Ann Surg Oncol DOI 10.1245/s10434-015-4577-1

ORIGINAL ARTICLE – THORACIC ONCOLOGY

Surgical Outcomes of Lung Cancer in Patients with Combined Pulmonary Fibrosis and Emphysema Takahiro Mimae, MD, PhD1, Kenji Suzuki, MD, PhD2, Masahiro Tsuboi, MD, PhD3,4, Kanji Nagai, MD, PhD3, Norihiko Ikeda, MD, PhD5, Tetsuya Mitsudomi, MD, PhD6, Hisashi Saji, MD, PhD7, Sakae Okumura, MD, PhD8, Meinoshin Okumura, MD, PhD9, Kenichi Yoshimura, MD, PhD10,11, and Morihito Okada, MD, PhD1 Department of Surgical Oncology, Hiroshima University, Minami-ku, Hiroshima, Japan; 2Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan; 3Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan; 4Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan; 5Department of Surgery I, Tokyo Medical University Hospital, Tokyo, Japan; 6Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan; 7Department of Chest Surgery, St. Marianna University School of Medicine, Kawasaki, Japan; 8Department of Thoracic Surgery, Cancer Institute Hospital, Tokyo, Japan; 9Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan; 10Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, Kanazawa, Japan; 11Department of Applied Biostatistics, Kobe University Graduate School of Medicine, Kobe, Japan 1

ABSTRACT Purpose. Lung cancers in patients with combined pulmonary fibrosis and emphysema (CPFE) are increasing. Objective of this investigation was to identify which clinicopathological features significantly affected surgical outcome of these patients. Methods. Among 4313 patients with primary lung cancers who underwent surgery between January 2008 and December 2010 in nine institutions in Japan, 265 had CPFE. We retrospectively compared 2176 and 157 patients without and with CPFE, respectively, and further analyzed 233 patients with CPFE whose detailed information was available. CPFE was defined as upper lobe emphysema and lower lobe fibrosis. Results. The rates of postoperative morbidity and mortality were higher and overall survival was poorer in patients with, than without CPFE. Among 233 patients with CPFE, the median values of %VC and FEV1.0 % were 98.4 and 71.5 %, respectively. The histological types comprised 111 squamous

Electronic supplementary material The online version of this article (doi:10.1245/s10434-015-4577-1) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2015 First Received: 25 November 2014 M. Okada, MD, PhD e-mail: [email protected]

cell carcinomas and 84 adenocarcinomas. Surgical procedures included 203 standard lobectomies/pneumonectomies and 30 lesser resections. Five patients (2 %) developed postoperative acute exacerbation of interstitial pneumonia. Six and 15 patients (3 and 6 %) died within 30- and 90-postoperative-day, respectively. Cancer was the cause of death at 90-day in only one patient. The 3-year overall survival rate for all patients was 58.4 %. Multivariate analysis showed that male sex, advanced age, advanced clinical stage and lower %VC predict a poor prognosis. Conclusions. Patients with lung cancer and CPFE had poor prognoses regardless of apparently good pulmonary function and showed quite high postoperative mortality rates. A lower %VC that might reflect the severity of pulmonary fibrosis was associated with poor prognoses.

Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder of the lungs that comprises upper lobe emphysema and lower lobe fibrosis.1,2 The incidence of detecting chronic obstructive pulmonary disease (COPD) including emphysema has recently increased and it is now the fourth most common cause of death worldwide.3 The incidence of lung cancer has increased in patients with COPD 4–6 and it is also high in patients with interstitial pneumonia and fibrotic lungs.7 Moreover, patients with CPFE are at high risk for lung cancer.8 Conversely, 8.9 % of patients with lung cancer have CPFE according to the

