Concise Clinical Review
Lung Cancer in Chronic Obstructive Pulmonary Disease
Enhancing Surgical Options and Outcomes
Stacy Raviv1, Keenan A. Hawkins1, Malcolm M. DeCamp, Jr.2,3, and Ravi Kalhan1,4
1
Division of Pulmonary and Critical Care Medicine, 2Division of Thoracic Surgery, 3Robert H. Lurie Comprehensive Cancer Center, and
4
Asthma-COPD Program, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Patients with chronic obstructive pulmonary disease (COPD) are at
increased risk for both the development of primary lung cancer, as
well as poor outcome after lung cancer diagnosis and treatment.
Because of existing impairments in lung function, patients with
COPD often do not meet traditional criteria for tolerance of
definitive surgical lung cancer therapy. Emerging information re-
garding the physiology of lung resection in COPD indicates that
postoperative decrements in lung function may be less than antic-
ipated by traditional prediction tools. In patients with COPD, more
inclusive consideration for surgical resection with curative intent
may be appropriate as limited surgical resections or nonsurgical
therapeutic options provide inferior survival. Furthermore, optimiz-
ing perioperative COPD medical care according to clinical practice
guidelines including smoking cessation can potentially minimize
morbidity and improve functional status in this often severely
impaired patient population.
Chronic obstructive pulmonary disease (COPD) is the fourth
leading cause of death in the United States (1). In addition to
the irreversible airflow obstruction that characterizes the dis-
ease, COPD is recognized as a systemic inflammatory disorder
with numerous additional pulmonary and extrapulmonary man-
ifestations, including an increased risk for development of
primary lung cancers (2). The association between COPD and
lung cancer has been reported in numerous studies and is
notably independent of patient age or extent of tobacco
exposure (3, 4). The risk of lung cancer in patients with COPD
is two- to fivefold greater compared with smokers without
COPD (57).
Although the risk of lung cancer in patients with COPD has
long been established, progress in surgical care as well as an
expanded understanding of the physiology of lung resection in
COPD may help improve outcomes for patients with COPD
and lung cancer. Central to achieving improved outcomes is
greater consideration of surgical resection with curative intent,
as limited surgical resections (810) or nonsurgical therapeutic
options (1113) provide inferior survival compared with re-
section. Furthermore, optimization of perioperative medical
care, as well as medical care in nonsurgical patients, can
potentially minimize morbidity and improve functional status
in this severely impaired population.
(Received in original form August 12, 2010; accepted in final form December 30, 2010)
Correspondence and requests for reprints should be addressed to Ravi Kalhan,
M.D., M.S., Asthma-COPD Program, Division of Pulmonary and Critical Care
Medicine, Northwestern University Feinberg School of Medicine, 676 N St. Clair
Street, Suite 1400, Chicago, IL 60611. E-mail: r-kalhan@northwestern.edu
Am J Respir Crit Care Med Vol 183. pp 11381146, 2011
Originally Published in Press as DOI: 10.1164/rccm.201008-1274CI on December 22, 2010
Internet address: www.atsjournals.org
POSSIBLE MECHANISMS FOR THE ASSOCIATION
BETWEEN COPD AND LUNG CANCER
Chronic inflammation associated with COPD likely plays a role
in the pathogenesis of lung cancer, just as chronic inflammation
contributes to malignant transformation in other organs (1416).
Inflammation in COPD may result in repeated airway epithelial
injury and accompanying high cell turnover rates and propaga-
tion of DNA errors resulting in amplification of the carcino-
genic effects of cigarette smoke (17). Although all lung cancer
cell types occur in the setting of COPD, airflow obstruction has
been specifically associated with increased risk for squamous
cell carcinoma (6, 18, 19). Some have postulated that impaired
mucociliary clearance of carcinogenic substances from cigarette
smoke, owing to chronic airflow obstruction, increases exposure
of the bronchial epithelium to these carcinogens and promotes
pathologic changes leading to squamous cell neoplasia (19).
Some of the hypothesized mechanisms of association between
COPD and lung cancer are shown in Figure 1.
