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RESEARCH ARTICLE

Impact of smoking status and chronic

obstructive pulmonary disease on pulmonary

complications post lung cancer surgery

Vishnu JeganathanID
1,2*, Simon Knight3, Matthew Bricknell2,4, Anna Ridgers1,2,4,

Raymond Wong
1,2

, Danny J. Brazzale
1,2

, Warren R. RuehlandID
1,2

, Muhammad

Aziz Rahman
2,5

, Tracy L. Leong
1,2,4

, Christine F. McDonald
1,2,4

1 Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia, 2 Institute

for Breathing and Sleep, Heidelberg, Victoria, Australia, 3 Department of Thoracic Surgery, Austin Health,

Heidelberg, Victoria, Australia, 4 Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia,

5 School of Health, Federation University Australia, Berwick, Victoria, Australia

* [email protected]

Abstract

Introduction

Smoking and chronic obstructive pulmonary disease (COPD) are associated with an

increased risk of post-operative pulmonary complications (PPCs) following lung cancer

resection. It remains unclear whether smoking cessation reduces this risk.

Methods

Retrospective review of a large, prospectively collected database of over 1000 consecutive

resections for lung cancer in a quaternary lung cancer centre over a 23-year period.

Results

One thousand and thirteen patients underwent curative-intent lobectomy or pneumonec-

tomy between 1995 and 2018. Three hundred and sixty-two patients (36%) were ex-smok-

ers, 314 (31%) were current smokers and 111 (11%) were never smokers. A pre-operative

diagnosis of COPD was present in 57% of current smokers, 57% of ex-smokers and 20% of

never smokers. Just over 25% of patients experienced a PPC. PPCs were more frequent in

current smokers compared to never smokers (27% vs 17%, p = 0.036), however, no differ-

ence was seen between current and ex-smokers (p = 0.412) or between never and ex-

smokers (p = 0.113). Those with a diagnosis of COPD, independent of smoking status, had

a higher frequency of both PPCs (65% vs 35%, p<0.01) and overall complications (60% vs
40%, p<0.01) as well as a longer length of hospital stay (10 vs 9 days, p<0.01).

Conclusion

Smoking and COPD are both associated with a higher rate of PPCs post lung cancer resec-

tion. COPD, independent of smoking status, is also associated with an increased overall

post-operative complication rate and length of hospital stay. An emphasis on COPD

PLOS ONE

PLOS ONE | https://doi.org/10.1371/journal.pone.0266052 March 29, 2022 1 / 14

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OPENACCESS

Citation: Jeganathan V, Knight S, Bricknell M,

Ridgers A, Wong R, Brazzale DJ, et al. (2022)

Impact of smoking status and chronic obstructive

pulmonary disease on pulmonary complications

post lung cancer surgery. PLoS ONE 17(3):

e0266052. https://doi.org/10.1371/journal.

pone.0266052

Editor: Stelios Loukides, National and Kapodistrian

University of Athens, GREECE

Received: November 10, 2021

Accepted: March 11, 2022

Published: March 29, 2022

Copyright: © 2022 Jeganathan et al. This is an
open access article distributed under the terms of

the Creative Commons Attribution License, which

permits unrestricted use, distribution, and

reproduction in any medium, provided the original

author and source are credited.

Data Availability Statement: Raw data cannot be

shared publicly as it is in a re-identifiable surgical

database. These restrictions were placed by the

Austin Health Human Research Ethics Committee.

This is to meet the requirements outlined in

Section 2.3.10 of the National Statement

(NHMRC). Please contact Austin Health, Office for

Research, ([email protected]) for more

information.

treatment optimisation, rather than smoking cessation in isolation, may help improve post-

operative outcomes.

Introduction

Lung cancer is the leading cause of cancer mortality worldwide [1]. In Australia, lung cancer is

responsible for close to a fifth of cancer-related deaths, with a five-year survival rate of 17% [2].

Smoking remains the most significant modifiable risk factor in lung cancer development.

Despite advances in tobacco control, data from the Australian Bureau of Statistics reveal that

13.8% of Australian adults still smoke daily [3]. In early stage non-small cell lung cancer

(NSCLC), surgery remains the primary treatment modality in those who are operative candi-

dates. The vast majority of patients who undergo lung cancer resection have smoked in the

past, and many are active smokers at the time of surgery [4–6]. Several studies show that smok-

ers, whether current or reformed, have higher rates of post-operative pulmonary complica-

tions (PPCs) after lung cancer resection than never smokers [6–8]. A fifth of all patients who

undergo major surgery and experience a PPC die within 30 days of the operation compared to

0.2–3% of those who do not [9]. Additionally, developing a PPC is associated with higher rates

of intensive care unit (ICU) admission and longer durations of hospital stay [10, 11].

Chronic obstructive pulmonary disease (COPD) coexists in 50–70% of patients with lung

cancer [12] and is an independent risk factor for the development of lung cancer, over and

above smoking [13, 14]. Smokers with COPD are twice as likely to develop lung cancer as

smokers without COPD [15]. Several studies have shown that the presence of COPD is associ-

ated with a higher frequency of PPCs [16–19].