T. Mimae et al.

previous report.9 Therefore, patients with CPFE should be strictly followed up. The type of therapy must be considered when a suspicious lung lesion is clinically or pathologically diagnosed as lung cancer. The 5-year overall survival rates and the median survival duration of patients with CPFE are 35–80 % and 2.1–8.5 years, respectively,10 whereas the median survival duration of patients with lung cancer and CPFE is 10.8 months on the previous report.9 Although others have investigated patients with CPFE,11,12 the cohorts were small and thus the features and prognosis of lung cancer in patients with CPFE remain unclear, especially after complete surgical resection. Here, we attempted to define the clinicopathological features of lung cancer in patients with CPFE. We also assessed prognosis including overall survival, cancer- and non-cancer-specific intervals in these patients according to clinical stages of lung cancer and % vital capacity (VC) as an indicator of lung function. This is first report about surgical outcomes of more than 100 lung cancers in patients with CPFE and the results will facilitate understanding of the characteristics and predictive prognostic factors of lung cancers in patients with CPFE. MATERIALS AND METHODS CPFE on Computed Tomography Lungs with CPFE were defined based on chest computed tomography (CT) findings as follows: emphysema defined as well-demarcated areas of decreased attenuation compared with a contiguous normal lung, having an absent or very thin (\1 mm) wall, and/or multiple bullae ([1 cm) with upper zone predominance; diffuse parenchymal lung disease with significant pulmonary fibrosis visualized as reticular opacities with peripheral and basal predominance, honeycombing, architectural distortion and/or traction bronchiectasis or bronchiolectasis; focal ground-glass opacities and/or associated areas of alveolar condensation that may be present but not prominent.2 Supplementary Fig. 1 shows a representative CT image of a lung with CPFE. All CT images of all patients with lung cancer who were treated by surgical resection between 2008 and 2010 at each institution were retrospectively re-examined. Pulmonary specialists and experienced radiologists at each institution diagnosed CPFE after reaching consensus regarding representative CT images and borderline images at a central conference.

Japan), Juntendo University School of Medicine (Tokyo, Japan), Yokohama City University Medical Center (Yokohama, Japan), National Cancer Center Hospital East (Kashiwa, Japan), Tokyo Medical University Hospital (Tokyo, Japan), Kinki University Faculty of Medicine (Osaka-Sayama, Japan), St. Marianna University School of Medicine (Kawasaki, Japan), Cancer Institute Hospital (Tokyo, Japan) and Osaka University Graduate School of Medicine (Osaka, Japan) between January 2008 and December 2010. The Institutional Review Boards of all participating institutions (Hiroshima University, eki-799) approved the study and waived the requirement for informed consent from individual patients as the study comprised a retrospective review of a prospective database. Among all of the defined patients, 265 had lung cancer with CPFE and we analyzed data from 233 of those with complete information about the extent of the surgery and lung function data including %VC and forced expiratory volume in one second % (FEV1.0 %). We compared 157 and 2176 patients with and without CPFE, respectively, or those with complete information about the extent of the surgery and lung functional data including %VC and FEV1.0 % at Hiroshima University Hospital, Juntendo University School of Medicine, National Cancer Center Hospital East, Tokyo Medical University Hospital because patients without CPFE were not available for investigation at the other five institutions. All patients who were staged according to the TNM Classification of Malignant Tumors, 7th edition were assessed by HRCT and FDG-PET/CT and then treated by R0 resection.13 Preoperative assessment, selection of extent of curative lung resection, and postoperative follow-up therapy proceeded as described.14 The present study also included patients who underwent palliative limited resection. The median follow-up was 27.8 (range, 0.3–65.2) months. Postoperative Complications Morbidity and mortality data were collected according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0).15 Morbidity related to respiratory status included acute exacerbation of idiopathic pulmonary fibrosis, acute respiratory distress syndrome (ARDS) except for acute exacerbation, prolonged air leakage ([7 days), pneumonia, bronchopleural fistula, and empyema. Thirtyand 90-day mortality rates after surgical resection were calculated. If the patients postoperatively died, the one most causative complication was defined as grade 5.

