Smoking cause lung cancer

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.

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

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Lung cancer is one of the most common malignancies in the world. (1) In Singapore, it is the most frequent cancer in men, and ranks third most common 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 States (4) 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 populations, 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 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 States (15) 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, studies (18,19) 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 N SCLC 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 non-smoker was defined as one who had never smoked before or smoked too little in the past to be regarded as an ex-smoker.

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 [greater than or equal to] 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

[chi square] 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 X [chi square] 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 than the smokers (mean age difference, -7.94 years; 95% confidence interval [CI], -10.7 to -5.18; p < 0.001).

Survival Data