Despite the established link between smoking, COPD and PPCs after lung cancer resection,

it is unclear whether reformed smokers have higher complication rates compared with those

who continue to smoke [7, 20]. Furthermore, there is uncertainty regarding the optimal timing

of smoking cessation prior to surgery, with potential benefits weighed against the risk of dis-

ease progression if operative management is delayed. Attitudes of thoracic surgeons are incon-

sistent, with no consensus on standard practice for pre-operative smoking cessation. A survey

of US thoracic surgeons demonstrated that most (60%) do not require a patient to cease smok-

ing prior to surgery, with those who do mandate cessation divided on the recommended dura-

tion of the smoking abstinence period [21]. Most US surgeons do not routinely refer to

smoking cessation programs or prescribe nicotine replacement therapy prior to surgery [21].

although nicotine dependence treatment is known to be highly effective in effecting short-

term cessation amongst cancer patients [22, 23].

Although international studies have examined smoking status, COPD and PPCs in patients

undergoing lung cancer resection [7, 16, 24], there have been no studies to date in an Austra-

lian population, and few studies of the size and breadth of ours. In a large cohort of patients

undergoing lung cancer resection in an Australian quaternary centre, our study aimed to

examine the relationship between PPCs and (i) pre-operative smoking status, and (ii) pre-

operative COPD diagnosis.

Methods

A retrospective review was undertaken of a prospectively maintained database of consecutive

operations performed for lung cancer resection. Data included demographic information, pre-

PLOS ONE Smoking and lung cancer surgery

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Funding: The authors received no specific funding

for this work.

Competing interests: The authors have declared

that no competing interests exist.

operative lung function and post-operative complications. Approval was granted by the insti-

tutional Health Research Ethics Committee.

Population

All patients who underwent lobectomy or pneumonectomy for lung cancer between 1995 and

2018 were included. Patients who had undergone segmentectomy or wedge resection were

excluded, as were those with benign tumours. Surgery was performed by a dedicated thoracic

surgical team, with post-operative care taking place on the thoracic surgical ward or in the

intensive care unit if invasive monitoring or additional organ support were required.

Pre-operative smoking status was categorised in three groups: current smokers, defined as

those who had smoked tobacco within 12 months leading up to surgery; ex-smokers, defined

as those who had ceased smoking more than 12 months before surgery; and never smokers.

Our ex-smoker definition is based on the low smoking relapse rate after 12 months of smoking

cessation [25]. Smoking data were obtained from self-report and collected by healthcare work-

ers including respiratory physicians, thoracic surgeons, and respiratory scientists.

Data collection

Data extracted included baseline demographics, (age, sex, body mass index), type of operation

performed, smoking exposure expressed in pack years, years since smoking cessation, pre-

operative lung function (spirometry and carbon monoxide transfer factor (TLCO)), histologi-

cal diagnosis, cancer stage (based on the International Association for the Study of Lung Can-

cer (IASLC) 7
th

edition of Tumour Node Metastasis Classification of Malignant Tumors) [26],

neoadjuvant treatment, post-operative length of stay, and complication rates.

The presence of COPD was determined on pre-bronchodilator spirometry, using a FEV1/

FVC ratio of <0.7. Pre-bronchodilator, rather than post bronchodilator, measurements were

used as approximately one quarter of the study population did not have post bronchodilator

spirometry performed. COPD severity was defined using the Global Initiative for Obstructive

Lung Disease (GOLD) criteria [27].

We compared pulmonary complications, overall complications, and length of stay between

current smokers, ex-smokers and never smokers. We also compared pulmonary complications

in those with and without a diagnosis of COPD. Pulmonary complications included: atelecta-

sis, sputum retention, pneumonia, acute respiratory distress syndrome (ARDS), respiratory

failure, air leak and empyema. Overall complications included: pulmonary complications,

arrythmias, myocardial infarction, thromboembolic disease, stroke, transient ischaemic attack,

renal failure, urinary tract infection, gastrointestinal bleed, ileus, wound infection / dehiscence

and 30-day mortality (S1 Appendix).

Statistical analysis

Statistical analysis was performed using SPSS v.25. Descriptive analyses were used to describe

the study variables. Means and standard deviations were calculated for continuous variables,

while proportions were used to describe categorical variables. For inferential analyses, chi-

squared tests were used to compare smoking status and COPD status with other study vari-

ables including post-operative complications. Binary logistic regression was used to assess the

strength of association, which yielded odds ratios (OR) and 95% confidence intervals (CI).

Then multivariate logistic regression was used to adjust potential confounding variables (age,

gender and BMI), which yielded adjusted OR (AOR) and 95% CI. Statistical significance was

set at p<0.05.

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Results

Baseline characteristics

Patient characteristics are shown in Table 1. A total of 1013 patients underwent curative-intent

lobectomy or pneumonectomy. The mean age was 66 years (SD 12), with a male predomi-

nance (61%) and a mean BMI of 27 kg/m
2

(SD 5).