Patients Statistical Analysis The present study included 4313 consecutive patients who underwent complete surgical resection of primary lung cancer at Hiroshima University Hospital (Hiroshima,

Continuous variables were analysed using the Mann– Whitney U test and categorical variables were assessed

Lung Cancer in Patients with CPFE

using the Chi squared test or Fisher’s exact test. Cancerand non-cancer-specific intervals were defined as the length of time that the patient survived after primary surgical treatment of cancer. Death due to other diseases was not included as an event in cancer-specific death and that due to cancer was not included as an event in non-cancerspecific death. Overall survival (OS) and the cumulative incidence of cancer- and non-cancer-related deaths were calculated using the Kaplan–Meier method. Survival curves were compared by univariate anlysis using the Wilcoxon test. P values and hazard ratios in the multivariate analyses were calculated using the Cox regression model. Prognosis was analysed during October 2013. All data were statistically analysed using EZR (Saitama Medical Centre, Jichi Medical University, Saitama, Japan),16 which is a graphical user interface for R (The R Foundation for Statistical Computing, version 2.13.0). More precisely, it is a modified version of R commander (version 1.6-3), which includes statistical functions that are frequently used in biostatistics. A P value of B0.05 was considered to be statistically significant. RESULTS Characteristics of Patients with Lung Cancer and with or without CPFE The median age, ratio of males, and number of packyears of smoking were higher in patients with, than without CPFE. Almost all patients had performance status 0 or 1 except for those whose clinical data were incomplete. On the other hand, no significant differences among clinical stage, %VC, and FEV1.0 % were detected between those with and without CPFE (Table 1). The operative and postoperative findings, pathological stage, rate of histologically confirmed squamous cell carcinoma (SCC), postoperative complications associated with respiratory status, introduction rate of home oxygen therapy, length of hospital stay after surgical resection, and 30- or 90-day mortality rates were significantly higher among patients with, than without CPFE. The surgical procedures for lung cancer were similar between the two groups (Table 2). Prognosis of Patients with Lung Cancer and with or without CPFE Figure 1a shows the OS curve for all patients. The OS rates for all patients were significantly poorer in the group with, than without CPFE (P \ 0.001; Fig. 1b). Figure 1c shows the OS rates for all patients according to clinical stage I, II and III cancers. The OS rates for patients with

clinical stage I lung cancer were also significantly poorer in the group with, than without CPFE (both P \ 0.001; Fig. 1d). Multivariate analysis of OS identified male sex, advanced age, advanced clinical stage (stage I vs. II/III), and CPFE as predictors of a poor prognosis (Supplementary Table 1). Characteristics of Patients with Lung Cancer and CPFE The median age was 73 (range, 52–89) years, 212 patients (91.0 %) were male and 166, 42 and 25 of them had clinical stage I, II and III tumors, respectively. Almost all patients had performance status 0 (n = 180) or 1 (n = 50) and 225 were ex- or current smokers. The median packyear was 53 (range, 0–324). Median (range) for %VC, FEV1.0 %, and %diffusing capacity for carbon monoxide (%DLCO) determined by pulmonary function test were 98.4 % (39.6–143 %), 71.5 % (35.4–138.4 %) and 45.9 % (18.1–113.8 %), respectively. The tumors were histologically adenocarcinoma (n = 84), squamous cell carcinoma (n = 111), large cell carcinoma (n = 15), pleomorphic carcinoma (n = 9) and other types (n = 14). Supplementary Tables 2 and 3 show the surgical procedures that included pneumonectomy (n = 5), lobectomy (n = 198), segmentectomy (n = 8) and wedge resection (n = 22). Postoperative complications associated with the respiratory system developed in 48 patients (acute exacerbation of interstitial pneumonia (n = 5), prolonged air leakage (n = 24), ARDS (excluding acute exacerbation) (n = 8), pneumonia (n = 13), bronchopleural fistula (n = 9) and empyema (n = 9)). Of the five patients who had acute exacerbation, 4 (80 %) died whereas 2 (25 %) of eight patients with ARDS excluding acute exacerbation died. Fourteen (6 %) patients had more than grade 3 respiratory related complications (Supplementary Table 4). The surgical procedures for lung cancer were similar between the two groups. The 30- and 90-day mortality rates were 2.6 % (6/233) and 6.4 % (15/233), respectively (Supplementary Table 3). Only one patient died of lung cancer within 90 days. The surgical procedures for lung cancer were similar between the two groups. Home oxygen therapy was postoperatively administered to 31 (13.0 %) patients. Predictive Prognostic Factors of Patients with Lung Cancer and with or without CPFE Figure 2a shows OS in all patients with lung cancer and CPFE. The multivariate findings of OS identified male sex, advanced age, advanced clinical stage (stage I vs. II/III), and lower %VC (C100 vs.\100 %) as predictors of a poor

