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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 Wong1,2, Danny J. Brazzale1,2, Warren R. RuehlandID 1,2, Muhammad
Aziz Rahman2,5, Tracy L. Leong1,2,4, Christine F. McDonald1,2,4
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
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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OPEN ACCESS
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-
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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) 7th 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/m2 (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 participantsa 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/m2), 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 operationb 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
Staged 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
Histologye 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 diagnosisf 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.
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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 participantsa 111 314 362
All complications 50 (45.0) 146 (46.5) 0.792 161 (44.5) 0.916 0.599
Pulmonary complicationsb 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.
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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 participantsa 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.
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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.
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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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