Given the hypothesis that lung cancer risk in COPD is
related to chronic airway inflammation, inhaled corticosteroids
have been considered as possible chemopreventive agents. One
multicenter cohort study of patients with COPD conducted in
the U.S. Veterans Administration Health System demonstrated
a dose-dependent decrease in the risk for lung cancer associated
with use of inhaled corticosteroids (20). A meta-analysis of
seven randomized trials examining the benefits of inhaled cor-
ticosteroids in COPD similarly showed a trend toward de-
creased lung cancer risk in the inhaled corticosteroidtreated
groups (21). However, the analyses were limited by short mean
follow-up times, a small number of incident lung cancer cases,
and the inclusion of studies not specifically designed to detect
differences in incident lung cancer.
A shared genetic susceptibility to development of COPD
and lung cancer may be present. Shared genetic loci have been
reported on chromosome 6q for both lung cancer risk and
reductions in lung function, as well as on chromosome 12 for
lung cancer, COPD, and reduced lung function (22). Various
studies have implicated numerous genes in the pathogenesis of
both COPD and lung cancer, including a1-antitrypsin (23) and
microsomal epoxide hydrolase (24, 25), among others. Such
possible shared genetic susceptibilities to emphysema and
smoking-related DNA damage may additionally contribute to
increased aggressiveness of tumor cells in patients with emphy-
sema. For example, tumor progression and metastasis, which
require matrix metalloproteinase activity, may be enhanced in
emphysematous lungs where an increased abundance of matrix
metalloproteinases has been associated with emphysema path-
ogenesis (26, 27).
Given these strong associations and the unique interplay
between lung cancer and COPD, physicians caring for patients
with lung cancer occurring in the setting of COPD must account
Concise Clinical Review
Figure 1. Hypothesized mechanisms of the association between
chronic obstructive pulmonary disease (COPD) and lung cancer.
for both diseases when formulating therapeutic plans. This is
the focus of the remainder of this review.
TRADITIONAL EVALUATION FOR SURGICAL RESECTION
OF LUNG CANCER
A large body of literature supports the use of pulmonary
function studies, cardiopulmonary exercise testing, and nuclear
perfusion scanning to guide assessment of pulmonary risk and
patient selection for lung resection (28, 29). Virtually all
patients with COPD fall outside the population of patients
who are generally considered safe to undergo lung resection
without further investigation (those with both FEV1 and carbon
monoxide diffusing capacity [DLCO] greater than or equal to
80% of predicted) (30). For these patients, predicted post-
operative FEV1 values (estimated using data from split function
lung perfusion scanning and the extent of planned resection)
between 700 and 1,000 ml or greater than 3040% of predicted
normal values have been thought to be safe for resection (31).
Similarly, a predicted postoperative value for DLCO greater than
40% of predicted normal has been suggested as a safe cutoff
(30, 32) (Table 1). Six-minute walk tests and cardiopulmonary
exercise testing can further provide information to help physi-
cians estimate the safety and feasibility of resection (30, 32).
Despite numerous studies suggesting specific numerical
cutoff values for safe resection, it is important to consider that
progressive developments in anesthetic techniques, minimally
invasive surgery, and intensive care unit quality of care all likely
contribute to a reduction in postoperative complications and
improvement in outcomes. Therefore, surgery may be a viable
option for many patients previously considered to be at un-
acceptably high surgical risk (33).
ROLE OF LIMITED SURGICAL RESECTION OF LUNG
CANCER IN COPD
Sublobar resection for nonsmall cell lung cancer is an impor-
tant consideration for patients with COPD, as preservation of
lung function in those with extremely low FEV1 might some-
times be better achieved with limited resection. This remains
a controversial issue, at least in part due to a lack of randomized
clinical trials comparing lobectomy with more modest resec-
tions. The only randomized trial to date showed that for T1N0
nonsmall cell lung cancer (<3 cm), sublobar resections are
1139
TABLE 1. TRADITIONAL CRITERIA FOR TOLERANCE OF
ANATOMIC SURGICAL RESECTION OF EARLY-STAGE
NONSMALL LUNG CANCER
Criterion Value
Preoperative FEV1 .1.5 L or .80% of predicted
Preoperative DLCO .80% of predicted
V_ O2 maximum .15 ml/kg/min
Predicted postoperative FEV1 .40% of predicted
Predicted postoperative DLCO .40% of predicted
Definition of abbreviations: DLCO 5 carbon monoxide diffusing capacity; V_ O2
maximum 5 maximal oxygen uptake.
associated with higher local recurrence rates, but only trends
toward worse overall and cancer-related survival (30% increase,
P 5 0.08 and 50% increase, P 5 0.09, respectively) (10).