T. Mimae et al. TABLE 1 Preoperative clinicopathological findings of patients with lung cancer and with or without combined pulmonary fibrosis and emphysema Variables

With CPFE (n = 157)

Without CPFE (n = 2176)

\0.001

Sex Female Male

12 (8)

860 (40)

145 (92)

1316 (60) \0.001

Age Median (IQR)

73 (67–77)

67 (61–74)

Clinical stage

0.36

I II

114 (73) 27 (17)

1665 (77) 313 (14)

III

16 (10)

172 (8)

IV

0 (0)

20 (1)

Unknown

0 (0)

6 (0.3)

Performance status

0.016

0

135 (86)

924 (42)

1

21 (13)

74 (3)

2

1 (1)

2 (0.1)

Unknown

0 (0)

1176 (54) \0.001

Smoking (pack-years) \40

39 (25)

1508 (69)

C40

118 (75)

668 (31)

%VC Median (IQR) FEV1.0 % (%) Median (IQR)

P

0.34 98.0 (89.3–108.5)

100.6 (89.2–112.2) 0.17

71.5 (64.9–75.7)

75.6 (69.1–80.7)

Missing data were excluded from analysis. Data are presented as counts and ratios (%) or as medians and ranges as appropriate %DLCO ratio of diffusing capacity for carbon monoxide, CPFE combined pulmonary fibrosis and emphysema, FEV1.0 % forced expiratory volume in one second %, IQR interquartile range, PaO2 partial pressure of oxygen in arterial blood, %VC ratio of forced vital capacity

prognosis (Table 3). Among them, clinical stage as an indicator of cancer progression and %VC as an indicator of lung function were included in a subsequent analysis. Figure 2b and c shows the OS of the patients with CPFE according to clinical stage I and II/III and %VC \100 or C100 %. The cumulative incidences of cancer- and noncancer-related deaths were examined according to clinical stage and %VC to determine the influence of these factors on cancer- or non-cancer-related death. Supplementary Fig. 2A shows the cumulative incidence of cancer death for all patients with CPFE. The incidence was significantly poorer for patients with CPFE and clinical stage I, than II/ III lung cancer (P = 0.010; Supplementary Fig. 2B) whereas the incidence for patients with %VC \100 and C100 % did not significantly differ (P = 0.30, Supplementary Fig. 2C). Supplementary Fig. 3A shows the cumulative incidence of non-cancer death for all patients with CPFE. The incidence for patients with clinical stage I and II/III disease did not significantly differ (P = 0.21, Supplementary Fig. 3B), but was significantly poorer for

patients with %VC \ 100 % than %VC C 100 % (P = 0.0048, Supplementary Fig. 3C). DISCUSSION Cottin defined CPFE in 2005,2,17 but the surgical outcomes of patients with lung cancer and CPFE remained obscure. However, when lung cancer is detected in patients with CPFE, physicians and surgeons need to decide whether or not to select surgical intervention. Information about the features and prognosis of lung cancer in patients with CPFE has become even more desirable. The present study assessed the surgical outcomes of [200 lung cancers in patients with CPFE admitted to several institutions. Almost all patients were male and ex- or current smokers. The major histological type of lung cancer in patients with CPFE was SCC that is related to smoking, whereas adenocarcinoma was the major histological type of lung cancer in patients without CPFE, which is similar to the Japanese general population.18 One reason for this is

Lung Cancer in Patients with CPFE TABLE 2 Operative and postoperative findings of patients with lung cancer and with or without combined pulmonary fibrosis and emphysema Variables

With CPFE (n = 157)

Without CPFE (n = 2176)

P

Pathological stage 0

0 (0)

I

80 (51)

1435 (67)

3 (0.1)

