Relationship between reduced forced expiratory volume in
one second and the risk of lung cancer: a systematic review
S Wasswa-Kintu, W Q Gan, S F P Man, P D Pare, D D Sin
See end of article for
Dr D D Sin, James Hogg
iCAPTURE Center for
Pulmonary Research, St
Paul’s Hospital, Room
#368A, 1081 Burrard
Street, Vancouver, BC,
Canada V6Z 1Y6; dsin@
3 November 2004
Accepted 8 April 2005
Thorax 2005;60:570–575. doi: 10.1136/thx.2004.037135
Background: Individuals with severely impaired lung function have an increased risk of lung cancer.
Whether milder reductions in forced expiratory volume in 1 second (FEV1) also increase the risk of lung
cancer is controversial. Moreover, there is little consensus on whether men and women have similar risks
for lung cancer for similar decreases in FEV1.
Methods: A search was conducted of PubMed and EMBASE from January 1966 to January 2005 and
studies that examined the relationship between FEV1and lung cancer were identified. The search was
limited to studies that were population based, employed a prospective design, were large in size (>5000
participants), and adjusted for cigarette smoking status.
Results: Twenty eight abstracts were identified, six of which did not report FEV1and eight did not adjust for
smoking. Included in this report are four studies that reported FEV1in quintiles. The risk of lung cancer
increased with decreasing FEV1. Compared with the highest quintile of FEV1(.100% of predicted), the
lowest quintile of FEV1(,,70% of predicted) was associated with a 2.23 fold (95% confidence interval
(CI) 1.73 to 2.86) increase in the risk for lung cancer in men and a 3.97 fold increase in women (95% CI
1.93 to 8.25). Even relatively small decrements in FEV1(,90% of predicted) increased the risk for lung
cancer by 30% in men (95% CI 1.05 to 1.62) and 2.64 fold in women (95% CI 1.30 to 5.31).
Conclusion: Reduced FEV1is strongly associated with lung cancer. Even a relatively modest reduction in
FEV1is a significant predictor of lung cancer, especially among women.
died from lung cancer in 1995.2In the US there were over
170 000 new cases of lung cancer and more than 160 000
deaths related to lung cancer in 2004.3This makes lung
cancer the leading cause of cancer deaths in both men and
women. Indeed, in the US, lung cancer causes more deaths
than the next three most common cancers combined (colon
cancer, n=48 100; breast cancer, n=40 000; and prostate
cancer, n=30 200).3
The leading cause of lung cancer is cigarette smoking.
Other risk factors include exposures to certain occupational
hazards, combustion generated carcinogens, and ambient
radiation.4 5Some have argued that reduced lung function is
another important risk factor for lung cancer.6–8However,
several epidemiological questions regarding this relationship
remain unanswered. Firstly, since individuals with reduced
lung function frequently have a significant smoking history,
it is not certain whether the relationship between lung
function and lung cancer is real or is simply confounded by
the effects of smoking. Secondly, it is not known whether the
relationship between impaired lung function and lung cancer
is dose dependent or threshold dependent. Thirdly, even if
there is a significant relationship between these two para-
meters, it is not known whether sex modifies this relationship.
To address these questions we conducted a systematic review
and meta-analysis of population based studies of the relation-
ship between lung function and lung cancer risk.
ung cancer is a major public health problem worldwide.
In 2000, 328 million people died from lung cancer
globally.1In Europe, 266 000 men and 64 000 women
Search for relevant studies
Using PubMed (1966–2004) and EMBASE databases, we
conducted a comprehensive literature search to identify
relevant studies published before January 2005 that exam-
ined the relationship between forced expiratory volume in
1 second (FEV1) and lung cancer. We used a disease specific
search term (lung neoplasm*) combined with lung function
specific search terms (FEV, FEV1, forced expiratory volume,
lung function) in all our searches. The electronic searches
were supplemented by scanning the reference lists from
retrieved articles to identify additional studies that may have
been missed during the initial search. We also contacted the
primary authors of the study for clarification of data where
Study selection and data abstraction
The primary outcome of this systematic review was to
compare the relative risk of lung cancer among subjects
who had impaired lung function, as measured by FEV1,
against those who had ‘‘normal’’ lung function at baseline
assessment. To mitigate publication bias, we limited our
search to studies that (1) were population based and did not
select participants on the basis of disease; (2) employed a
prospective design; (3) were large in size (at least 5000
participants at baseline); (4) used standardised methods for
measuring FEV1; (5) adjusted for important confounders
including age, sex, race, height, and smoking status; and (6)
divided the cohort into quintiles. The latter criterion allowed
us to determine the shape of the relationship between FEV1
and lung cancer.