Complicating the findings, the study contained a mixture of
patients undergoing both segmentectomy and wedge resection
and also suffered from loss of follow-up of some patients.
Most of the remaining literature comparing segmentectomy
and wedge resection with traditional lobectomy involves pa-
tients who were poor lobectomy candidates, often because of
poor lung function. A meta-analysis concerning survival after
lobectomy and limited resection for stage I nonsmall cell lung
cancer (34), as well as a number of prospective nonrandomized
studies (some including patients who were deemed fit to tolerate
lobectomy), suggest, like the one randomized trial, that 5-year
survival rates are not different with limited resection (3537).
Although a number of retrospective studies also suggest
similar survival rates in individuals who have undergone
lobectomy versus segmentectomy or wedge resection (9, 38
44), an equally significant body of retrospective evidence
demonstrates worse 5-year survival among those who have
had sublobar resection (4549). These disparate findings make
clinical interpretation and application difficult and likely result
from significant selection bias. Negative studies, with respect to
survival, may also be influenced by the size of tumors included
for study. Limited resection for tumors less than 2 cm in
diameter has, for the most part, been found not to come at
the expense of worse survival (37, 47, 49, 50). However,
a relatively large study of 100 patients with tumors not more
than 1 cm in diameter found that overall 5-year survival was
best with lobectomy, intermediate for segmentectomy, and
worst for wedge resection, with higher recurrence rates (com-
bined local and distant) seen for wedge resections compared
with the larger resections (46).
A study of 1,165 Medicare patients supports the concept that
the size of the primary tumor is an important parameter when
considering limited resection. Patients who underwent lobec-
tomy or limited resection for stage I lung cancer less than or
equal to 2 cm in diameter were evaluated for overall and lung
cancerspecific survival, adjusting for patient preoperative
characteristics. The adjusted hazard ratios for all cause mortal-
ity and lung cancerspecific death for limited resection (per-
formed in 196 patients) were not significantly different from
those of lobectomy patients. In the subgroup of individuals with
primary tumors between 2 and 3 cm in diameter, limited
resection was associated with increased overall and lung cancer
specific mortality.
A total of 2,090 cases of stage I nonsmall cell lung cancer
less than or equal to 1 cm were reviewed through the Surveil-
lance, Epidemiology, and End Results (SEER) registry. There
were no significant differences in overall or cancer-specific
survival between patients treated by lobectomy and those 688
treated by limited resection (segmentectomy and wedge re-
section) (51). It is important to note that both segmentectomies
1140 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
and wedge resections were included in the limited resection
group in both the Medicare and SEER registries, and retro-
spective comparisons of wedge resection to segmentectomy
have demonstrated worse survival and increased local recur-
rence with wedge resection (49, 52, 53).
Taken together, available data suggest that limited resections
should be avoided in patients who can tolerate lobectomy.
Prospective studies that validate the concept that limited resection
is equal to lobectomy for patients with tumors less than 2 cm in
diameter would be valuable, particularly in the context of patients
with COPD with low FEV1. At present, sublobar resection is a
reasonable option for a select set of patients who are poor
candidates for lobectomy, particularly those for whom low
FEV1 presents serious perioperative risks. Even in such patients,
segmentectomy should be considered superior to wedge resection.
COMPLETE ANATOMIC RESECTION OF LUNG CANCER
WITH OR WITHOUT CONCOMITANT LUNG VOLUME
REDUCTION SURGERY IN COPD
Since Cooper and colleagues published a favorable report on
a series of patients undergoing lung volume reduction surgery
for end-stage emphysema (54), clinicians have considered
combining lung volume reduction surgery (LVRS) with tumor
resection in otherwise traditionally poor surgical candidates.
The goal of LVRS is the reduction of lung hyperinflation
through resection of poorly functioning, emphysematous por-
tions of lung, allowing for improved exercise tolerance, better
bronchial clearance, improved quality of life, and survival (55
57). Numerous case series have suggested that the presence of
COPD may significantly affect the relationship between pre-
dicted and actual postoperative changes in pulmonary function,
even when volume reduction per se is not the primary purpose
of the procedure. Table 2 summarizes findings of a number of
such studies, particularly as they relate to FEV1.