II

40 (25)

347 (16)

III

37 (24)

326 (15)

IV

0 (0)

31 (1)

Unknown

0 (0)

34 (2)

Adenocarcinoma

57 (36)

1559 (72)

Squamous cell carcinoma

75 (48)

385 (18)

\0.001

Histology

Large cell carcinoma Pleomorphic carcinoma Others Unknown

6 (4) 7 (4)

85 (4) 15 (0.7)

12 (8)

128 (6)

0 (0)

4 (0.2)

Procedure Pneumonectomy Lobectomy

0.40 5 (3)

64 (3)

133 (85)

1735 (80)

Segmentectomy

7 (4)

165 (8)

Wedge resection

12 (8)

212 (10)

?

38 (24)

177 (8)



119 (76)

1999 (92)

\0.001

Postoperative complication related to respiratory

\0.001

Home oxygen therapy ?

12 (8)



145 (92)

904 (42)

0 (0)

1267 (58)

Unknown Hospital stay after surgical resection Median (IQR)

\0.001

5 (0.2)

\0.001 10 (8–14)

9 (7–11)

30-day mortality

0.015

?

4 (3)

11 (0.5)



153 (97)

2165 (99)

?

12 (8)

23 (1)



145 (92)

2153 (99)

\0.001

90-day mortality

Missing data were excluded from analysis. Data are presented as counts and ratios (%) or as medians and interquartile ranges as appropriate CFPE combined pulmonary fibrosis and emphysema, IQR interquartile range

that smoking cigarettes is a key factor in the development of emphysema in normal lungs. In addition, OS and 30-day mortality rates were poorer in patients with lung cancer and with, than without CPFE. The 30-day mortality rate of those without CPFE was similar to that in the Japanese registry study in 2010.19 On the other hand, the mortality rate at 90-day (6 %) was twice as many as that at 30-day, hence, we might have to evaluate the risk of lung cancer in patients with CPFE based on the 90-day mortality rate to avoid underestimation. Lung function appeared normal in patients with CPFE, as described,1,10 because CPFE comprises lung fibrosis that

brings about sclerosis of the lung with a lower VC and a higher FEV1.0 %, and emphysema that enlarges the alveolar cavities of the lungs20 results in a higher VC and lower FEV1.0 %. Thus, in consideration of the poor prognosis of patients with lung cancer accompanied by CPFE, decisions about surgical approaches to lung cancer should be based not only on lung functional values but also on radiological CT findings that show the extent of lung fibrosis and emphysema. However, to quantify lung fibrosis and emphysema on CT is difficult and thus, another indicator is necessary. In the present study, as well as previous studies,1,10 %DLCO was low in patients with CPFE; a

T. Mimae et al.

Overall survival -All patients-

Overall survival -All patients-

b

1.0

1.0

0.8

0.8

Probability of survival

Probability of survival

a

0.6

0.4

0.2

0

All patients (n = 2333)

12

24

36

48

60

0.6

0.4

851

1. CPFE (n = 157) 2. non-CPFE (n = 2176)

0.2

0

Elapsed time (months)

Patients at risk 2333 2021 1803 1507

P < 0.001

12

24

36

48

331

Patients at risk 1. 157 108

82

50

2. 2176 2013 1721 1457 Overall survival -All patients-

c

d 1.0

P < 0.001

0.8

0.6

0.4

1. cStage I (n = 1779) 0.2

2. cStage II (n = 340)

12

24

36

48

60

841

330

0.8

0.6

0.4

1. CPFE (n = 114) 2. non-CPFE (n = 1665)

0.2

0

Elapsed time (months)

12

24

36

48

60

Elapsed time (months)

Patients at risk

Patients at risk

1. 1779 1585 1447 1240 2. 340 276 224 179

708 99

277 40

3. 188

37

11

140

1

P < 0.001

3. cStage III (n = 188) 0

10

Overall survival -cStage I-

Probability of survival

Cumulative incidence of death

1.0

60

Elapsed time (months)

113

75

1. 114

83

66

39

2. 1665 1502 1381 1201

8

1

700

276

FIG. 1 Kaplan–Meier overall survival among all patients with lung cancer (a), those with or without CPFE (b), those according to clinical stage I, II, and III (c), and patients with clinical stage I lung cancer with or without CPFE (d). Three-year OS rates for all patients was 80.4 % (95 % CI 78.6–82.0 %) (a). Three-year OS rates for all patients with CPFE was 53.9 % (95 % CI 44.8–62.1 %), and those without CPFE was 82.1 % (95 % CI 80.4–83.8 %) (P \ 0.001, b).

