Cancer Chemother Pharmacol (2014) 73:1217–1225 DOI 10.1007/s00280-014-2458-0
Original Article
Safety and efficacy of gemcitabine or pemetrexed in combination with a platinum in patients with non‑small‑cell lung cancer and prior interstitial lung disease Moon Ki Choi · Jung Yong Hong · Wonjin Chang · Moonjin Kim · Sungmin Kim · Hyun Ae Jung · Su Jin Lee · Silvia Park · Man Pyo Chung · Jong‑Mu Sun · Keunchil Park · Myung‑Ju Ahn · Jin Seok Ahn
Received: 12 September 2013 / Accepted: 20 March 2014 / Published online: 3 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The incidence of lung cancer in patients with interstitial lung disease (ILD) is higher than in the general population; however, the clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with ILD remain unclear. This study was conducted to elucidate the safety and efficacy of palliative chemotherapy with gemcitabine or pemetrexed, both in combination with a platinum agent in NSCLC patients with ILD. Patients and methods Patients with advanced or recurrent NSCLC and ILD who received gemcitabine or pemetrexed in combination with a platinum agent as first-line chemotherapy were retrospectively analyzed. Clinical outcomes, including response rate, overall survival (OS), and progression-free survival (PFS), in addition to the acute exacerbation of ILD after chemotherapy were investigated. Results Between January 2007 and December 2011, 52 patients were analyzed. The median age at chemotherapy was 67. Thirty-two patients (61.5 %) had adenocarcinoma histology. With respect to the types of ILD, idiopathic interstitial pneumonia (IIP) and non-IIP were observed in 42 (80.8 %) and 10 (19.2 %) patients, respectively. The FEV1 level was less than 80 % of the predicted value in 15 of the 41 patients in whom it was measured. The overall response M. K. Choi · J. Y. Hong · W. Chang · M. Kim · S. Kim · H. A. Jung · S. J. Lee · S. Park · J.-M. Sun · K. Park · M.-J. Ahn · J. S. Ahn (*) Division of Hematology‑Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon‑dong, Gangnam‑gu, Seoul 135‑710, Korea e-mail: [email protected] M. P. Chung Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
rate was 42.3 % (95 % CI 28.8–55.9), and the median PFS was 5.4 months (95 % CI 4.6–6.2). The median OS was 7.9 months (95 % CI 5.5–10.3), and the 1-year survival rate was 31.7 % (95 % CI 19.0–44.4). Eight patients (15.4 %) died within 3 months of first-line chemotherapy. Multivariate analysis demonstrated that a heavy smoking history (40 or more pack-year smoking history) was an independent adverse prognostic factor for OS. An acute exacerbation of ILD (AE-ILD) caused by first-line chemotherapy was noted in 5.8 % of patients. Conclusion Our results suggest that gemcitabine or pemetrexed in combination with platinum agents could be a feasible option for advanced NSCLC with ILD with some risk of AE-ILD or early death. To establish the efficacy of palliative chemotherapy for patients with NSCLC and ILD, further well-controlled prospective studies are needed. Keywords Non-small-cell lung cancer · Interstitial lung disease · Chemotherapy · Platinum doublet
Introduction Interstitial lung disease (ILD) represents a heterogeneous group of disorders with either known or unknown etiology that have differing pathogeneses and prognoses. Lung cancer, which is the leading cause of cancer-related death worldwide, is mainly attributed to cigarette smoking and exposure to inhaled carcinogens. The incidence of lung cancer in patients with ILD is higher than in the general population [1, 2]. Furthermore, it has been noted that ILD and cancer have common pathogenetic mechanisms such as inflammation, coagulation, dysregulated apoptosis, focal hypoxia, and the accumulation of myofibroblasts as well as extracellular matrix accumulation [3, 4].