This evidence suggests that only minimal decrements (or
even improvements) in FEV1 may occur after lung resection in
patients with COPD. However, use of spirometry alone may be
inadequate as a tool to predict postoperative loss of physical
functioning and exercise capacity. One small study of 11
patients with COPD undergoing lobectomy or bilobectomy,
mostly for primary lung cancer, demonstrated no significant
change in FEV1 or DLCO 3 months postoperatively, but did
show a significant decrease in maximal oxygen uptake (V _ O2)
from a mean value of 17.8 ml/kg/minute to a mean value of
14.1 ml/kg/minute (58). Similarly, a larger study of 100 patients
with COPD and patients without COPD undergoing lobectomy
showed that whereas patients with COPD lost less FEV1 than
their non-COPD counterparts, the loss of maximal V _ O2 was
similar between the patients without COPD and patients with
COPD with normal FEV1. However, those with mildly reduced
preoperative FEV1 showed smaller relative decreases in max-
imal V_ O2 postoperatively, and those with the lowest preopera-
tive FEV1 values actually showed an increase in maximal V _ O2
after surgery (59).
Functional improvements after lung resection were also
demonstrated in another series in which 21 patients with severe
emphysema (mean FEV1 29% predicted and mean DLCO 34%
predicted) underwent tumor resection and additional lung
volume reduction either via the resection of lung cancer in a
severely emphysematous lobe (in 9 patients) or the combination
of lobectomy or wedge resection with lung volume reduction
surgery (in the other 12 patients) (60). Despite postoperative
complications including prolonged air leak in 11 patients and
reintubation in 2 patients, these individuals demonstrated an
increase in 6-minute walk distances from a mean of 854 ft
VOL 183 2011
before surgery to 1,240 ft 6 months postoperatively. This func-
tional improvement was accompanied by significant decreases
in the number of patients who required supplemental oxygen
after surgery (60).
Unfortunately, radiographic and physiological measure-
ments have not proven to be useful predictors of functional
improvement after lung volume reduction surgery. Although
the ratio of residual volume to total lung capacity as well as the
ratio of upper lobe to lower lobe emphysema were statistically
significantly associated with postoperative FEV1 and maximal
exercise capacity in the National Emphysema Treatment Trial
(NETT), the magnitude of the association was extremely weak,
making it difficult to apply to clinical practice (61). Other
measures such as inspiratory resistance have shown promise in
small series (62) but are not widely clinically available and have
not been reproduced in larger studies (61).
Given this uncertainty, determining which patients with
COPD should undergo anatomic resection (lobectomy) of lung
cancer with our without concurrent lung volume reduction
surgery is difficult. Including the radiographic characteristics
of the group that benefited most in the NETT (upper lobe
predominant, heterogeneously distributed emphysema) when
considering anatomic resection seems the most reasonable
approach when evaluating whether patients with COPD and
lung cancer are appropriate candidates for lobectomy (57). We
recommend that patients with lung cancer and COPD not
meeting traditional criteria for safe anatomic resection (i.e.,
predicted postoperative FEV1 less than 3040% predicted or
predicted postoperative DLCO less than 40%) be considered for
lobectomy nonetheless if their tumor is in the upper or middle
lobe in an area of significant emphysema, and if the emphysema
is upper lobe predominant and heterogeneous in distribution.
Such patients can also be considered for concurrent lung
volume reduction surgery in the contralateral lung, but it should
be emphasized that this approach has not been studied in
a systematic manner: True LVRS is a nonanatomically guided
surgery that does not observe lobar boundaries whereas com-
bining LVRS with lung cancer resection would involve lobec-
tomy in the lung containing cancer. Because of the lack of data
to guide the selection of patients for this approach, we do not
advocate that this be performed in current clinical practice. We
do suggest that this is an appropriate area for systematic clinical
studies to be undertaken, focusing on both intermediate- and
long-term outcomes of patients with COPD with lung cancer. In
addition, we do not recommend concurrent lung volume re-
duction surgery at the time of limited resection of lung cancers
in nonemphysematous lobes or segments. An illustrative exam-
ple of lung cancer resection in a patient from our clinical
program is presented in Figure 2.
MODIFICATION OF PREOPERATIVE FUNCTION:
MEDICAL THERAPY, PULMONARY REHABILITATION,
AND SMOKING CESSATION
Preoperative functional status may be optimized with appropri-
ate medical therapy, pulmonary rehabilitation, and smoking
cessation. Although it seems logical that interventions, such
as pulmonary rehabilitation, which improve COPD-specific
functional scores (such as the body mass indexobstruction
dyspneaexercise index [BODE]) (63), might translate into
improved perioperative morbidity and mortality, whether this
is actually the case has not been tested in clinical studies.