Three-year OS rates for clinical stage I, II, and III were 86.5 % (95 % CI 84.7–88.1 %), 65.2 % (95 % CI 59.6–70.3 %) and 52.2 % (95 % CI 44.3–59.6 %) (P \ 0.001, c). Three-year OS rates for patients with clinical stage I lung cancer and with CPFE was 60.9 % (95 % CI 49.9–70.2 %), and those without CPFE was 88.1 % (95 % CI 86.3–89.6 %) (P \ 0.001, d). CI confidence interval, CPFE combined pulmonary fibrosis and emphysema, OS overall survival

median of about 40 % was a borderline indication for surgery and thus %DLCO might serve as a surrogate indicator of idiopathic pulmonary fibrosis.21,22 Whether routine examination of %DLCO during preoperative evaluations is necessary remains unclear, but it should be

preoperatively assessed among heavy smokers and patients with emphysematous and/or fibrous lungs. The multivariate analyses revealed that a lower (\100 %) %VC was an independent predictive prognostic factor, whereas a higher FEV1.0 % ([70 %) was

Lung Cancer in Patients with CPFE

Probaility of survival

a

b FIG. 2 Kaplan–Meier curves of overall survival of all patients with

Overall survival

1.0

lung cancer and with combined pulmonary fibrosis and emphysema, and according to clinical stage I or II/III cancer and %VC (\100 and C100 %). Three-year OS rates for all patients (a), patients with CPFE and clinical stage I and II/III cancer (b) and for those with %VC\100 or C100 % (c): a 58.4 % (51.0–65.0 %), b 62.7 % (53.8–70.4 %) versus 47.5 % (34.4–59.5 %); P = 0.0070 and c 48.7 % (38.6–58.1 %) versus 69.8 % (59.3–78.0 %); P = 0.0047, respectively

0.8

0.6

0.4

0.2

0

All patients (n = 233)

12

24

36

48

60

Elapsed time (months)

Patients at risk 233 168

Probaility of survival

b

130

82

24

5

Overall survival

1.0

P = 0.0070

0.8

0.6

0.4

0.2

0

1. cStage I (n = 167) 2. cStage II/III (n = 68) 12

24

36

48

60

Elapsed time (months)

Patients at risk 1. 166 125 2. 67 43

99 31

58 24

4 1

Overall survival

c

P = 0.0047

1.0

Probaility of survival

16 8

0.8

0.6

0.4

0.2

0

1. %VC ≥ 100% (n = 108) 2. %VC < 100% (n = 125) 12

24

36

48

60

Elapsed time (months)