(i) Pre-operative smoking status

Three hundred and sixty-two patients (36%) were ex-smokers, 314 (31%) were current smok-

ers and 111 (11%) were never smokers. Two hundred and twenty-six patients (22%) did not

have their smoking status recorded in the database, hence they were excluded from the smok-

ing status vs. complications analysis. Ex-smokers were older than never smokers (69 vs 63

years, p<0.001), with no age difference between current and never smokers (64 vs 63 years,

p = 0.497). Compared to the never smokers, both current smokers and ex-smokers were more

likely to be males (p<0.001). Current smokers had a higher mean pack-year smoking exposure

history compared to ex-smokers (p<0.001).

(ii) Pre-operative lung function and COPD diagnosis

Fifty-eight patients (6%) did not have lung function recorded in the database. Pre-operative

spirometric values were higher in never smokers compared to both current and ex-smokers

(Table 1), with mean percentage predicted FEV1s of 94%, 81% (p<0.001) and 84% (p<0.001),

respectively. A similar pattern was seen with TLCO, with mean percentage predicted values in

never smokers of 83%, compared to 70% (p<0.001) in current smokers and 73% (p<0.001) in

ex-smokers. A pre-operative diagnosis of COPD was present in 20% of never smokers, com-

pared to 57% of current smokers and 57% of ex-smokers. The never smokers had COPD of

mild or moderate severity.

Surgical and neoadjuvant treatment

Nine hundred patients (89%) underwent lobectomy, and the remaining 113 (11%) underwent

pneumonectomy. Video-assisted thoracoscopy (VATS) was used in 111 (11%) patients. Addi-

tionally, 56 patients (6%) received neoadjuvant radiotherapy or chemotherapy, with no differ-

ence seen based on smoking status (3% of never smokers, 6% of current smokers and 6% of

ex-smokers).

Histology/Staging

Eight hundred and thirty-two patients (82%) had a pathological diagnosis of NSCLC, of which

521 (51%) were adenocarcinoma and 279 (28%) squamous cell carcinoma (SCC). NSCLC was

more common amongst current smokers (85% vs 63%, OR 3.25, 95% CI 1.98–5.31, p<0.001)

and ex-smokers (87% vs. 63%, OR 4.02, 95% CI 2.46–6.60, p<0.001) compared to never smok-

ers. Similarly, SCC was more frequent in current smokers (30%, OR 5.5, 95% CI 2.58–1.7,

p<0.001) and ex-smokers (32%, OR 5.92, 95% CI 2.79–12.6, p<0.001), compared to never

smokers (7%). There was no difference in the frequency of adenocarcinoma in current or ex-

smokers compared to never smokers. Conversely, carcinoid tumours were less common

amongst current smokers (3% vs 28%, OR 0.07, 95% CI 0.03–0.15, p<0.001) and ex-smokers

(4% vs 28%, OR 0.10, 95% CI 0.05–0.20, p<0.001) than among never smokers.

Most patients had Stage I disease (56%), with 26% having Stage II and 17% Stage III disease.

Never smokers were more likely to be diagnosed with Stage I disease compared to both ex-

smokers (68% vs. 55%, p = 0.021) and current smokers (68% vs. 52% p = 0.005). Conversely,

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current smokers were more likely to be diagnosed with stage II disease compared to never

smokers (29% vs. 19%, p = 0.033). There was a trend towards higher rates of stage III disease

in current and ex-smokers compared to never smokers.

Table 1. Patient characteristics.

Variables Never smokers, n(%) Current smokers, n(%) p1 Ex-smokers, n(%) p2 p3

Total participants
a

111 314 362

Age (years), Mean (±SD) 62.5 (16.9) 63.5 (10.3) 0.497 69.1 (9.5) 0.000 0.000
Male 30 (27.0) 205 (65.3) 0.000 254 (70.2) 0.000 0.175

BMI (kg/m
2
), Mean (±SD) 27.0 (5.1) 26.0 (5.3) 0.085 27.5 (4.5) 0.356 0.000

BMI categories 84 243 269

Underweight (<18.5) 3 (3.6) 17 (7.0) 0.259 3 (1.1) 0.128 0.001

Healthy weight (18.5–24.9) 34 (40.5) 134 (55.1) 0.020 98 (36.4) 0.504 0.000

Overweight (25.0–29.9) 47 (56.0) 92 (37.9) 0.004 168 (62.5) 0.286 0.000

Primary operation
b

111 314 362

Lobectomy 105 (94.6) 281 (89.5) 0.109 318 (87.8) 0.043 0.502

Pneumonectomy 6 (5.4) 33 (10.5) 0.109 44 (12.2) 0.043 0.502

FEV1 (%), Mean (±SD) 94.3 (20.0) 81.2 (17.9) 0.000 83.8 (19.6) 0.000 0.082
FVC (%), Mean (±SD) 97.8 (18.1) 94.5 (15.6) 0.072 95.9 (17.0) 0.318 0.278
FEV1/FVC, Mean (±SD) 0.75 (0.1) 0.67 (0.1) 0.000 0.67 (0.1) 0.000 0.841
TLCO (%), Mean (±SD) 83.1 (16.4) 69.8 (16.6) 0.000 72.7 (18.3) 0.000 0.034
Pack-years, Mean (±SD)c 48.6 (24.7) 39.2 (25.5) 0.000
COPD present 22 (19.8) 180 (57.3) 0.000 205 (56.6) 0.000 0.856