Medical Therapy
There is a paucity of data to demonstrate that medical
optimization improves perioperative outcomes. Medical ther-
Concise Clinical Review 1141

TABLE 2. SUMMARY OF REPORTS OF LUNG CANCER RESECTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND THE
IMPACT ON FEV1
Number of
Author, Year (Ref.) Patients Subjects Type of Surgery Mean Preoperative FEV1 Postoperative FEV1

Munoz et al., 1 Left upper lobe malignant Wedge resection of nodule 0.66 L (21% predicted) 0.70 L
1996 (99) nodule with resection of separate
emphysematous left
lower lobe areas
Korst et al., 32 13 with preoperative Lobectomy Low FEV1 group: 1.35 L Low FEV1 group:
1998 (100) FEV1 < 60% predicted; (49% predicted); high 3.7% increase from
19 with preoperative FEV1 group: 1.87 L preoperative value;
FEV1 6080% predicted (69% predicted) higher FEV1 group:
15.7% reduction from
preoperative value*
Sekine et al., 521 48 patients with COPD, Lobectomy COPD group: 1.8 L; COPD group: 13.1%
2003 (101) 473 patients without COPD non-COPD group: 2.3 L reduction from
preoperative value*;
non-COPD group:
change of 29.2%
reduction from
preoperative value
Choong et al., 21 Severe emphysema Lobectomy or 0.70 L (29% predicted) 1.0 L (40% predicted)
2004 (60) wedge, with or without
lung volume reduction
in a lobe separate
from the tumor
Bobbio et al., 11 Patients with COPD Lobectomy or bilobectomy 1.4 L (53% predicted) 1.4 L (53% predicted)
2005 (58)
Baldi et al., 137 88 patients with COPD, Lobectomy COPD group: 56% predicted; COPD group: 64%
2005 (102) 49 patients without COPD non-COPD group: 98% predicted; non-COPD
predicted group: 78% predicted
Iwasaki et al., 50 Patients with COPD Lobectomy (31 patients), Among subjects with Decreases in FEV1 were
2005 (103) segmentectomy (11 patients), FEV1 > 50 and , 80% lower than predicted
bilobectomy (8 patients) predicted:1.53 L; among preoperatively
subjects with FEV1 , 50%
predicted: 1.03 L
Subotic et al., 82 35 patients with COPD, Lobectomy and COPD group: 1.60 L COPD group: 12% reduction
2007 (104) 47 patients without COPD pneumonectomy for lobectomy, 1.91 L from preoperative value
for pneumonectomy; for lobectomy, 18%
non-COPD group: 2.85 L reduction for
for lobectomy, 2.93 L for pneumonectomy;
pneumonectomy non-COPD group:
25% reduction from
preoperative value for
lobectomy,* 43%
reduction for
pneumonectomy*
Schattenberg et al., 79 Patients with COPD Lobectomy 1.2 L 8% reduction from
2007 (105) preoperative value
immediately after
surgery. Values
returned to baseline
3 mo postoperatively
Kushibe et al., 100 30 patients with COPD, 70 Lobectomy COPD with FEV1 > 80%: COPD with FEV1 > 80%:
2008 (106) patients without COPD 2.09 L; COPD with 11.6% reduction from
FEV1 , 80%: 1.37 L; preoperative value;
non-COPD group: 2.48 L COPD with FEV1 ,
80%: 4.7% increase
from preoperative
value; non-COPD
group: 14.7%
reduction from
preoperative value

Definition of abbreviation: COPD 5 chronic obstructive pulmonary disease.

* P , 0.05 for comparison between groups.

P , 0.0005 for comparison with preoperative value.

P , 0.005 for comparison with both non-COPD and COPD/normal FEV1 groups.
1142 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
apy for COPD can be maximized according to guidelines set by
the Global Initiative for Chronic Obstructive Lung Disease
(GOLD) and the American Thoracic Society and the European
Respiratory Society guidelines for COPD management (64, 65).
Guidelines from these sources include the use of bronchodilators
(particularly long-acting), often in combination, as well as inhaled
corticosteroids for patients with recurrent COPD exacerbations.