Patients at risk 1. 108 2. 125

84 84

65 65

44 38

18 6

3 2

associated with a marginally poorer prognosis. Although the finding that a higher FEV1.0 % was an adverse prognostic factor might be unanticipated, a higher FEV1.0 % under these circumstances represents advanced lung fibrosis. Surgeons should consider these findings. Our results indicated that the poorer prognosis of patients with lung cancer and CPFE was related to lung fibrosis, but not to good lung function (FEV1.0 %). The cumulative incidence of cancer and non-cancer death was investigated according to clinical stage of lung cancer and %VC (\100 vs. C100 %). That cancer-related death was affected by clinical stage whereas death was not related to other diseases is reasonable, as is the finding that %VC as a parameter of lung function influenced noncancer-related death but did not significantly correlate with cancer-related death. Other diseases accounted for 54 (53 %) of 102 causes of death, indicating that the prognosis of lung cancer in patients with CPFE was affected by the background lung function being compromised by fibrosis and emphysema. The notion that lung cancer is more aggressive in patients with, than without CPFE is unlikely. Postoperative respiratory-related complications were frequent and severe in the present study. Interstitial pneumonia was acutely exacerbated in 5 (2.1 %) of 233 patients. Acute exacerbation in patients with CPFE after complete resection for lung cancer was a fatal postoperative complication in 4 (80 %) of 5 patients in the present study. In addition, air leakage was prolonged in 24 (10.3 %) of 233 patients. The nature of the lungs in patients with CPFE causes difficulties with repairing lung fistulae. One limitation of the present study is the retrospective design. Nevertheless, the results should be useful for surgeons to decide indications for the surgical resection of lung cancers in patients with CPFE. Another limitation was incomplete %DLCO data that would show the diffusing capacity of the lungs and represents the extent of lung fibrosis. Less than half of the patients underwent a lung functional examination and hence we excluded %DLCO from the prognostic analysis. In summary, patients with lung cancer and CPFE had a poor prognosis while spirometry showed apparently good pulmonary function. A lower %VC that might reflect the severity of pulmonary fibrosis was associated with a poor

T. Mimae et al. TABLE 3 Univariate and multivariate analysis of overall survival in patients with lung cancer and with combined pulmonary fibrosis and emphysema Variables

n

Univariate analysis 3-year OS rate (%) (95 % CI)

Gender

Multivariate analysis P

Adjusted HR (95 % CI)

P

Female

21 (ref)

81.4 (52.4–93.6)

Male

212

56.4 (48.7–63.3)

0.021

3.3 (1.2–9.2)

0.024

Age (year)

\70 C70

89 (ref) 144

69.1 (57.5–78.1) 51.1 (41.5–59.9)

0.023

1.6 (1.1–2.5)

0.024

Clinical stage

I

166 (ref)

62.7 (53.8–70.4)

II or III

67

47.5 (34.4–59.5)

0.0070

1.9 (1.3–3.0)

0.0018

Smoking (pack-years)

\40

74 (ref)

67.3 (53.3–77.9)

C40

159

56.9 (47.9–65.0)

0.11

1.2 (0.7–1.8)

0.51

%VC

[100

108 (ref)

69.8 (59.3–78.0) 0.0047

1.7 (1.1–2.5)

0.013

0.087

1.5 (1.0–2.3)

0.050

0.46

1.2 (0.9–1.6)

0.19

\100

125

48.7 (38.6–58.1)

FEV1.0 %

\70

106 (ref)

68.2 (57.6–76.7)

C70

127

50.5 (40.5–59.7)

Procedure

Limited

30 (ref)

58.9 (35.8–76.0)

Standard

203

58.2 (50.4–65.3)

Missing data were excluded from analysis CI confidence interval, HR hazard ratio, FEV1.0 % forced expiratory volume in one second %, OS overall survival, %VC ratio of vital capacity

prognosis when such patients underwent surgical resection for lung cancer. Surgeons should carefully decide operative indications for lung cancers in patients with CPFE with a low %VC. The mortality rate was quite high and non-cancer-related causes of death were more prevalent after curative resection for lung cancer in patients with CPFE. The present findings provide important information for physicians and surgeons that will help with selecting the optimal treatment to improve the prognosis of patients with lung cancer and CPFE. ACKNOWLEDGMENT We are grateful to Kazuya Takamochi, MD, Aritoshi Hattori, MD, Keiju Aokage, MD, Yoshihisa Shimada, MD, Takuya Iwasaki, MD, Teppei Nishii, MD, Masayuki Nakao, MD, Soichiro Funaki, MD, Tomoharu Yoshiya, MD, Shinsuke Sasada, MD, and Norifumi Tsubokawa, MD for collecting data about the patients at the participating institutions. DISCLOSURE

No conflict of interest.

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Lung Cancer in Patients with CPFE

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Surgical Outcomes of Lung Cancer in Patients with Combined Pulmonary Fibrosis and Emphysema.

Lung cancers in patients with combined pulmonary fibrosis and emphysema (CPFE) are increasing. Objective of this investigation was to identify which c...
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