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It has been reported that ILD patients can experience acute exacerbations, without a clinically apparent cause, characterized by rapidly progressive and severe respiratory failure with new lung opacities and pathological lesions of diffuse alveolar damage [5]. Moreover, in the case of lung cancer combined with ILD, acute exacerbation frequently occurs after anticancer treatment. This has raised the question of whether anticancer treatments, especially chemotherapy, might cause an acute exacerbation. There have only been a few reports focusing on the exacerbation of ILD associated with chemotherapy in patients with lung cancer. Recently, in two retrospective studies, combination chemotherapy with carboplatin and weekly paclitaxel was reported to cause an acute exacerbation of ILD in four out of 15 patients (27 %) with NSCLC, and in only one out of 18 patients (5.6 %) with ILD [6, 7]. On the other hand, Okuda et al. [8] reported that combination chemotherapy with vinorelbine and platinum agents caused an acute exacerbation of ILD in three out of 19 patients (15.8 %) with advanced NSCLC and ILD. To date, no large-scale prospective studies have demonstrated the efficacy of chemotherapy in terms of survival improvement in NSCLC patients with ILD, and only a few retrospective analyses evaluating the clinical effects of chemotherapy for NSCLC with ILD are available [6–9]. At present, there is neither evidence nor consensus as to whether palliative chemotherapy is an appropriate approach for NSCLC with ILD. In this context, we conducted a retrospective analysis of palliative chemotherapy with gemcitabine or pemetrexed, both in combination with a platinum agent, to assess its efficacy and tolerability in NSCLC patients with ILD.
seventeen patients (11.5 %) were managed with best supportive care only because of the patient’s request (n = 7), ineligibility for intensive treatment as judged by the treating physician (n = 5) or death before initiation of treatment (n = 4). The cause was not described in one patient. The clinical parameters analyzed at the time of palliative chemotherapy included age, sex, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status (PS), stage at diagnosis, histologic type, prior treatment before palliative chemotherapy, chemotherapy regimen, pulmonary function testing, and other laboratory results. ILD was diagnosed based on pathologic findings or evidence from a conventional CT or high resolution CT (HRCT) of the chest such as reticular opacities, traction bronchiectasis, ground-glass opacities, or honeycombing. ILD was classified into two types, either idiopathic interstitial pneumonia (IIP) or non-IIP. The latter type included ILD associated with pneumoconiosis, collagen vascular disease, and other syndromes.
Methods
Definition of acute exacerbation of ILD (AE‑ILD)
Patients
AE-ILD was diagnosed if the following criteria were satisfied: (1) subjective worsening of dyspnea within the past month; (2) new ground-glass opacities or consolidation on chest radiography or HRCT; (3) hypoxemia with a decline of 10 mmHg in partial pressure of oxygen from the previous level; and (4) no evidence of infection, pulmonary embolism, congestive heart failure, or pneumothorax as a cause of acute worsening.
We retrospectively reviewed the medical records of NSCLC patients with ILD who were diagnosed at Samsung Medical Center, Korea between January 2007 and December 2011. This retrospective analysis was approved by the Samsung Medical Center Institutional Review Board. A total of 148 NSCLC patients with ILD were identified. Among them, 61 (41.2 %) patients received palliative chemotherapy. Of these, 52 patients were treated with gemcitabine or pemetrexed, both in combination with a platinum agent, and nine patients received other regimens such as taxane plus a platinum agent (n = 4), gefitinib (n = 3) and etoposide plus a platinum agent (n = 2). Forty-nine (33.1 %) patients underwent curative surgery with or without adjuvant treatment, and 21 (14.2 %) patients received definitive radiotherapy with concurrent or sequential chemotherapy. The remaining
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Treatment Patients received gemcitabine at a dose of 1,000 mg/m2 on day 1 and 8 or pemetrexed at a dose of 500 mg/m2 on day 1, which was followed by carboplatin with an area under the curve (AUC) of 5.5 on day 1 or cisplatin at a dose of 70 mg/m2 on day 1. These agents were administered every 3 weeks. All patients received standard supportive care, as appropriate. Dose reduction, omission, and discontinuation of chemotherapy were based on the physician’s discretion. Treatment was continued until there were disease progression, unacceptable toxicity, or the patient refused further treatment.