In an analysis of data from the NETT, oral steroid use at the
time of surgery was found to be an independent predictor of major
cardiac morbidity in a multivariable analysis (66). Although it is
possible that use of oral steroid at the time of surgery was a marker
for COPD severity or poorly controlled disease (and cardiac
disease has been shown to increase with worsening COPD) (67),
maximal reduction of systemic corticosteroid to a dose equivalent
to 20 mg of prednisone daily is appropriate in preparation for lung
volume reduction surgery (68), and was a prerequisite for in-
clusion in the NETT (69). This likely applies to the patient with
COPD undergoing lung resection for lung cancer as well.
Pulmonary Rehabilitation
A program of rehabilitative exercise has been shown to improve
exercise capacity in nonsurgical patients with COPD (70, 71).
Such preoperative exercise training may improve V _ O2 sufficiently
to move a patient from a physiologically unresectable category
(maximal V _ O2 , 10 mg/kg/min) to a potentially resectable one.
In the NETT, preoperative rehabilitation was most beneficial in
patients who had never participated in a program previously,
although changes after rehabilitation were not predictive of dif-
ferential mortality or improvement in exercise capacity after
surgery (72).
No definitive data exist to show that pulmonary rehabilitation
alters short- or long-term outcome after lung cancer resection. A
study of 22 patients with lung cancer and COPD, and who
underwent lobectomy, examined postoperative outcomes after 2
weeks of preoperative aggressive pulmonary exercise and chest
VOL 183 2011
Figure 2. This computed tomography scan serves as an
illustrative example from the authors clinical program of
early-stage lung cancer in a patient with chronic obstruc-
tive pulmonary disease (COPD). This 76-year-old man
with GOLD (Global Initiative for Chronic Obstructive Lung
Disease) stage 2 COPD had an incidentally detected 1.3 3
1.3 cm right upper lobe lung nodule. Preoperative post-
bronchodilator FEV1 was 1.52 L (52% of predicted), FVC
was 3.06 (75% of predicted), FEV1/FVC ratio was 50%,
and diffusion capacity to carbon monoxide (DLCO) was
47% of predicted. His preoperative 6-minute walk dis-
tance was 347 m. He underwent 4 weeks of preoperative
pulmonary rehabilitation and continued treatment with
long-acting bronchodilators. A minimally invasive right
upper lobectomy was performed and documented stage
1A nonsmall cell lung cancer. Two weeks postopera-
tively, he returned to pulmonary rehabilitation for an
additional 8 weeks. Four months postoperatively, his
FEV1 had increased to 1.74 L (57% predicted), his FVC
was 3.27 (77% predicted), his DLCO was unchanged, and
his 6-minute walk distance was 376 m.
physiotherapy (73). These patients had decreased rates of pro-
longed oxygen supplementation and need for tracheotomy, as
well as shorter postoperative hospital stays, compared with 60
historical control subjects who did not undergo rehabilitation.
Application of these results is limited by the single-center ex-
perience, small sample size, and use of historical control subjects.
However, given the safety of pulmonary rehabilitation as well as
its documented benefits in nonsurgical patients with COPD,
a recommendation of a pulmonary rehabilitation program both
before and after lung cancer resection seems appropriate in
patients with moderate to severe COPD.
Smoking Cessation
Many patients with COPD are active smokers at the time of
cancer diagnosis. Given the relationship between smoking and
respiratory complications in the postoperative period (74, 75),
smoking cessation has been proposed as a method to reduce
perioperative risk. Because a small number of studies have,
perhaps paradoxically, suggested an increased risk for post-
operative pulmonary complications in patients who quit smok-
ing within 2 months of surgery (74, 76, 77), some physicians
have not aggressively advocated smoking cessation in the period
immediately before lung cancer resection surgery. Hypotheses
proposed to explain the reported increase in risk with smoking
reduction or cessation in the immediate preoperative period
include nicotine withdrawal and increased volumes of sputum
production, which have been observed transiently among recent
quitters of cigarette smoking (78). Increased sputum volume may
be exacerbated by a concurrent reduction in irritant-induced
coughing among those who have recently quit smoking compared
with those who continue to smoke (in whom ongoing exposure to
irritants in cigarette smoke induces continued coughing and more
effective bronchial clearance) (74, 79). Some speculate that this
reduction in coughing in recent quitters occurs before recovery of
ciliary function and other antimicrobial and antiinflammatory
Concise Clinical Review
functions of the respiratory epithelium, making recent quitters
particularly vulnerable to postoperative pulmonary complications
(74). Beyond these possible explanations, it is important to
consider the possible effects of selection bias in these observa-
tional studies, as sicker subjects at increased risk for postopera-
tive pulmonary complications may have been more likely to
reduce cigarette use before surgery (74).