From each relevant article two investigators (SW, WQG)
abstracted the following information: first author, publica-
tion year, population sampled, sample size, lung cancer
incidence or mortality, follow up time, age, sex, smoking
history, FEV1, and other factors (table 1). Any questions or
discrepancies regarding these data were resolved through
iteration and consensus.
Quintile 5 was defined as the group with the best FEV1and
quintile 1 as the group with the worst FEV1. For the primary
end point we included all incident cases of lung cancer or
deaths from lung cancer, whichever were reported in the
original study. There were no studies in which both of these
variables were reported. A weighted mean difference techni-
que was used to pool the original data together. The weighted
mean difference was derived using an inverse variance
weighted method.9For each outcome the heterogeneity of
the results across the studies was tested using a Cochran Q
test. If significant heterogeneity was observed (p,0.10), a
random effects model—which assigns a weight to each study
based on individual study variance as well as between study
variance—was used to pool the results together. In the
absence of significant heterogeneity a fixed effects model
was used.9Data analysis was conducted for men and women
separately and combined. All analyses were conducted
using Review Manager Version 4.2 (Revman; Cochrane
Collaboration, Oxford, UK).
The study selection process is summarised in fig 1. The
electronic literature search yielded 333 citations from
PubMed and 16 from EMBASE. The abstracts of these
articles were reviewed for suitability. The reasons for
exclusion are summarised in fig 1. In all, we identified four
studies which met the inclusion and exclusion criteria and
were used in the analyses.10–13In three of these studies10 11 13
we abstracted the salient data from published reports and in
the fourth12we used the public use data files from the
National Center for Health Statistics.14The relevant baseline
data from each of the selected studies are summarised in
table 1 and the FEV1 data for each quintile group are
summarised in table 2. In total, the analysis included 204 990
participants of whom 6185 had or died from lung cancer. The
average age of the participants ranged from 42 to 47 years at
baseline across the original studies. The follow up time was
9–18 years (table 1).
After adjustments for important covariates such as age,
cigarette smoking, and body mass index, participants in
quintile 5 (the group with the best FEV1) had the lowest risk
of lung cancer while those in quintile 1 (the group with the
worst FEV1) had the highest risk of lung cancer (table 3).
Surprisingly, even those in quintiles 3 and 4, who had
relatively well preserved lung function (mean FEV1 ,80–
100% of predicted), also had an increased risk of lung cancer.
The relationship was particularly notable in women where
those in quintiles 3 and 4 had risks of lung cancer that were
3.5 and 2.6 fold higher, respectively, than those in quintile 5.
The relationship between FEV1quintiles and the incidence
of lung cancer in both men and women is summarised in
table 3 and illustrated in fig 2. The slope of the relationship
was significantly steeper in women than in men (p,0.001).
Moreover, for every quintile, the relative risk of lung cancer
Baseline characteristics of included studies
or litres (l))End point Covariate
1996 Renfrew and
15411 443915NR 45.8 Male: 45*
Mortality Age, cigarette smoking,
diastolic blood pressure,
concentration, BMI, social
1990 High risk men
(92% white) for
disease in USA
1286611910.5 46 (5.5)100643.21 l or 88% Mortality Age, height, number of
cigarettes per day,
thiocyanate, age at which
smoking began, use of filter
cigarettes, tar and nicotine
content, alcoholic drinks/
week, diastolic blood
540211318 47 (14)45.24289 MortalityAge, sex, race, smoking
171311 15149 42 (NR) 46.3 Male: 51
Male: 3.09 l
Female: 2.19 l
IncidenceAge, former and current
smokers, smoking duration,
quantity, and inhalation
SD, standard deviation; FEV1, forced expiratory volume in 1 second; NR, not reported; BMI, body mass index.
*These values represent the percentage of participants who smoked >15 cigarettes daily.
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Study selection process. FEV1, forced expiratory volume in
Relationship between lung function and lung cancer 571
was higher in women than in men. These data suggest that
the effects of reduced FEV1are amplified in women.