Statistical analysis Treatment outcomes were estimated as overall response rate, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). Tumor response was determined according to RECIST 1.0. OS was defined as the time elapsed from the date of first-line chemotherapy to the date of death or last follow-up. PFS was defined as the time
Cancer Chemother Pharmacol (2014) 73:1217–1225
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Fig. 1 a Progression-free survival (PFS) and b overall survival (OS). The median PFS, MST, and 1-year survival rate were 5.4, 7.9 months, and 31.7 %, respectively
from the date of first-line chemotherapy to the date of disease progression or death from any cause. The period to the onset of acute exacerbation was calculated from the date of initial chemotherapy. Survival curves were generated using the Kaplan– Meier method, and the log-rank test was used to compare the survival curves. The clinicopathologic characteristics and response rates of first-line chemotherapy were compared between two groups using the chi-square test. To identify prognostic factors for survival, a Cox proportional hazards model was used for univariate and multivariate analyses. Significant prognostic variables in the univariate analysis for OS were included in the multivariate analysis. P > 0.05 was considered statistically significant (Fig. 1).
Results Patients’ characteristics Fifty-two NSCLC patients with ILD receiving palliative chemotherapy with a platinum agent plus gemcitabine or pemetrexed were included in this analysis. All but two patients had pathologically or cytologically proven advanced or recurrent NSCLC. Two patients did not have advanced or recurrent disease at the time of palliative chemotherapy because one refused surgery and the other was not suitable for surgery or RT. ILD was diagnosed either at the time of (n = 32) or before (n = 20) the diagnosis of lung cancer. Table 1 presents
the baseline characteristics of all patients. The median age at the time of first-line chemotherapy was 67 years (range 46–85), and the median ECOG PS was 1 (range 0–2). Seven patients were never-smokers. Of 45 smokers, 25 patients were 40 or more pack-year smokers. Thirty-two patients (61.5 %) had adenocarcinoma histology. As first-line chemotherapy, gemcitabine and a platinum agent were administered to 39 patients (75.0 %), and pemetrexed and a platinum agent were given to 13 patients (25.0 %). With respect to the type of ILD, IIP and non-IIP were observed in 42 (80.8 %) and 10 (19.2 %) patients, respectively. Of ten non-IIP patients, five had ILD associated with occupational or environmental exposure, mainly pneumoconiosis, and five had ILD associated with collagen vascular disease. Five patients (9.6 %) had pathologically confirmed ILD by surgical lung biopsy. Thirty-two patients (61.5 %) were diagnosed with ILD and lung cancer simultaneously, and 20 (39.5 %) were already diagnosed with ILD before the diagnosis of lung cancer. In the case of preexisting ILD, the median interval from the diagnosis of ILD to the diagnosis of lung cancer was 2.9 years (range 0.5–30). Clinical outcomes of palliative chemotherapy The median follow-up duration was 33.2 months (range 5.8–74.1). Among 52 patients, there were 22 (42.3 %) partial responses and 19 (36.5 %) patients with stable disease. Thus, the DCR was 78.8 %. Seven patients (13.5 %) showed progressive disease. The median PFS was
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Table 1 Patients characteristics
All patients n = 52 (%)
Gemcitabine group n = 39 (%)
Pemetrexed group n = 13 (%)
P value
Age Median (range) (years)
67 (46–85)
66 (46–76)
69 (55–85)
Male
45 (86.5)
35 (89.7)
10 (76.9)
Female
7 (13.5)
4 (10.3)
3 (23.1)
0–1
47 (90.4)
38 (97.4)
9 (69.2)
≥2
5 (9.6)
1 (2.6)
4 (30.8)
23 (59.0)
4 (30.8)
Sex
0.347
ECOG PS
0.011
Smoking status Current
0.160 27 (51.9)
Former
12 (30.8)