Given the suggested increased risk of pulmonary complica-
tions among recent quitters undergoing pulmonary resection in
small studies, a prospective study of nonsmokers and smokers
undergoing thoracotomy for primary or secondary lung tumors
was conducted (80). Three hundred patients were divided into
groups of nonsmokers (21%), past quitters of greater than 2
months in duration (62%), recent quitters of less than 2 months
in duration (13%), and ongoing smokers (4%). Pulmonary
complications occurred in 8, 19, 23, and 23% of these groups,
respectively, with no significant difference between the three
subgroups of current and former smokers.
Most recently, in-hospital outcomes for 7,990 primary lung
cancer resections in the Society of Thoracic Surgeons General
Thoracic Surgery Database were evaluated in the context of
smoking (81). A multivariable logistic regression model demon-
strated an increased risk for in-hospital mortality among both
current smokers and recent quitters (those who had quit between
14 d and 1 mo before surgery) compared with nonsmokers (ad-
justed odds ratios were 3.5 [95% confidence interval, 1.111] for
current smokers and 4.6 [95% confidence interval, 1.218] for
those who had quit 14 d to 1 mo before surgery compared with
nonsmokers). However, no significant differences in outcomes
were reported between recent quitters and current smokers. In
addition, those smokers who had quit more than 1 month before
surgery did not have statistically significantly increased mortality
rates compared with nonsmokers. Pulmonary complication rates,
compared with those of nonsmokers, were increased only in those
patients who continued to smoke and not in recent quitters (81).
For patients with COPD, the time of lung cancer diagnosis
represents a critical window of opportunity for smoking cessa-
tion, with studies showing quit rates of 5060% after diagnosis
(82, 83). Compared with patients with lung cancer who continue
to smoke, studies have reported improved performance status
up to 6 and 12 months after diagnosis among quitters (83), as
well as improved overall quality of life, improved appetite, and
less fatigue, cough, shortness of breath, lung cancer symptoms,
and illness affecting normal activities (82). Smoking cessation has
additionally been found to increase both overall and disease-
specific survival in lung cancer (8486).
Because of the opportunity to achieve abstinence from
cigarette smoking that is presented by the preoperative period
before lung cancer surgery, we strongly recommend that pa-
tients quit smoking regardless of timing before surgery, and be
provided medical assistance to do so. If possible, delaying sur-
gical resection such that 1 month of smoking abstinence has
been achieved may reduce risk of postoperative complications
to the level of nonsmokers. However, if it is not feasible to delay
surgery, there is no evidence to support the concept that quitting
within 1 to 2 months of surgery confers greater risk than con-
tinued smoking.
PROGNOSIS FOR PATIENTS WITH COPD
AND LUNG CANCER
The overall prognosis for patients with COPD and lung cancer
is worse than that of patients with lung cancer without COPD
(87, 88). Certainly those patients denied surgery, or offered
only limited resection because of impaired pulmonary func-
tion, may not have the option of surgical cure. In addition,
1143
nonsurgical treatment options (limited by scant available
supporting data and often reserved for poor surgical candi-
dates) such as radiation therapy (89, 90), radiofrequency ablation
(11, 91), stereotactic body radiotherapy (92), and cryotherapy
(91) have resulted in poorer survival and increased rates of local
recurrence compared with surgical treatment.
The impact of COPD on survival after resection of lung
cancer is uncertain. One series demonstrated that for patients
with stage I disease and low predicted postoperative FEV1
values (less than 40%), 5-year survival postresection is sig-
nificantly lower, compared with patients with better lung func-
tion (35 vs. 65%) (93). Given that the immediate postoperative
mortality and rates of tumor recurrence were similar in the two
groups, the increased 5-year mortality in the high-risk group was
presumed to be due to nononcological factors. This lower survival
rate for patients with severely limited respiratory reserve is
consistent with reports by other groups (94, 95).