In table 4 we have summarised the remaining large epide-
miological studies that evaluated the relationship between
FEV1and the risk of lung cancer. Similar to the results of
the present meta-analysis, all of these studies showed that
reduced FEV1 was a significant risk factor for lung
cancer.7 8 15–20These results could not be used in the meta-
analysis, however, because of the marked heterogeneity in
the way in which the data were collected and reported
across the studies.
This systematic review of population based studies which
have examined the relationship between lung function and
lung cancer has produced several interesting observations.
Firstly, independent of cigarette smoking history, reduced
FEV1 increases the risk for lung cancer in the general
population. Secondly, the relationship is severity dependent
such that individuals with the worst lung function have the
highest risk whereas those with preserved lung function have
the lowest risk. Thirdly, the relationship is alinear; relatively
small differences in FEV1which are commonly considered
within the normal range (for example, from 90% of predicted
to 100% of predicted) increase the risk of lung cancer by 30–
60%. Fourthly, the risk appears to be amplified in women.
The finding that reduced FEV1at baseline is significantly
associated with an increased risk of lung cancer is consistent
with several previous reports.7 8 15–21Although baseline health
status, degree of abnormality in lung function, and length of
follow up varied considerably between the various cohorts,
the associations were remarkably similar.
There are several possible explanations for a relationship
between lung function and lung cancer. Firstly, the outcomes
may share a causal pathway. One possible shared pathway is
lung and airway inflammation which are known to correlate
with the decline in lung function among smokers.22 23
Inflammation is thought to be an important mechanism
responsible for the proteolytic lung destruction and small
airway remodelling and narrowing which reduce lung
function in smokers and in chronic obstructive pulmonary
disease (COPD),22and is also implicated in the decline in lung
function in asthma24
and pulmonary fibrosis.25
reduced FEV1may be part of the process related to lung
and airway inflammation. Airway inflammation may also
have a major role in the pathogenesis of lung cancer.26
Cigarette smoke and other noxious irritants incite a vigorous
inflammatory reaction in the airways leading to the recruit-
ment and activation of pro-inflammatory cells such as
Lung function levels (% predicted) in quintile groups for each study
Quintile 1Quintile 2Quintile 3 Quintile 4Quintile 5
Van Den Eeden
Van Den Eeden
*Percentage predicted values were calculated using Hankinson’s equation
women had a mean height of 160 cm, and the mean age was 46 years.
49with the assumption that the men in the study had a mean height of 170 cm and
Relative risk (with 95% confidence interval) of lung cancer for men and women in different quintiles of lung function
Quintile 1 Quintile 2 Quintile 3Quintile 4Quintile 5
Van Den Eeden
2.53 (1.68 to 3.82)
3.56 (1.02 to 12.43)
3.16 (1.20 to 8.33)
1.86 (1.32 to 2.64)
2.23 (1.73 to 2.86)
1.93 (1.27 to 2.94)
2.44 (1.17 to 5.05)
1.03 (0.35 to 3.06)
1.60 (1.35 to 1.90)
1.67 (1.42 to 1.93)
1.80 (1.17 to 2.77)
2.80 (1.32 to 5.93)
1.11 (0.35 to 3.46)
1.45 (1.20 to 1.75)
1.54 (1.30 to 1.82)
1.36 (0.86 to 2.16)
0.50 (0.11 to 2.34)
0.94 (0.29 to 3.10)
1.34 (1.04 to 1.72)
1.30 (1.05 to 1.62)
Van Den Eeden
4.39 (1.86 to 10.38)
5.99 (0.75 to 47.94)
1.95 (0.32 to 11.70)
3.97 (1.93 to 8.25)
4.14 (1.73 to 9.87)
8.58 (1.09 to 67.36)
1.45 (0.27 to 7.69)
3.71 (1.80 to 7.69)
4.01 (1.68 to 9.58)
8.76 (1.09 to 70.11)
1.80 (0.52 to 6.30)
3.46 (1.75 to 6.75)
3.63 (1.51 to 8.76)
1.08 (0.07 to 17.29)
1.55 (0.41 to 5.81)
2.64 (1.30 to 5.31)
Pooled summary for men
2.36 (1.88 to 3.00)1.72 (1.48 to 1.99) 1.62 (1.38 to 1.90)1.38 (1.13 to 1.70) 1.00
All data were merged using a fixed effects model because there was no significant heterogeneity in data across the studies (p.0.10).