6 (46.2)
4 (10.3)
3 (23.1)
26 (50.0)
18 (46.2)
8 (61.5)
≥40
25 (48.1)
20 (51.3)
Not described
1 (1.9)
1 (2.6)
0
2 (3.8)
2 (5.1)
0
Never Smoking amount, pack-year
Original Article
Safety and efficacy of gemcitabine or pemetrexed in combination with a platinum in patients with non‑small‑cell lung cancer and prior interstitial lung disease Moon Ki Choi · Jung Yong Hong · Wonjin Chang · Moonjin Kim · Sungmin Kim · Hyun Ae Jung · Su Jin Lee · Silvia Park · Man Pyo Chung · Jong‑Mu Sun · Keunchil Park · Myung‑Ju Ahn · Jin Seok Ahn
Received: 12 September 2013 / Accepted: 20 March 2014 / Published online: 3 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The incidence of lung cancer in patients with interstitial lung disease (ILD) is higher than in the general population; however, the clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with ILD remain unclear. This study was conducted to elucidate the safety and efficacy of palliative chemotherapy with gemcitabine or pemetrexed, both in combination with a platinum agent in NSCLC patients with ILD. Patients and methods Patients with advanced or recurrent NSCLC and ILD who received gemcitabine or pemetrexed in combination with a platinum agent as first-line chemotherapy were retrospectively analyzed. Clinical outcomes, including response rate, overall survival (OS), and progression-free survival (PFS), in addition to the acute exacerbation of ILD after chemotherapy were investigated. Results Between January 2007 and December 2011, 52 patients were analyzed. The median age at chemotherapy was 67. Thirty-two patients (61.5 %) had adenocarcinoma histology. With respect to the types of ILD, idiopathic interstitial pneumonia (IIP) and non-IIP were observed in 42 (80.8 %) and 10 (19.2 %) patients, respectively. The FEV1 level was less than 80 % of the predicted value in 15 of the 41 patients in whom it was measured. The overall response M. K. Choi · J. Y. Hong · W. Chang · M. Kim · S. Kim · H. A. Jung · S. J. Lee · S. Park · J.-M. Sun · K. Park · M.-J. Ahn · J. S. Ahn (*) Division of Hematology‑Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon‑dong, Gangnam‑gu, Seoul 135‑710, Korea e-mail: [email protected] M. P. Chung Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
rate was 42.3 % (95 % CI 28.8–55.9), and the median PFS was 5.4 months (95 % CI 4.6–6.2). The median OS was 7.9 months (95 % CI 5.5–10.3), and the 1-year survival rate was 31.7 % (95 % CI 19.0–44.4). Eight patients (15.4 %) died within 3 months of first-line chemotherapy. Multivariate analysis demonstrated that a heavy smoking history (40 or more pack-year smoking history) was an independent adverse prognostic factor for OS. An acute exacerbation of ILD (AE-ILD) caused by first-line chemotherapy was noted in 5.8 % of patients. Conclusion Our results suggest that gemcitabine or pemetrexed in combination with platinum agents could be a feasible option for advanced NSCLC with ILD with some risk of AE-ILD or early death. To establish the efficacy of palliative chemotherapy for patients with NSCLC and ILD, further well-controlled prospective studies are needed. Keywords Non-small-cell lung cancer · Interstitial lung disease · Chemotherapy · Platinum doublet
Introduction Interstitial lung disease (ILD) represents a heterogeneous group of disorders with either known or unknown etiology that have differing pathogeneses and prognoses. Lung cancer, which is the leading cause of cancer-related death worldwide, is mainly attributed to cigarette smoking and exposure to inhaled carcinogens. The incidence of lung cancer in patients with ILD is higher than in the general population [1, 2]. Furthermore, it has been noted that ILD and cancer have common pathogenetic mechanisms such as inflammation, coagulation, dysregulated apoptosis, focal hypoxia, and the accumulation of myofibroblasts as well as extracellular matrix accumulation [3, 4].
