Original Article
Smoking History Predicts for Increased Risk of Second Primary Lung Cancer: A Comprehensive Analysis John M. Boyle, MD1; Daniel J. Tandberg, MD1; Junzo P. Chino, MD1; Thomas A. D’Amico, MD2; Neal E. Ready, MD, PhD3; and Chris R. Kelsey, MD1
BACKGROUND: Tobacco use is the most important risk factor for the development of lung cancer. The objective of the current study was to determine the effect of smoking on the development of second primary lung cancers (SPLCs) and other clinical outcomes after surgery for non-small cell lung cancer (NSCLC). METHODS: All patients who underwent surgery for NSCLC at the study institution from 1995 through 2008 were identified. Rates of SPLC were analyzed based on smoking status and pack-year exposure. Multivariate analysis was performed to determine risk factors for SPLC. Overall survival, local control, distant metastases, and postoperative mortality were also examined. RESULTS: A total of 1484 patients were identified, including 98 never-smokers. The incidence of SPLC at 3 years, 5 years, and 8 years was 5%, 8%, and 16%, respectively. Only 1 never-smoker developed an SPLC. On multivariate analysis, which was restricted to ever-smokers with pack-years as a continuous variable, smoking history was found to be the only independent risk factor for SPLC (hazard ratio, 1.08; 95% confidence interval, 1.02-1.16 [P 5.031]), corresponding to an 8% increased risk per 10 packyear exposure. There were no differences in rates of local control or distant metastases based on smoking status. There was a trend toward lower postoperative mortality in never-smokers compared with ever-smokers (0% vs 3.3%; P 5.069). Overall survival was found to be significantly worse for current smokers compared with former and never-smokers. CONCLUSIONS: SPLCs are rare in never-smokers. Increasing tobacco exposure is associated with a higher risk of SPLC in patients with a history of smoking. Current smokers have an increased risk of mortality whereas former and never-smokers have comparable survival. Cancer 2015;121:598-604. C 2014 American Cancer Society. V KEYWORDS: second primary lung cancer, lung cancer, smoking, survival, smoking cessation.
INTRODUCTION Lung cancer is the third most common malignancy in the United States, with a projected 224,210 new cases expected in 2014. It is the number one cause of cancer death, with an estimated 159,260 deaths expected to occur during the same time period.1 Tobacco use, primarily through cigarette smoking, has been established as the most important risk factor for the development of lung cancer, with approximately 90% of cases linked to smoking.2 Smoking history has also been associated with diagnosis at a later stage,3 increased operative mortality,4,5 higher rates of local disease recurrence,6 and worse long-term survival.6-10 However, to the best of our knowledge, not all studies have confirmed the aforementioned observations. For example, one study found that although smoking history predicted a decline in performance status after surgical management, it had no predictive value for long-term survival.11 Similarly, another large study found that after accounting for covariates and medical comorbidities, smoking history had no effect on postoperative mortality or overall survival (OS).12 These discrepancies in the literature create ambiguity regarding the effect of smoking on outcomes for patients undergoing surgical management for lung cancer, particularly in terms of OS. Among survivors of non-small cell lung cancer (NSCLC), there remains a substantial risk of developing a second primary lung cancer (SPLC), with an estimated annual risk of 1% to 2%, corresponding to an absolute risk of 13% to 20% at 6 to 8 years.13-16 There are a paucity of data concerning risk factors for the development of SPLC in the available literature13,16-21 and first principles would implicate smoking history as a risk factor. Furthermore, the risk of SPLC in neversmokers, who comprise an increasing percentage of lung cancer cases, requires further investigation. In an effort to further
Corresponding author: John M. Boyle, MD, Department of Radiation Oncology, Duke University Medical Center, DUMC Box 3085, Durham, NC 27710; Fax: (919) 668-7345; [email protected] 1 Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina; 2Division of Cardiothoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina; 3Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Presented at the 56th Annual Meeting of the American Society of Radiation Oncology; September 14-17, 2014; San Francisco, CA. DOI: 10.1002/cncr.29095, Received: August 23, 2014; Revised: September 10, 2014; Accepted: September 12, 2014, Published online October 3, 2014 in Wiley Online Library (wileyonlinelibrary.com)
598
Cancer
February 15, 2015
Smoking and Second Primary Lung Cancer/Boyle et al
elucidate and quantify the association between smoking, the development of SPLC, and other clinical outcomes, the current analysis was undertaken.
