Ann Surg Oncol
DOI 10.1245/s10434-012-2230-9
ORIGINAL ARTICLE – HEALTHCARE POLICY AND OUTCOMES
Tobacco Use Is Associated with Increased Recurrence and Death
from Gastric Cancer
E. C. Smyth, MD1, M. Capanu, PhD2, Y. Y. Janjigian, MD1, D. K. Kelsen, MD1, D. Coit, MD3, V. E. Strong, MD3,
and M. A. Shah, MD1,4
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; 2Department of Epidemiology and
Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Department of Surgery,
Memorial Sloan-Kettering Cancer Center, New York, NY; 4Weill Cornell Medical College, New York, NY
1
ABSTRACT
Background. Tobacco use increases the risk of developing gastric cancer. We examined the hypothesis that gastric
cancer developing in patients with a history of tobacco use
may be associated with increased risk of cancer-specific
death after curative surgical resection.
Methods. From the Memorial Sloan-Kettering Cancer
Center Gastric Cancer prospective surgical database, we
collected baseline demographic data and tumor characteristics from all patients who had undergone curative
resection for gastric cancer between 1995 and 2009 and
who had not received pre- or postoperative chemo- or
radiotherapy. A smoking history was defined as [100
cigarettes’ lifetime use. The primary end point was gastric
cancer disease-specific survival (DSS); secondary end
points were 5-year disease-free survival (DFS) and overall
survival (OS). Gastric cancer–specific hazard was modeled
by Cox regression.
Results. A total of 699 eligible patients were identified
with a median age of 70 years (range 25–96 years); 410
(59%) were current or previous smokers. Smoking was
associated with gastroesophageal junction/cardia tumors
and white non-Hispanic ethnicity. Multivariate analysis
included the following variables: tumor stage, age, performance status, diabetes mellitus, gender, and tumor
Presented in part at the 2010 ASCO annual meeting as a
gastrointestinal (noncolorectal) cancer poster presentation
[J Clin Oncol. 2010;28(Suppl.):15s, abstract 4095].
Ó Society of Surgical Oncology 2012
First Received: 13 June 2011
M. A. Shah, MD
e-mail: [email protected]
location. In this analysis, the hazard ratio for gastric cancer
DSS in smokers was 1.43 (95% confidence interval
1.08–1.91, P = 0.01). Smoking was also an independent
significant risk factor for worse 5-year DFS (hazard ratio
1.46, P = 0.007) and OS (hazard ratio 1.48, P = 0.003).
Among 516 patients for whom tobacco pack-year usage
was available, both heavy (C 20 pack-years) and light
(\20 pack-years) tobacco use was significantly associated
with DSS, DFS, and OS.
Conclusions. Smoking history appears to be an independent risk factor for death from gastric cancer in patients
who have undergone curative surgical resection.
Gastric cancer is the second most common cause of
cancer death worldwide and is responsible for 700,349
deaths annually.1 Tobacco use is associated with the
development of gastric cancer, with a hazard ratio for risk
of developing the disease ranging 1.3–1.7 in several series.2–4 In addition, gastric cancer risk increases with
increasing cigarette consumption.2–5 More than a billion
people use tobacco products worldwide, with rising consumption in developing countries where gastric cancer
incidence remains the highest.1 Notably, the effect of
tobacco use on gastric cancer biology remains unknown.
The prognosis of patients with localized gastric cancer is
primarily related to their tumor, node, metastasis system
stage grouping, although additional tumor characteristics,
such as Lauren’s histology and tumor location, also influence the risk of gastric cancer recurrence and death from
gastric cancer after curative-intent resection.6 The significance of prior or current tobacco use on risk of gastric
cancer recurrence after resection has not been previously
reported. In other tobacco-related malignancies, including
squamous cell carcinoma of the head and neck, cervical
E. C. Smyth et al.
cancer, anal cancer, and transitional cell carcinoma of the
bladder, a history of or current use of cigarettes is associated with increased risk of disease recurrence.7–11 A
molecular rationale for a difference in disease biology has
been demonstrated in lung cancer. Specifically, adenocarcinoma of the lung in never smokers, when compared to
former smokers, has been demonstrated to be a distinct
biologic entity with unique molecular characteristics and
behavioral patterns.12,13
We hypothesize that gastric cancers occurring in the
setting of prior or current tobacco use may have a worse
prognosis, and may be associated with an increased risk of
recurrence and gastric cancer related death after curative
surgical resection. We specifically examined the influence
of tobacco use on gastric cancer disease-specific survival
(DSS) after curative resection in a large cohort of consecutive patients undergoing curative resection of gastric
cancer in a single academic cancer center.