A retrospective review of patients with pathologic stage IA
lung cancer, all treated by complete resection by lobectomy,
examined outcomes among patients with and without COPD
(96). Frequencies of acute lung injury, bronchial fistula,
empyema, and prolonged mechanical ventilation were similar
between the 80 patients with COPD and 362 patients without
COPD; however, patients with COPD had higher rates of
postoperative pneumonia and tracheotomy. Overall survival in
the COPD group was significantly worse, with 5-year survivals
of 91.6 and 77.0% among patients without COPD and patients
with COPD, respectively (P , 0.0001). Of the patients without
COPD, 13.5% had recurrence of their lung cancer, whereas
21.3% of patients with COPD had undergone recurrence by 10
years of follow-up. Multivariable analysis of risk factors for
disease-free survival documented increased risk related only
for tumor size (hazard ratio, 1.775; 95% confidence interval,
1.2602.501) and the presence of COPD (hazard ratio, 2.079;
95% confidence interval, 1.1873.641). Results were similar for
a multivariable analysis of overall survival. In contrast, a pro-
spective study of 1,370 patients with COPD and 1,558 patients
without COPD with surgically treated lung cancer found no
difference in overall 5-year survival between patients with
COPD and patients without COPD (97). These results are
supported by data indicating that smoking status, but not
degree of airway obstruction, impacts disease-specific survival
in surgically resected stage IA and IB lung cancers (84).
Possibly suggesting an explanation for the seemingly con-
tradictory findings described previously, another report in-
dicates that computed tomographydiagnosed emphysema,
but not physiological measurement of airflow obstruction, is
associated with decreased overall and disease-specific survival
in early-stage lung cancer (98). This study monitored 100
smokers who underwent lobectomy for mostly stage I non
small cell lung cancers. Although there were no differences in
pathologic stage or degree of smoking exposure between the
patients with and without emphysema, both overall and
disease-free survival were better in those with no emphysema
(5-yr disease-free survival, 73.6 vs. 44.0%; P 5 0.005). In contrast,
when patients were stratified by FEV1 (>70% predicted or
,70% predicted), there was no difference in overall or disease-
free survival. This finding raises several questions, perhaps most
importantly whether emphysema serves as the biological link
between COPD and lung cancer more than airway disease.
CONCLUSIONS
Given the currently accepted surgical guidelines and often
underappreciated limited detriment (and sometimes benefit)
of lung resection on lung function in patients with COPD, these
1144 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
patients likely represent a surgically undertreated group. In
addition to the standard preoperative evaluation, patients with
COPD with potentially resectable lung cancers should be
routinely evaluated with anticipation of how such a resection
might impact lung function postoperatively specifically in the
context of emphysema. Such consideration may serve to widen
the pool of surgical candidates and improve prognosis for pa-
tients with lung cancer with severe COPD. We suggest that if
the primary tumor occurs in the upper or middle lobe in an area
of significant emphysema in a patient with heterogeneous dis-
tribution of emphysema that is upper lobe predominant, ana-
tomic resection with lobectomy should be strongly considered. If
this is not the case, sublobar resection should be considered with
segmentectomy preferred over wedge resection.
Until further research offers effective prevention, earlier
detection, and/or improved treatment of this devastating dis-
ease, physicians must continue to carefully use currently avail-
able therapeutic measures. Given that lung cancer, with its
relatively poor overall prognosis, is commonly associated with
symptomatic and often debilitating COPD, strict attention to
quality of life becomes paramount. All patients should receive
vigorous counseling regarding smoking cessationboth before
and after cancer diagnosis. Medical therapy of COPD should be
optimized, with the intention of improving perioperative mor-
bidity and enhancing quality of life. Attention to smoking
cessation, pulmonary rehabilitation, and optimal medical ther-
apy can maximize functional status, manage symptoms, and
empower patients to take an active role in improving outcomes.
Further examination of the biological links between COPD
and lung cancer as well as consideration as to whether patients
with COPD represent an appropriate group for radiographic
lung cancer screening will be critical to reduce the high burden
that lung cancer poses on patients living with COPD.
Author Disclosure: R.K. has served on the advisory board for Boehringer-
Ingelheim, Takeda Pharmaceuticals, AstraZeneca, Dey Pharmaceuticals, and
Forest Laboratories; has received honoraria for lectures from GlaxoSmithKline,
Boehringer-Ingelheim, AstraZeneca, and Pfizer; has received industry-sponsored
grants from GlaxoSmithKline and Boehringer-Ingelheim; and has received
sponsored grants from the Respiratory Health Association of Metropolitan
Chicago and NIH. M.D. has been a consultant for PneumRx and Portaero and
has a spouse who holds stock in Thoratec Corporation. K.H. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. S.R. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript.
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