MATERIALS AND METHODS The current study was approved by the Institutional Review Board committee (study PRO000021301). The study population included all patients who underwent surgery with definitive intent for a de novo diagnosis of NSCLC, with or without adjuvant chemotherapy and/or radiotherapy, at Duke University Medical Center between 1995 and 2009. Patients presenting with synchronous primary tumors were excluded. Although follow-up was not standardized, patients were generally followed with computed tomography (CT) imaging every 4 months to 6 months after surgery for the first 2 to 3 years, and then annually thereafter. The primary outcome of interest was the rate of SPLC. Other outcomes evaluated included OS, local control, distant metastases, and postoperative mortality, defined as death within 30 days of surgery or during the initial hospitalization. Baseline clinical and pathologic factors, in addition to smoking history, were assessed for prognostic significance. Specifically, we collected detailed information regarding tobacco exposure, including daily cigarette use, duration of smoking history, and quit date if applicable. Smoking history was quantified in pack-years, calculated by multiplying the number of packs of cigarettes smoked per day by the number of years smoked. Patients were stratified into never-smokers, former smokers who quit >5 years before surgery, former smokers who quit
Smoking History Predicts for Increased Risk of Second Primary Lung Cancer: A Comprehensive Analysis John M. Boyle, MD1; Daniel J. Tandberg, MD1; Junzo P. Chino, MD1; Thomas A. D’Amico, MD2; Neal E. Ready, MD, PhD3; and Chris R. Kelsey, MD1
BACKGROUND: Tobacco use is the most important risk factor for the development of lung cancer. The objective of the current study was to determine the effect of smoking on the development of second primary lung cancers (SPLCs) and other clinical outcomes after surgery for non-small cell lung cancer (NSCLC). METHODS: All patients who underwent surgery for NSCLC at the study institution from 1995 through 2008 were identified. Rates of SPLC were analyzed based on smoking status and pack-year exposure. Multivariate analysis was performed to determine risk factors for SPLC. Overall survival, local control, distant metastases, and postoperative mortality were also examined. RESULTS: A total of 1484 patients were identified, including 98 never-smokers. The incidence of SPLC at 3 years, 5 years, and 8 years was 5%, 8%, and 16%, respectively. Only 1 never-smoker developed an SPLC. On multivariate analysis, which was restricted to ever-smokers with pack-years as a continuous variable, smoking history was found to be the only independent risk factor for SPLC (hazard ratio, 1.08; 95% confidence interval, 1.02-1.16 [P 5.031]), corresponding to an 8% increased risk per 10 packyear exposure. There were no differences in rates of local control or distant metastases based on smoking status. There was a trend toward lower postoperative mortality in never-smokers compared with ever-smokers (0% vs 3.3%; P 5.069). Overall survival was found to be significantly worse for current smokers compared with former and never-smokers. CONCLUSIONS: SPLCs are rare in never-smokers. Increasing tobacco exposure is associated with a higher risk of SPLC in patients with a history of smoking. Current smokers have an increased risk of mortality whereas former and never-smokers have comparable survival. Cancer 2015;121:598-604. C 2014 American Cancer Society. V KEYWORDS: second primary lung cancer, lung cancer, smoking, survival, smoking cessation.
INTRODUCTION Lung cancer is the third most common malignancy in the United States, with a projected 224,210 new cases expected in 2014. It is the number one cause of cancer death, with an estimated 159,260 deaths expected to occur during the same time period.1 Tobacco use, primarily through cigarette smoking, has been established as the most important risk factor for the development of lung cancer, with approximately 90% of cases linked to smoking.2 Smoking history has also been associated with diagnosis at a later stage,3 increased operative mortality,4,5 higher rates of local disease recurrence,6 and worse long-term survival.6-10 However, to the best of our knowledge, not all studies have confirmed the aforementioned observations. For example, one study found that although smoking history predicted a decline in performance status after surgical management, it had no predictive value for long-term survival.11 Similarly, another large study found that after accounting for covariates and medical comorbidities, smoking history had no effect on postoperative mortality or overall survival (OS).12 These discrepancies in the literature create ambiguity regarding the effect of smoking on outcomes for patients undergoing surgical management for lung cancer, particularly in terms of OS. Among survivors of non-small cell lung cancer (NSCLC), there remains a substantial risk of developing a second primary lung cancer (SPLC), with an estimated annual risk of 1% to 2%, corresponding to an absolute risk of 13% to 20% at 6 to 8 years.13-16 There are a paucity of data concerning risk factors for the development of SPLC in the available literature13,16-21 and first principles would implicate smoking history as a risk factor. Furthermore, the risk of SPLC in neversmokers, who comprise an increasing percentage of lung cancer cases, requires further investigation. In an effort to further
Corresponding author: John M. Boyle, MD, Department of Radiation Oncology, Duke University Medical Center, DUMC Box 3085, Durham, NC 27710; Fax: (919) 668-7345; [email protected] 1 Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina; 2Division of Cardiothoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina; 3Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Presented at the 56th Annual Meeting of the American Society of Radiation Oncology; September 14-17, 2014; San Francisco, CA. DOI: 10.1002/cncr.29095, Received: August 23, 2014; Revised: September 10, 2014; Accepted: September 12, 2014, Published online October 3, 2014 in Wiley Online Library (wileyonlinelibrary.com)
598
Cancer
February 15, 2015
Smoking and Second Primary Lung Cancer/Boyle et al
elucidate and quantify the association between smoking, the development of SPLC, and other clinical outcomes, the current analysis was undertaken.
MATERIALS AND METHODS The current study was approved by the Institutional Review Board committee (study PRO000021301). The study population included all patients who underwent surgery with definitive intent for a de novo diagnosis of NSCLC, with or without adjuvant chemotherapy and/or radiotherapy, at Duke University Medical Center between 1995 and 2009. Patients presenting with synchronous primary tumors were excluded. Although follow-up was not standardized, patients were generally followed with computed tomography (CT) imaging every 4 months to 6 months after surgery for the first 2 to 3 years, and then annually thereafter. The primary outcome of interest was the rate of SPLC. Other outcomes evaluated included OS, local control, distant metastases, and postoperative mortality, defined as death within 30 days of surgery or during the initial hospitalization. Baseline clinical and pathologic factors, in addition to smoking history, were assessed for prognostic significance. Specifically, we collected detailed information regarding tobacco exposure, including daily cigarette use, duration of smoking history, and quit date if applicable. Smoking history was quantified in pack-years, calculated by multiplying the number of packs of cigarettes smoked per day by the number of years smoked. Patients were stratified into never-smokers, former smokers who quit >5 years before surgery, former smokers who quit