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Cancer Chemother Pharmacol (2014) 73:1217–1225
It has been reported that ILD patients can experience acute exacerbations, without a clinically apparent cause, characterized by rapidly progressive and severe respiratory failure with new lung opacities and pathological lesions of diffuse alveolar damage [5]. Moreover, in the case of lung cancer combined with ILD, acute exacerbation frequently occurs after anticancer treatment. This has raised the question of whether anticancer treatments, especially chemotherapy, might cause an acute exacerbation. There have only been a few reports focusing on the exacerbation of ILD associated with chemotherapy in patients with lung cancer. Recently, in two retrospective studies, combination chemotherapy with carboplatin and weekly paclitaxel was reported to cause an acute exacerbation of ILD in four out of 15 patients (27 %) with NSCLC, and in only one out of 18 patients (5.6 %) with ILD [6, 7]. On the other hand, Okuda et al. [8] reported that combination chemotherapy with vinorelbine and platinum agents caused an acute exacerbation of ILD in three out of 19 patients (15.8 %) with advanced NSCLC and ILD. To date, no large-scale prospective studies have demonstrated the efficacy of chemotherapy in terms of survival improvement in NSCLC patients with ILD, and only a few retrospective analyses evaluating the clinical effects of chemotherapy for NSCLC with ILD are available [6–9]. At present, there is neither evidence nor consensus as to whether palliative chemotherapy is an appropriate approach for NSCLC with ILD. In this context, we conducted a retrospective analysis of palliative chemotherapy with gemcitabine or pemetrexed, both in combination with a platinum agent, to assess its efficacy and tolerability in NSCLC patients with ILD.
seventeen patients (11.5 %) were managed with best supportive care only because of the patient’s request (n = 7), ineligibility for intensive treatment as judged by the treating physician (n = 5) or death before initiation of treatment (n = 4). The cause was not described in one patient. The clinical parameters analyzed at the time of palliative chemotherapy included age, sex, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status (PS), stage at diagnosis, histologic type, prior treatment before palliative chemotherapy, chemotherapy regimen, pulmonary function testing, and other laboratory results. ILD was diagnosed based on pathologic findings or evidence from a conventional CT or high resolution CT (HRCT) of the chest such as reticular opacities, traction bronchiectasis, ground-glass opacities, or honeycombing. ILD was classified into two types, either idiopathic interstitial pneumonia (IIP) or non-IIP. The latter type included ILD associated with pneumoconiosis, collagen vascular disease, and other syndromes.
Methods
Definition of acute exacerbation of ILD (AE‑ILD)
Patients
AE-ILD was diagnosed if the following criteria were satisfied: (1) subjective worsening of dyspnea within the past month; (2) new ground-glass opacities or consolidation on chest radiography or HRCT; (3) hypoxemia with a decline of 10 mmHg in partial pressure of oxygen from the previous level; and (4) no evidence of infection, pulmonary embolism, congestive heart failure, or pneumothorax as a cause of acute worsening.
We retrospectively reviewed the medical records of NSCLC patients with ILD who were diagnosed at Samsung Medical Center, Korea between January 2007 and December 2011. This retrospective analysis was approved by the Samsung Medical Center Institutional Review Board. A total of 148 NSCLC patients with ILD were identified. Among them, 61 (41.2 %) patients received palliative chemotherapy. Of these, 52 patients were treated with gemcitabine or pemetrexed, both in combination with a platinum agent, and nine patients received other regimens such as taxane plus a platinum agent (n = 4), gefitinib (n = 3) and etoposide plus a platinum agent (n = 2). Forty-nine (33.1 %) patients underwent curative surgery with or without adjuvant treatment, and 21 (14.2 %) patients received definitive radiotherapy with concurrent or sequential chemotherapy. The remaining
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Treatment Patients received gemcitabine at a dose of 1,000 mg/m2 on day 1 and 8 or pemetrexed at a dose of 500 mg/m2 on day 1, which was followed by carboplatin with an area under the curve (AUC) of 5.5 on day 1 or cisplatin at a dose of 70 mg/m2 on day 1. These agents were administered every 3 weeks. All patients received standard supportive care, as appropriate. Dose reduction, omission, and discontinuation of chemotherapy were based on the physician’s discretion. Treatment was continued until there were disease progression, unacceptable toxicity, or the patient refused further treatment.