Mild 11 (50.0) 65 (36.1) 0.204 81 (39.7) 0.341 0.469

Moderate 11 (50.0) 105 (58.3) 0.456 110 (53.9) 0.744 0.385

Severe 0 (0) 10 (5.6) 0.605 13 (6.4) 0.621 0.736

Stage
d

108 307 356

1 73 (67.6) 160 (52.1) 0.005 196 (55.1) 0.021 0.449

2 20 (18.5) 89 (29.0) 0.033 91 (25.6) 0.133 0.322

3 15 (13.9) 58 (18.9) 0.240 69 (19.4) 0.194 0.873

Histology
e

111 314 362

Adenocarcinoma 62 (55.9) 159 (50.6) 0.344 186 (51.4) 0.409 0.847

Squamous 8 (7.2) 94 (29.9) 0.000 114 (31.5) 0.000 0.662

Adenosquamous 0 (0) 8 (2.5) 0.090 13 (3.6) 0.043 0.435

Carcinoid 31 (27.9) 8 (2.5) 0.000 14 (3.9) 0.000 0.335

Others 10 (9.0) 45 (14.3) 0.151 35 (9.7) 0.836 0.259

Pathological diagnosis
f

111 314 362

Non small cell lung cancer 70 (63.1) 266 (84.7) 0.000 316 (87.3) 0.000 0.334

Small cell lung cancer 0 (0) 4 (1.3) 0.232 1 (0.3) 0.579 0.131

BMI: body mass index, FEV1: forced expiratory volume in 1 second, FVC: forced vital capacity, TLCO: transfer factor of the lung for carbon monoxide, COPD: chronic

obstructive pulmonary disease.

p1 indicates comparison between never smokers and current smokers; p2 indicates comparison between never smokers and ex-smokers; p3 indicates comparison

between current smokers and ex-smokers.

a: Smoking status was not recorded for 226 patients; hence they were excluded from the smoking status vs. complications analysis.

b: Totals: Lobectomy: 900, Pneumonectomy 113.

c: Pack-year data was missing for 6 current smokers and 9 ex-smokers.

d: Totals: Stage I: 559, Stage II: 261, Stage III: 193.

e: Totals: Adenocarcinoma: 521, Squamous: 279, Adenosquamous: 23, Carcinoid: 73, Others: 117.

f: Totals: Non-small cell lung cancer: 832, Small cell lung cancer: 7, Carcinoid 73.

https://doi.org/10.1371/journal.pone.0266052.t001

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Post-operative complications

Post-operative complication rates are shown in Table 2. About a quarter (26%) of patients

experienced a PPC, with 71 patients experiencing more than one. The rates of specific compli-

cations were: atelectasis 4%, sputum retention 4%, pneumonia 7%, ARDS 1%, respiratory fail-

ure 4%, air leak 12% and empyema 1%.

There were no differences in overall complication rates according to smoking status. PPCs

were more frequent in current smokers compared to never smokers (27% vs 17%, p = 0.036),

however there was no difference between current and ex-smokers (p = 0.412) or between

never- and ex-smokers (p = 0.113). There were no differences in individual PPC rates or mean

lengths of stay according to smoking status, other than increased sputum retention for current

smokers compared to ex-smokers (p = 0.026).

As demonstrated in Table 3, those with a diagnosis of COPD had a higher frequency of

both PPCs (65% vs 35%, AOR 1.76, 95% CI 1.02–2.41, p<0.01) and overall complications

(60% vs 40%, AOR 1.53, 95% CI 1.17–2.01, p<0.01). Of the individual pulmonary complica-

tions, sputum retention (77% vs 23%, AOR 3.93, 95% CI 1.49–10.4), respiratory failure (78%

vs 22%, AOR 3.21, 95% CI 1.13–9.12) and air leak (66% vs 34%, AOR 2.85, 95% CI 1.12–7.20)

were more common in those with COPD. Mean length of stay was longer in those with COPD

(10.3 vs 9.0 days, p<0.01). Table 4 shows that the complication rates in those with COPD did

not differ between never and current smokers, apart from air leak being more common in cur-

rent smokers (p<0.01). Table 5 shows that sputum retention was more common amongst cur-

rent smokers compared to ex-smokers with COPD (AOR 10.9, 95% CI 1.58–74.9).

Discussion

This study is the first to examine the association between smoking, COPD and post-operative

complications following lung cancer resection in an Australian population. With 23 years of

prospective follow up, this study is the longest single centre lung cancer resection cohort

reported to date, as well as being one of the largest, world-wide. The study demonstrated a

higher rate of PPCs following lung cancer surgery in current smokers compared to never

Table 2. Complication rates grouped by smoking status.

