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© 1999 American Society for Clinical Oncology Smoking Before Surgery Predicts Poor Long-Term Survival in Patients With Stage I Non–Small-Cell Lung CarcinomasFrom the Departments of Surgery and Pathology, Institute of Pulmonary Cancer Research, Chiba University School of Medicine, Chiba, Japan. Address reprint requests to Takehiko Fujisawa, MD, Department of Surgery, Institute of Pulmonary Cancer Research, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
PURPOSE: The majority of lung carcinoma patients requiring resection have smoking habits prior to surgical treatment, and the correlation of smoking with postoperative complications is well known. However, few studies have investigated the correlation between long-term survival and cigarette smoking in patients with primary, resected lung carcinoma. We analyzed the relationship between clinical factors, including cigarette smoking before surgery, and 10-year survival in stage I non–small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: Cigarette smoking habit and other factors influencing either the overall survival or the disease-specific survival rates of patients with stage I primary, resected NSCLC were evaluated according to the Cox proportional hazards model using a total of 369 patients with stage I–NSCLC. RESULTS: Comparison of the cause of death in patients with 30 or more pack-years and patients with less than 30 pack-years showed significant differences in the prevalence of recurrent disease and onset of nonmalignant disease. Multivariate analysis demonstrated significant correlations between overall survival and age and pack-years. Disease-specific survival showed significant correlations with age, tumor classification, and visceral pleural invasion. CONCLUSION: Smoking pack-years is an important clinical prognostic factor in evaluating overall long-term survival in patients with stage I primary, resected NSCLC.
RESECTION IS ACCEPTED to be the definitive therapy for primary lung carcinomas. Five-year survival rates are closely correlated with disease stage, so that for stage I patients with complete resection, the 5-year survival rate is 60% to 70%, which is generally recognized as an acceptable result.1-10 However, the cause of death among patients with stage I lung carcinoma included not only disease recurrence but also nonrecurrent disease. Analyses of death by nonrecurrent diseases are important to further improve the long-term survival in patients with stage I lung carcinomas. Direct and indirect tobacco smoking are a leading cause of lung carcinoma. The majority of lung carcinoma patients undergoing resection have smoking habits before surgical treatment, and the correlation of smoking with postoperative complications has been reported.11 However, few studies have been reported on the correlation between long-term survival and cigarette smoking in patients with primary, resected lung carcinoma.12-14 In this article, we analyze the relationship between clinical factors, including cigarette smoking before surgery, and 10-year survival in stage I non–small-cell lung carcinoma (NSCLC) with complete resection.
Patients The study group comprised 375 patients who underwent complete resection during the period from 1981 to 1993 at our institution and were confirmed as having stage I NSCLC by pathologic examination of the resected materials. Six patients (five with squamous cell carcinomas and one with adenocarcinoma, all men) who died within 1 month after surgery were excluded from survival analyses. The cancer histologic types included 147 squamous cell carcinomas, 216 adenocarcinomas, and 12 large-cell carcinomas. The patient group consisted of 124 women and 251 men who ranged in age from 34 to 87 years (mean age, 62.2 years). Pathologic tumor-node-metastasis (TNM) classification showed that there were 210 T1N0 and 163 T2N0 tumors. Histologic type, differentiation, TNM classification, and resectability were classified according to the criteria of the American Joint Committee on Cancer15 and the general rules for clinical and pathologic recording of lung cancer described by the Japan Lung Cancer Society.16 Cellular differentiation was graded as well, moderate, or poor for those patients with non–large-cell histology. Large-cell carcinoma was classified as undifferentiated.17 History of cigarette smoking was evaluated according to the description given in the patient's chart. When distant or local disease recurrence developed, any treatment was permitted. For the first year after surgery, patients were followed up every month, then every 3 months from 2 to 5 years after surgery and every 6 months thereafter. Additional follow-up was conducted (and survival was determined) by telephone or postcard contact with the patient. Postoperative smoking status was evaluated by telephone contact with the patient or family members. Cause of death was confirmed by telephone contact with the doctor who followed the patient. At the last follow-up, for overall survival curves, an observation was censored if the patient was alive; for disease-specific curves, data were censored if the patient was alive or had died from a cause other than NSCLC. All but two patients were followed up at the end of 1995. These two patients showed no clinical signs of recurrence until postoperative days 785 and 1053, and are noted as censored observations in the current study.
Survival Rate and Statistical Analysis
Cause of Death and Type of Recurrence Six patients died within 1 month after surgery (1.6% of 375 patients) because of pneumonias (two patients), bronchial fistulas (two patients), and heart infarction (two patients). All were male and ranged in age from 48 years to 80 years (mean age, 66.5 years). Cigarette smoking ranged from 22.5 to 90 pack-years (mean, 58.25 pack-years), and histologic types were all squamous cell carcinomas, except for one adenocarcinoma. Of 369 patients used for survival analysis, 68 patients died from recurrent disease and 37 patients died from nonrecurrent diseases. The type of disease recurrence included local recurrence in four patients, distant metastases in 60 patients, and both in five patients. Nonrecurrent causes consisted of 13 second primary malignancies, including one lung, two stomach, and two kidney carcinomas. Respiratory insufficiencies caused by infection or emphysema accounted for 24 deaths. A comparison of cause of death between patients with 30 or more pack-years and patients with less than 30 pack-years showed a significant difference in the number of recurrent and nonmalignant diseases (Table 1).
