.3 (p < 0.0001). These data suggested that cigarette smoking not only causes carcinogenesis but it also affects the progression of lung cancer.
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Comment
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In this study we showed a significantly smaller population of early stage disease in heavy smokers than in never-smokers, and a survival benefit in never-smokers was observed in patients with adenocarcinoma. These findings thus imply that tobacco smoke modulates cancer progression and/or that tobacco-related lung adenocarcinoma shows an aggressive behavior. Wu and colleagues [16] also demonstrated that never-smokers showed a significantly better cancer-specific survival rate at 5 years after surgery (72.1 %) in comparison with smokers (50.7 %), although the cell-type or stage was not taken into account in that analysis. A multivariate analysis of the present study, however, revealed the smoking status (never-smoker versus smoker) and the pathologic stage (IA vs IB) to be independent prognostic factors, but not gender (male versus female). In squamous cell carcinomas, the reason why there was no difference in survival between subgroups according to the PYI score is unknown. Squamous cell carcinoma is the most significantly associated with cigarette smoking or environmental factors among all histologic types of lung cancers. Therefore, in adenocarcinoma even never-smokers might be exposed to other environmental factors such as air pollution, asbestos, or [passive smoke 17, 18; however, the patients' history of exposure to such factors could not be examined in this study.
We also showed a significant difference in survival between heavy smokers and never-smokers to be observed only in stage I adenocarcinoma. Toh and colleagues [13] reported the degree of tobacco smoking not to influence the prognosis of advanced NSCLC although the therapeutic response was significantly affected by smoking. In our previous study [19], the degree of tobacco smoking was also revealed not to be a prognostic factor in the cohort of the total operative NSCLC. Tobacco-derived toxic compounds may promote invasion or metastasis; however, once metastasizing to regional nodes or distant organs, the modulating effects of smoking on tumor behavior and patient survival did not show any influence.
Recently, several types of somatic mutations of epidermal growth factor receptor (EGFR) have been identified and shown to be prevalently associated in never-smoker adenocarcinoma, Japanese ethnicity, and sensitivity to tyrosine kinase inhibitors [20, 21]. Adenocarcinomas with such features may be an entity other than adenocarcinoma in smokers. In the cohort of this study the theoretical proportion of patients possessing a somatic mutation in the gene of EGFR in their adenocarcinoma cells might be approximately 32% [21]; however, whether such a population would have a favorable prognosis is still unknown. In 304 stage I adenocarcinomas of the present study, 34 patients with bronchioloalveolar carcinoma (BAC) were included. The BAC has been known to have a unique entity in light of its favor of local extension than distant spread and no linkage to smoking [22], although the prognosis of BAC is equivalent to other histologic types [23]. In this study, whether a histologic subtype is BAC or not is not a prognostic factor in stage I adenocarcinomas. Although no statistical significance was observed, respective 5-year survival rates of never-smokers and smokers with BAC were 80% and 60% in this study (data not shown). Adverse effect of smoking on the prognosis of BAC, however, is still to be elucidated.
In conclusion, the smoking status was found to be a significant prognostic factor for stage I lung adenocarcinoma.
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Abstract
Introduction