Variables Never smokers, n(%) Current smokers, n(%) p1 Ex-smokers, n(%) p2 p3

Total participants
a

111 314 362

All complications 50 (45.0) 146 (46.5) 0.792 161 (44.5) 0.916 0.599

Pulmonary complications
b

19 (17.1) 85 (27.1) 0.036 88 (24.3) 0.113 0.412

Atelectasis 4 (21.1) 13 (15.3) 0.544 14 (15.9) 0.801 0.268

Sputum retention 6 (31.6) 20 (23.5) 0.474 11 (12.5) 0.061 0.026

Pneumonia 5 (26.3) 22 (25.9) 0.949 26 (29.5) 0.804 0.703

ARDS 0 (0) 5 (5.9) N/A 2 (2.3) N/A 0.089

Respiratory failure 4 (21.1) 14 (16.5) 0.629 12 (13.6) 0.611 0.140

Air leak 7 (36.8) 35 (41.2) 0.744 44 (50.0) 0.313 0.955

Empyema 1 (5.3) 3 (3.5) 1.000 5 (5.7) 0.988 0.932

Length of stay in days, Mean (±SD) 9.0 (7.1) 9.5 (6.6) 0.465 9.6 (6.9) 0.423 0.908

p1 indicates comparison between never smokers and current smokers; p2 indicates comparison between never smokers and ex-smokers; p3 indicates comparison

between current smokers and ex-smokers.

ARDS: Acute respiratory distress syndrome.

a: Smoking status was not recorded for 226 patients; hence they were excluded from the smoking status vs. complications analysis.

b: Some participants had more than one pulmonary complication.

https://doi.org/10.1371/journal.pone.0266052.t002

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smokers, which is comparable with previous literature [6, 24]. There was an increase in PPCs,

overall complications and length of stay in those with COPD compared to those without, inde-

pendent of smoking status. There was no significant difference in PPCs, overall complications

or length of stay in ex-smokers compared to either current or never smokers.

There have been several studies examining smoking cessation and its effect on lung cancer

surgery complication rates. Consistent with the results of our study, Fukui et al. demonstrated

a higher PPC rate in smokers compared to never smokers in 666 patients who underwent lung

cancer resections in a single centre in Japan [24]. In that study, however, differential results

were noted in ex-smokers, with decreasing odds of a PPC associated with a longer duration of

Table 3. Complication rates grouped by COPD status.

Variables COPD No COPD Unadjusted analyses Adjusted analyses

p ORs 95% CIs p AORs� 95% CIs

Total participants
a

500 455

Post-operative complications 267 (59.7) 180 (40.3) 0.000 1.75 1.35–2.26 0.002 1.53 1.17–2.01

Pulmonary complications 159 (65.4) 84 (34.6) 0.000 2.06 1.52–2.79 0.001 1.76 1.02–2.41

Atelectasis 22 (56.4) 17 (43.6) 0.866 0.92 0.37–2.31 0.890 0.93 0.35–2.51

Sputum retention 34 (77.3) 10 (22.7) 0.010 3.25 1.30–8.13 0.006 3.93 1.49–10.4

Pneumonia 44 (68.8) 20 (31.3) 0.140 1.87 0.81–4.31 0.096 2.21 0.87–5.63

ARDS 4 (50.0) 4 (50.0) 0.706 0.75 0.17–3.35 0.637 0.69 0.15–3.22

Respiratory failure 28 (77.8) 8 (22.2) 0.033 2.83 1.07–7.49 0.029 3.21 1.13–9.12

Air leak 72 (66.1) 37 (33.9) 0.155 1.82 0.79–4.16 0.027 2.85 1.12–7.20

Empyema 7 (63.6) 4 (36.4) 0.823 1.17 0.30–4.51 0.901 0.90 0.18–4.43

Length of stay, Mean (±SD) 10.3 (7.4) 9.0 (6.9) 0.006 Mean difference (-1.29) (-2.21) to (-0.38)

OR: Odds Ratio, AOR: Adjusted Odds Ratio, 95% CI: 95% Confidence Interval, ARDS: Acute respiratory distress syndrome.

� Adjusted for: age, gender and BMI.

a: Lung function was not recorded in 58 patients; hence they were excluded from the COPD status vs. complications analysis.

https://doi.org/10.1371/journal.pone.0266052.t003

Table 4. Complication rates grouped by smoking status (current and never-smokers) amongst COPD patients.