Statistical analysis Treatment outcomes were estimated as overall response rate, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). Tumor response was determined according to RECIST 1.0. OS was defined as the time elapsed from the date of first-line chemotherapy to the date of death or last follow-up. PFS was defined as the time
Cancer Chemother Pharmacol (2014) 73:1217–1225
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Fig. 1 a Progression-free survival (PFS) and b overall survival (OS). The median PFS, MST, and 1-year survival rate were 5.4, 7.9 months, and 31.7 %, respectively
from the date of first-line chemotherapy to the date of disease progression or death from any cause. The period to the onset of acute exacerbation was calculated from the date of initial chemotherapy. Survival curves were generated using the Kaplan– Meier method, and the log-rank test was used to compare the survival curves. The clinicopathologic characteristics and response rates of first-line chemotherapy were compared between two groups using the chi-square test. To identify prognostic factors for survival, a Cox proportional hazards model was used for univariate and multivariate analyses. Significant prognostic variables in the univariate analysis for OS were included in the multivariate analysis. P > 0.05 was considered statistically significant (Fig. 1).
Results Patients’ characteristics Fifty-two NSCLC patients with ILD receiving palliative chemotherapy with a platinum agent plus gemcitabine or pemetrexed were included in this analysis. All but two patients had pathologically or cytologically proven advanced or recurrent NSCLC. Two patients did not have advanced or recurrent disease at the time of palliative chemotherapy because one refused surgery and the other was not suitable for surgery or RT. ILD was diagnosed either at the time of (n = 32) or before (n = 20) the diagnosis of lung cancer. Table 1 presents
the baseline characteristics of all patients. The median age at the time of first-line chemotherapy was 67 years (range 46–85), and the median ECOG PS was 1 (range 0–2). Seven patients were never-smokers. Of 45 smokers, 25 patients were 40 or more pack-year smokers. Thirty-two patients (61.5 %) had adenocarcinoma histology. As first-line chemotherapy, gemcitabine and a platinum agent were administered to 39 patients (75.0 %), and pemetrexed and a platinum agent were given to 13 patients (25.0 %). With respect to the type of ILD, IIP and non-IIP were observed in 42 (80.8 %) and 10 (19.2 %) patients, respectively. Of ten non-IIP patients, five had ILD associated with occupational or environmental exposure, mainly pneumoconiosis, and five had ILD associated with collagen vascular disease. Five patients (9.6 %) had pathologically confirmed ILD by surgical lung biopsy. Thirty-two patients (61.5 %) were diagnosed with ILD and lung cancer simultaneously, and 20 (39.5 %) were already diagnosed with ILD before the diagnosis of lung cancer. In the case of preexisting ILD, the median interval from the diagnosis of ILD to the diagnosis of lung cancer was 2.9 years (range 0.5–30). Clinical outcomes of palliative chemotherapy The median follow-up duration was 33.2 months (range 5.8–74.1). Among 52 patients, there were 22 (42.3 %) partial responses and 19 (36.5 %) patients with stable disease. Thus, the DCR was 78.8 %. Seven patients (13.5 %) showed progressive disease. The median PFS was
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Table 1 Patients characteristics
All patients n = 52 (%)
Gemcitabine group n = 39 (%)
Pemetrexed group n = 13 (%)
P value
Age Median (range) (years)
67 (46–85)
66 (46–76)
69 (55–85)
Male
45 (86.5)
35 (89.7)
10 (76.9)
Female
7 (13.5)
4 (10.3)
3 (23.1)
0–1
47 (90.4)
38 (97.4)
9 (69.2)
≥2
5 (9.6)
1 (2.6)
4 (30.8)
23 (59.0)
4 (30.8)
Sex
0.347
ECOG PS
0.011
Smoking status Current
0.160 27 (51.9)
Former
12 (30.8)
6 (46.2)
4 (10.3)
3 (23.1)
26 (50.0)
18 (46.2)
8 (61.5)
≥40
25 (48.1)
20 (51.3)
Not described
1 (1.9)
1 (2.6)
0
2 (3.8)
2 (5.1)
0
Never Smoking amount, pack-year