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logarithmic scale. Open circles are data for women and solid circles are
data for men; p,0.001 for the comparison of slopes between men and
Risk of lung cancer in men and women on a natural
572 Wasswa-Kintu, Gan, Man, et al
leucocytes which, in turn, propagate the inflammatory
cascade through the release of various cytokines and reactive
oxidative species.27These latter molecules can cause oxidative
damage and promote DNA mutagenesis in the surrounding
lung cells.28If the rate of cell division exceeds the rate at
which reactive oxidative species related DNA damage can be
repaired, DNA mutagenesis may occur and the risk for cancer
increases.28Reactive oxidative species may also directly
activate various oncogenes in the surrounding cells and
tissues (for example, jun and fos) which may further increase
the risk of lung cancer.29Consistent with this inflammatory
hypothesis for lung cancer, the incidence of lung cancer is
increased in inflammatory lung conditions such as idiopathic
pulmonary fibrosis,30asbestosis, and sarcoidosis.31A corollary
of the ‘‘sharedpathogenesis’’hypothesisisthat thegeneswhich
impart risk for COPD and lung cancer may be common. For
instance, individuals who have polymorphisms in genes which
influence the oxidant/antioxidant balance in favour of reactive
oxidative species may be susceptible to both.
A second possible explanation for the relationship is that
the lung dysfunction secondarily enhances the risk of cancer.
Individuals who have reduced FEV1may have an impaired
Published studies on the association between impaired lung function (FEV1) and the risk of lung cancer morbidity or
smokers (%) Outcome, n
follow up Comparison Adjusted factors
population in Detroit
>25 43.9Incidence, 77 25Predictor: FEV1% pred
Every 1 unit decrease of
FEV1% pred, regression
Age, sex, smoking
men on Hawaiian
island of Oahu
>45 47.0Incidence, 172 22Predictor: FEV1% pred
Quartile 3 v 4: RR=1.0
(0.6 to 1.9)*
Quartile 2 v 4: RR=2.5
(1.5 to 4.1)*
Quartile 1 v 4: RR=2.1
(1.3 to 3.5)*
Age, detailed smoking
Random sample of
community white adults
from six US cities
842754.8 25–7439.8 Mortality, 61 9–12 Predictor: FEV1quartile
Quartile 3 v 4: RR=3.99
Quartile 2 v 4: RR=2.00
Quartile 1 v 4: RR=8.27
Random sample of all
men in Aalborg,
>46 NR Incidence?, 35 11 Predictor: FEV1%/H3?
Per litre below expected
RR=2.1 (1.3 to 3.4)*
Age, smoking status
Random sample of
>20 63.0Mortality, 22510 Predictor: FEV1% pred
40–79% v >80%:
RR=2.1 (1.3 to 3.4)*
,40 v >80:
RR=3.9 (2.2 to 7.2)*
Age, sex, smoking
White American men
including a sample of
patients with moderate
to severe obstruction
from the IPPB Trial and
volunteers from JHLP
Predictor: FEV1% pred
,60% v >60%:
60–85% v .85%:
,60% v .85%:
shortness of breath
Random sample of
men from the Vale of
employees in two
27180 30–64NR Mortality, 10320–25Predictor: FEV1%/H3?
0–1 SD below average
1–2 SD below average
.2 SD below average
Stratified by age
group and area
Random sample of
male gold miners in
20650 45–54 NRMortality, 74 16–18Predictor: FEV1/H3?
0–1 SD below average
1–2 SD below average
.2 SD below average
Stratified by age
SD, standard deviation; FEV1, forced expiratory volume in 1 second; RR, relative risk; NR, not reported; IPPB, Intermittent Positive Pressure Breathing Trial; JHLP, Johns Hopkins Lung Project.
*Relative risk and 95% confidence interval.
?Ratio of FEV1to standing height3.
`RR was derived by comparison of the ratios (observed/expected) in different groups. Expected deaths were determined using log rank method.
Relationship between lung function and lung cancer573
ability to clear inhaled carcinogens from their airways. This
could lead to increased contact time between carcinogens and
airway epithelial cells. However, this seems unlikely because
individuals in quintiles 3 and 4 had ‘‘normal’’ FEV1levels and
yet had an increased risk of lung cancer.