Variables Current smokers with

COPD

Never smokers with

COPD

Unadjusted analyses Adjusted analyses

p ORs 95% CIs p AORs� 95% CIs

Total participants 180 22

Post-operative

complications

97 (88.2) 13 (11.8) 0.644 0.81 0.33–1.99 0.384 0.64 0.24–1.73

Pulmonary complications 58 (92.1) 5 (7.9) 0.364 1.62 0.57–4.60 0.777 1.18 0.38–3.64

Atelectasis 6 (66.7) 3 (33.3) 0.803 1.33 0.14–12.8 0.202 17.3 0.22–

1375

Sputum retention 17 (85.0) 3 (15.0) 0.785 1.42 0.12–17.5 0.577 2.30 0.12–42.8

Pneumonia 13 (86.7) 2 (13.3) 0.844 1.30 0.10–17.7 0.737 1.71 0.07–39.3

ARDS 1 (100) 0 (0) 0.571 NA NA NA NA NA

Respiratory failure 9 (100) 0 (0) 0.086 NA NA NA NA NA

Air leak 24 (100) 0 (0) 0.003 NA NA NA NA NA

Empyema 2 (100) 0 (0) 0.429 NA NA NA NA NA

Length of stay, Mean (±SD) 10 (6.5) 10 (8.0) 0.976 Mean difference
(-0.05)

(-3.01) to

(2.92)

OR: Odds Ratio, AOR: Adjusted Odds Ratio, 95% CI: 95% Confidence Intervals, ARDS: Acute respiratory distress syndrome.

� Adjusted for: age, gender and BMI.

https://doi.org/10.1371/journal.pone.0266052.t004

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smoking cessation, and some reduction even after cessation for under a month. Lugg et al.

examined a group of 462 patients undergoing lung cancer resections in a thoracic centre in the

UK, and also found a higher rate of PPCs in smokers compared to never smokers [7]. There

was a trend towards a lower PPC rate in ex-smokers, which was defined as those who had

stopped any time prior to surgery. Nonetheless, they found no difference in PPCs in ex-smok-

ers who had quit for more than or less than six weeks. Rodriguez et al. performed a case con-

trol study in 378 patients, examining current smokers and recently (within 16 weeks)

reformed smokers, and found no difference in rates of pneumonia and atelectasis [20].

Part of the reason for the mixed evidence of the benefit of smoking cessation may lie in the

different definitions used in the studies to characterise ex-smokers. We used a more parsimo-

nious definition in our ex-smoker classification of one year of abstinence, as have other

authors [28]. There is no consensus on the duration of smoking abstinence required in order

to be defined as an ex-smoker. The most liberal definition of an ex-smoker is someone who

has not smoked in the past 24 hours. We know that likelihood of quitting smoking on any

given attempt is low, and that it takes multiple quit attempts to successfully abstain from smok-

ing [29]. It is also known that smoking cessation for 12 months or more significantly reduces

the risk of relapse [25]. Life insurance companies consider individuals as current smokers if

they have smoked even one cigarette in the preceding 12 months [30]. The rate of smoking

relapse after lung cancer resection is high. Cooley et al. studied a group of 84 ever-smokers

who underwent lung cancer resection and found that, after one month, 18% had relapsed,

increasing to 33% at two months and 42% at four months [31]. Ten participants who had quit

before their diagnosis of lung cancer resumed smoking after surgery. Out of the ten, eight had

abstained from cigarettes for a least a year prior to their lung cancer diagnosis. Even with our

strict definition, some participants classified as ex-smokers in our study could have relapsed in

the post-operative period. At the one-month mark in Cooley’s study, 13% admitted to a

resumption of smoking, with a positive urine cotinine analysis (reflecting nicotine intake),

increasing the proportion to 18%. The above-mentioned studies by Fukui, Lugg and Rodriguez

all relied on self-report, where it is possible that some of the participants who reported they

were ex-smokers (especially those who had quit recently), were still smoking, skewing the

results. Our definition of an ex-smoker may make it less likely to find differences between

Table 5. Complication rates grouped by smoking status (current and ex-smokers) amongst COPD patients.

Variables Current smokers with COPD Ex-smokers with COPD Unadjusted analyses Adjusted analyses

p ORs 95% CIs p AORs 95% CIs

Total participants 180 205

Post-operative complications 97 (49.2) 100 (50.8) 0.317 1.23 0.82–1.83 0.121 1.42 0.91–2.22

Pulmonary complications 58 (49.6) 59 (50.4) 0.464 1.18 0.76–1.82 0.343 1.26 0.78–2.03

Atelectasis 6 (46.2) 7 (53.8) 0.173 3.14 0.59–16.8 0.060 12.8 0.90–182

Sputum retention 17 (63.0) 10 (37.0) 0.024 4.68 1.17–18.7 0.015 10.90 1.58–74.9

Pneumonia 13 (39.4) 20 (60.6) 0.953 1.04 0.28–3.88 0.229 3.14 0.49–20.3

ARDS 1 (33.3) 2 (66.7) 0.952 1.08 0.08–14.4 0.754 1.67 0.07–42.2

Respiratory failure 9 (42.9) 12 (57.1) 0.328 1.95 0.51–7.49 0.144 3.68 0.64–21.1

Air leak 24 (43.6) 31 (56.4) 0.735 0.77 0.18–3.42 0.920 0.91 0.15–5.60

Empyema 2 (28.6) 5 (71.4) 0.943 0.93 0.14–6.23 0.215 5.31 0.38–74.1

Length of stay, Mean (±SD) 10 (6.5) 10.1 (7.6) 0.871 Mean difference (0.12) (-1.30) to (1.53)

OR: Odds Ratio, AOR: Adjusted Odds Ratio, 95%CI: 95% Confidence Interval, ARDS: Acute respiratory distress syndrome.