Overall Survival
Disease-Specific Survival
Multivariate Analysis
Next, multivariate analysis of disease-specific survival was performed using the five clinical prognostic factors with significant differences in univariate analysis. Multivariate analysis demonstrated a significant correlation of disease-specific survival with age (P = .0296 and P = .0062), tumor classification (P = .0328), and visceral pleural invasion (P = .0078) and no significant correlation with sex and cigarette smoking (Table 5).
Relationship Between Postoperative Smoking Status and Outcome
Correlation Between Clinical Features and Smoking Pack-Years
Extensive studies have been carried out on survival rates in stage I NSCLC. Histologic type, tumor status, visceral pleural, and satellite lesions have been shown to be important prognostic factors.1-10 Furthermore, molecular and biologic markers, including tumor-associated antigens, aberrant gene expression, and enzyme, hormone and other biologic parameters, were also considered to be potential predictors of survival.20,21 However, cigarette smoking, one of the most important clinical factors in the occurrence of lung carcinoma, has not been included in the analysis on the duration of survival in patients with stage I NSCLC. Surgical treatment is the only curative modality for patients with NSCLC. However, the long-term survival rate in patients with stage I NSCLC is not completely satisfactory for two reasons: recurrent disease and nonrecurrent causes of death. Few studies have defined how cigarette smoking before surgical treatment relates to recurrent or nonrecurrent causes of postoperative death in stage I NSCLC. In this study, cigarette smoking pack-years was shown to be an independent prognostic factor for evaluating overall survival in patients with stage I NSCLC, in addition to age. However, in analyses of disease-specific survival of stage I NSCLC patients, tumor classification and visceral pleural invasion were independent prognostic factors but pack-years were not. We also found that the cause of death was not related to cigarette smoking restarted after surgery. These results suggest that cigarette smoking before surgery greatly influenced overall survival. This is the first study to demonstrate the significant correlation between cigarette smoking and long-term survival in stage I NSCLC patients. Dresler et al22 reported an excellent rate of smoking cessation both before surgery and long-term and higher recurrence rates in patients with the shorter smoking cessation period. However, their study did not obtain data on pathologic stage, and survival rates were not examined. Harpole et al14 reported a prognostic model of disease recurrence and death in stage I NSCLC using presentation, histopathology, oncoprotein expression, and smoking history, but they demonstrated no significant impact on cancer-specific survival. Cigarette smoking causes not only lung carcinoma but lung damage as well; therefore, the frequency of postoperative complications in respiratory organs is greater in patients with primary resected lung carcinoma who smoke heavily before surgery than in those who do not smoke heavily.11 In this study, we found that the number of nonmalignant and malignant causes of death were significantly greater in patients with primary resected stage I NSCLC with 30 or more pack-years of cigarette smoking compared with those with less than 30 pack-years of cigarette smoking. Cigarette smoking before surgery strongly influences both short-term survival and long-term survival and is an independent prognostic factor in stage I NSCLC. The mechanisms of how smoking habits influence prognosis are still unclear, but it is reported that smoking causes the decrease of systemic and local immunity in the airway.23-25 It is possible that the biologic nature of lung carcinomas in patients with 30 or more smoking pack-years is more malignant than that in patients with less than 30 smoking pack-years, and may be related to gene mutation caused by cigarette smoke. Thus, the biologic malignancy of the primary lesion and a decreased immune status of the airways could explain the higher disease recurrence and poorer prognosis in patients who are heavy smokers. Most lung cancers are also associated with multiple genetic alterations and the presence of preneoplastic bronchial lesions. Wistuba et al26 reported that genetic changes similar to those found in lung cancers could be detected in the nonmalignant bronchial epithelium of current and former smokers and might persist for many years after smoking cessation. Mao et al27 reported clonal genetic alterations in the respiratory epithelium of current and former smokers. These reports support our data showing a trend of the higher occurrence rate of second malignancies in heavy smokers. The survival rates of T1N0 and T2N0 carcinomas are quite different; therefore, it is questionable whether T1N0 and T2N0 carcinomas should be included in the same stage. The TNM classification system, decided by the International Union Against Cancer in 1996, included T1N0 in stage IA and T2N0 in stage IB. In this study, we observed that the tumor classification in overall survival was not an independent prognostic factor in stage I NSCLC by multivariate analysis, which indicates that the T1N0 and T2N0 classifications are homogeneous. However, in disease-specific survival, tumor classification is an independent prognostic factor by multivariate analysis, which supports the new TNM classification in stage I lung carcinoma proposed by the International Union Against Cancer. In conclusion, smoking pack-years is considered to be an important clinical prognostic factor in evaluating overall long-term survival.
Supported in part by Grants-in-Aid for Scientific Research no. 05453481 and 11357012 from the Ministry of Education, Science, Sports, and Culture of Japan
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Dresler CM, Bailey M, Roper CR, et al: Smoking cessation and lung cancer resection. Chest 110:1199-1202, 1996 23. Thomas RW, Holt RG, Keast D: Development of alterations in the primary immune response of mice by exposure to fresh cigarette smoke. Int Arch Allergy 46:481-486, 1974 24. Daniele RP, Dauber JH, Altose MD, et al: Lymphocytes studies in asymptomatic cigarette smokers. Am Rev Respir Dis 116:997-1005, 1977[Medline] 25. Chalmer J, Holt PG, Keast D: Cell-mediated immune responses to transplanted tumors in mice chronically exposed to cigarette smoke. J Natl Cancer Inst 55:1129-1134, 1975
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Mao L, Lee JS, Kurie JM, et al: Clonal genetic alterations in the lung of current and former smokers. J Natl Cancer Inst 89:857-862, 1997 Submitted July 7, 1998; accepted March 2, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