In the present study the relationship between FEV1and
lung cancer was modified by sex. Whether women are more
susceptible to lung cancer than men is controversial. Several
increased susceptibility for lung cancer in women compared
with men.32 33However, other studies have shown the
reverse, with men being more susceptible to lung cancer
than women,34while other studies have demonstrated equal
susceptibility.35 36Notwithstanding these data, there is little
doubt that there are important biological and histologi-
cal differences in lung cancer between women and men.
For instance, in women, adenocarcinoma is by far the lead-
ing histological subtype of lung cancer whereas, in men,
squamous and adenocarcinomas are equally prevalent.37
Interestingly, the contribution of cigarette smoking to the
risk is less apparent for adenocarcinomas than for all other
histological subtypes.38Although lung cancer is rare in
lifetime non-smokers, if it develops in these individuals it is
usually an adenocarcinoma.39Moreover, smoking cessation
rapidly reduces the risk for squamous cell carcinoma while
the risk for adenocarcinomas decreases much more slowly.40
In general, women have a higher frequency of GCRTA
mutations41and transversions42in the p53 gene in resected
lung tumour specimens than men, even though the level of
exposure to carcinogens from cigarette smoking may be lower
in women.41Furthermore, higher levels of smoking related
hydrophobic DNA adducts have been reported in the lung
cancers and adjacent tissues in women.43 44Female smokers
also exhibit significantly higher expression levels of lung
CYP1A1 than men.45Increased CYP1A1 expression is impor-
tant in determining individual susceptibility to lung cancer
and may be a critical factor for influencing differences
between sexes in levels of aromatic/hydrophobic DNA
adducts in the lung.45 46A lower DNA repair capacity in
women than in men may also contribute to the variation in
susceptibility between women and men.47
There are several limitations to this study. Cigarette
smoking is a risk factor for lung function11 12and lung
cancer37and could confound the relationships observed
between FEV1and lung cancer. However, all of the original
studies included in the meta-analysis carefully controlled for
the effects of cigarette smoking, making it unlikely that our
results could be explained away by smoking. Nevertheless,
we cannot fully discount the possibility of residual con-
founding by smoking. Secondly, we did not have data on the
specific histological subtypes of cancer so the relationship
between FEV1 and specific histological subtypes of lung
cancer remains largely unknown, although the results of a
previous study suggest that adenocarcinomas are more likely
to develop in those who have small decreases in FEV1and
squamous cell carcinomas are more likely in those with
severe impairment of lung function.48Thirdly, publication
bias is a concern. To mitigate this bias we chose only large
population based studies. Since small positive studies are
more likely to get published than small negative studies, by
not including results from small studies the relative risk
estimates of reduced FEV1of the current meta-analysis may
be lower than those previously published.7 17Fourthly, most
of the original studies were conducted in relatively young
individuals, so the findings of the present meta-analysis may
not be generalisable to the older population who develop lung
Lung cancer is the most lethal cancer in the world. The
only reasonable chance for cure is to uncover the disease at a
localised stage. However, patients are rarely symptomatic at
early stages of disease when curative resection would be
possible. Most patients present at advanced stages of the
disease, so screening and early diagnosis of lung cancer are
therefore imperative in reducing case fatality rates. The
present study demonstrates a strong inverse relationship
between FEV1and lung cancer which applies to all levels of
FEV1. The risk increases even with a relatively modest
reduction in FEV1, especially among women. We found that
women were approximately twice as likely to develop lung
cancer as men for the same marginal decrements in FEV1.
The potential clinical implication is that, in smokers and
former smokers, FEV1may provide criteria beyond age and
smoking intensity to identify smokers at high risk for lung
cancer; this discriminatory power of lung function testing
may be important in selecting smokers for enrollment in
chemoprevention and early detection trials. Furthermore,
since lung cancer can occur in individuals with only small
decreases in FEV1 (especially in women), the traditional
boundaries of ‘‘normal’’ FEV1may need to be modified for
S Wasswa-Kintu, W Q Gan, S F P Man, P D Pare, D D Sin, Department
of Medicine (Respiratory Division), University of British Columbia and
The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary
Research, St Paul’s Hospital, Vancouver, British Columbia, Canada
DDS is supported by a Canada Research Chair (Respiration) and a
Michael Smith/St Paul’s Hospital Foundation Professorship in COPD.
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