� Adjusted for: age, gender and BMI.

https://doi.org/10.1371/journal.pone.0266052.t005

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never and ex-smokers, although more likely to find differences between current and ex-

smokers.

Similarly, there is no universally accepted definition of a PPC, resulting in rates ranging

from 5% in a study that characterised PPC as atelectasis requiring bronchoscopy and or pneu-

monia (Rodriguez et al) to 32% in another study that defined a PPC as hypoxia, pneumonia,

atelectasis and or uncontrolled sputum production (Fukui et al) [20, 24]. It is possible that

studies with a more inclusive PPC definition would be better powered to find a difference in

complication rates. Compared to the above studies our definition of a PPC was more compre-

hensive, and hence a better representation of the true respiratory complication rate and the

effect smoking status has on this.

Despite the mixed evidence of its value in the perioperative period, smoking cessation is

still beneficial in early stage lung cancer, with reduced risk of cancer recurrence, lower rates of

development of a secondary primary tumour and improved long term survival in those who

quit [32]. Long term survival is thought to be driven by a reduction in both cardiorespiratory

and cancer-related deaths. Indeed, a new lung cancer diagnosis may be an effective time to

employ smoking cessation strategies, with a retrospective analysis showing that an intensive

smoking cessation program prior to lung cancer resection achieved smoking cessation rates of

just over 50% at 24 months [33]. For these reasons, we believe that smoking cessation should

still be actively pursued in the preoperative period.

In concordance with our results, several previous studies have shown a higher frequency of

PPCs in patients with COPD [16–19]. The COPD incidence of 57% in smokers or ex-smokers

in our study population is comparable with that in other lung cancer cohorts [12, 34]. Given

the increased perioperative risk associated with COPD, the question is raised as to whether

post-operative outcomes can be improved through peri-operative optimisation of COPD man-

agement. Our management of patients with lung cancer has always been multidisciplinary,

involving regular meetings between respiratory physicians, thoracic surgeons, oncologists,

radiologists, pathologists, and radiotherapists. This has included regular referral of patients to

respiratory physicians for pre-operative maximisation of COPD therapy, as well as consensus

decision-making regarding the appropriateness of surgery as the treatment modality. Key aims

of COPD management include optimisation of function and prevention of exacerbations. Not

only are exacerbations associated with increased mortality [35], but the risk of exacerbation is

increased post thoracic surgery [36], and those with reduced lung function have poorer surgi-

cal outcomes [37]. Thus, therapies that improve lung function and reduce the risk of exacerba-

tion could be expected to be beneficial in the perioperative setting.

Long-acting bronchodilators improve lung function and symptoms, and decrease exacerba-

tions [38]. There is some evidence that inhaled long-acting muscarinic antagonists (LAMAs)

and long-acting beta agonists (LABAs) reduce post-operative complications, however studies

have mostly been retrospective in nature, with small numbers of participants [39–41]. The

combination of LAMA and LABA has been shown to improve lung function, symptoms and

exacerbation rates more than bronchodilator monotherapy [42]. Makino et al. performed a

retrospective analysis of 33 patients, comparing combination LAMA/LABA with bronchodila-

tor monotherapy, demonstrating a reduction in the rate of post-operative pneumonia in the

combination group, but no difference in any other pulmonary or cardiovascular complication

[43]. Inhaled corticosteroids (ICS) are recommended in patients with recurrent exacerbations

of their COPD, concomitant asthma, and/or elevated serum eosinophil levels [27]. Bölükbas

et al. compared LAMA/LABA vs. LAMA/LABA/ICS therapy prospectively in a group of 46

patients newly diagnosed with both lung cancer and moderate to severe COPD [44]. After one

week of treatment, lung function improved in both groups, with more patients in the triple

therapy group having a greater than 10% improvement in FEV1 as well as a decrease in GOLD

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COPD severity class. A statistically significant reduction in PPCs was seen in the triple therapy

group as well, driven by reductions in pneumonia and sputum retention. We have found no

other trials looking at ICS therapy or dual versus mono bronchodilator therapy in patients

undergoing lung cancer resection. Despite a lack of high quality evidence it would seem appro-

priate to maximise bronchodilatation in patients with COPD in the peri-operative period, and

to consider the addition of ICS in those with moderate to severe COPD, an allergic phenotype,

or an elevated serum eosinophil count.

Pre-operative pulmonary rehabilitation or “prehabilitation” may also reduce perioperative

risk. Pulmonary rehabilitation programs have been shown to improve symptoms and quality

of life and to reduce exacerbations [45, 46]. Although most programs are 6–8 weeks in dura-

tion, there is evidence that shorter duration programs can be beneficial. Mujoiv et al. demon-

strated that a 2–4 week period of pre-operative pulmonary rehabilitation improved lung

function in a group of patients with NSCLC and COPD awaiting surgery, although bronchodi-

lator therapy was included as part of the program, which may have contributed to this

improvement [47]. In a randomised controlled trial (n = 101) of a one week high intensity

inpatient exercise program prior to lobectomy, Lai et al demonstrated a reduction in PPCs and

length of stay in the exercise group [48]. A meta-analysis showed that inspiratory muscle train-

ing reduces PPCs and length of stay in cardiac, pulmonary, and abdominal surgical patients

[49], and a recent randomised controlled trial demonstrated similar benefits in a group of

patients with lung cancer [50]. Many of the studies examining the impact of prehabilitation on

complications of lung cancer resection have included unselected populations, rather than

those who have comorbid COPD. A meta-analysis performed by Li et al. included three rando-

mised controlled trials looking at PPCs in those with COPD and lung cancer. Whilst there was

an overall reduction in length of stay, there was only a trend to a reduction in PPCs, that did

not reach statistical significance, however numbers were small [51]. We believe it would be

reasonable to recommend exercise therapy prior to surgery if this does not delay surgery.

More studies targeting the COPD population specifically are required to determine the type

and duration of the exercise program.

The proportion of never smokers with COPD in our study (just on 20%) is reflective of the

literature [12, 52]. The airflow obstruction in the never smokers in our study could relate to

second-hand smoke exposure, air pollution, or asthma. We were unable to determine the exact

aetiology as comorbid conditions and environmental exposures were not recorded in the data-

base. There is a possibility that airflow obstruction was over diagnosed in older patients, as we

used a fixed 0.7 cut off for FEV1/FVC ratio, rather than an age adjusted lower limit of normal

[52]. As the ex-smokers in our study were older than the current smokers, this may have led to

a higher complication rate in the ex-smokers. It is possible this may have contributed to the

lack of difference in complications seen between current and ex-smokers.

There are a few limitations of our study. The first is that we were not able assess the impact

of a shorter period of smoking cessation on complication rates. Although our definition of a

current smoker allows us to characterise more accurately those who were probably still smok-

ing, it does not allow us to make a granular assessment of the impact of smoking cessation in

the days to weeks prior to surgery. Using a shorter period of abstinence to define quitting as

well as using objective testing for cigarette use would be a way to examine this in the future.

The second limitation is the use of pre-, rather than post-bronchodilator spirometry, to define

COPD. This may have overestimated the number of patients who truly had COPD, although it

is not uncommon to use pre-bronchodilator spirometry to diagnose COPD if post-bronchodi-

lator spirometry is not available. The third limitation is that we do not have data on pre-exist-

ing comorbidities that may have increased the post-operative complication rate. In our cohort

of smokers and in those with COPD, cardiovascular disease would likely have been the most

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significant comorbidity. This may have contributed to the overall complication rate but is

unlikely to significantly impact the pulmonary complication rate. Notwithstanding these limi-

tations, our study is an important addition to the literature, given our large study population

and comprehensive data set. Complications were clearly defined and prospectively recorded.

Spirometry was available on nearly all our patients and hence we were able to comment use-

fully on the likelihood of a concurrent diagnosis of COPD, its severity, and the impact of the

COPD diagnosis on outcomes.

Conclusion

Smoking and COPD are both associated with a higher rate of PPCs post lung cancer resection.

COPD, independent of smoking status, is also associated with an increased overall post-opera-

tive complication rate and length of hospital stay. Smoking cessation should be pursued in the

preoperative period, however an emphasis on COPD treatment optimisation, rather than

smoking cessation in isolation, may maximise post-operative outcomes. Future studies should

assist in determining the most appropriate peri-operative program of smoking cessation, “pre-

habilitation” and pharmacotherapy to maximise outcomes in patients undergoing lung cancer

surgery.

Supporting information

S1 Appendix. Smoking, COPD, lung cancer.

(DOCX)

Author Contributions

Conceptualization: Vishnu Jeganathan, Simon Knight, Matthew Bricknell, Anna Ridgers,

Raymond Wong, Danny J. Brazzale, Warren R. Ruehland, Muhammad Aziz Rahman,

Tracy L. Leong, Christine F. McDonald.

Data curation: Vishnu Jeganathan, Simon Knight, Matthew Bricknell.

Formal analysis: Muhammad Aziz Rahman.

Methodology: Vishnu Jeganathan, Simon Knight, Matthew Bricknell, Anna Ridgers, Ray-

mond Wong, Danny J. Brazzale, Warren R. Ruehland, Muhammad Aziz Rahman, Tracy L.

Leong, Christine F. McDonald.

Resources: Simon Knight.

Supervision: Tracy L. Leong, Christine F. McDonald.

Writing – original draft: Vishnu Jeganathan, Matthew Bricknell.

Writing – review & editing: Vishnu Jeganathan, Simon Knight, Matthew Bricknell, Anna Rid-

gers, Raymond Wong, Danny J. Brazzale, Warren R. Ruehland, Muhammad Aziz Rahman,

Tracy L. Leong, Christine F. McDonald.

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PLOS ONE Smoking and lung cancer surgery

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