METHODS
This retrospective study was performed after receiving
institutional review board approval. The study sponsor had
no role in the study design, collection, analysis and interpretation of data, in the writing of the report, or in the
decision to submit the paper for publication.
We identified patients with resected gastric cancer from
a prospectively maintained surgical database at Memorial
Sloan-Kettering Cancer Center (MSKCC). Inclusion criteria were as follows; (1) surgical resection for histologically
confirmed primary gastric or gastroesophageal adenocarcinoma between the years 1995 and 2009, (2) no evidence
of metastatic disease, and (3) R0 resection (i.e., no positive
surgical margins or positive peritoneal cytology). Esophageal carcinomas, defined as the bulk of tumor present in the
esophagus (Siewert I tumors) were excluded. Patients who
received perioperative or adjuvant therapy were also
excluded to avoid the confounding effects of difference in
response to or tolerance of treatment between smoking and
nonsmoking cohorts.
Review of the electronic medical record of eligible
patients was performed systematically by trained physicians by using standardized intake forms. Collected
variables were related to patient demographics and pathologic variables and included age at diagnosis, gender,
Eastern Cooperative Oncology Group (ECOG) performance score, tumor T and N stage (AJCC 6th edition),
location of primary tumor, tumor differentiation, Lauren’s
histology, presence of diabetes, and smoking history.14
Smoking status was obtained from the patient history
identified in the electronic medical record as documented at
the first medical or surgical oncology visit. A positive
smoking history was defined as a documented lifetime use
of more than 100 cigarettes.15 We defined light tobacco use
as lifetime smoking of \20 pack-years, and heavy tobacco
use was defined as C20 pack-year lifetime use. Patients for
whom smoking history was unavailable (n = 26) were
excluded.
The primary analysis evaluates DSS defined as the time
from surgical resection to death from gastric cancer or to
last follow-up. In the death from gastric cancer DSS Cox
regression model, deaths due to other causes (n = 62) are
censored at the time of death. In addition, in the primary
DSS analysis, patients with an unknown cause of death
(n = 45) were included as events. We also performed DSS
sensitivity analyses in which patients with unknown cause
of death were (1) excluded from the analysis, (2) censored
at their death date, and (3) included as events if death
occurred within 5 years from surgery (n = 26) and censored for deaths beyond 5 years (n = 19). Secondary
analyses included overall survival (OS), defined as the time
from surgical resection to death or last follow-up, and
disease-free survival (DFS) within 5 years after surgical
resection, defined as the time from surgery to recurrence or
death that occurred in the first 5 years. In the 5-year DFS
analysis, patients surviving for longer than 5 years without
documented recurrence are censored at 5 years. Subset
analysis included evaluation of the effect of pack-years of
smoking on DSS, 5-year DFS, and OS. Cox regression was
used to assess the association of DSS, OS, disease recurrence, or death within 5 years with known prognostic
variables. Associations between categorical variables were
assessed by Fisher’s exact test, while the Wilcoxon rank
sum test was used for continuous variables.
RESULTS
Patient Characteristics
Between 1/5/1995 and 2/24/2009, 699 eligible patients
were identified. As patients who received pre- or postoperative therapy were excluded, the study population was
enriched for early stage cancers. Median age at diagnosis
was 70 years (range 25–96 years), and the majority of
patients were smokers (n = 410, 59%). Smoking history
was associated with male gender, white non-Hispanic
ethnicity, and proximal/gastroesophageal junction tumors
(Tables 1, 2). Lauren’s histology did not vary according to
smoking status, although this classification was not reported in 28% of patients (Table 2). Pathologic parameters are
provided in Table 3. Tumor depth and nodal status was
similar for both smoking and nonsmoking patient groups.
Over three-quarters of patients had T1 or T2 tumors, and
[60% had no lymph node involvement. There was no
Smoking and Gastric Cancer Recurrence
TABLE 1 Patient characteristics
Characteristic
TABLE 3 Tumor staging
Smoker
Nonsmoker
Male
292 (71%)
124 (43%)
Female
118 (29%)
165 (57%)
Gender
Age at diagnosis, y
71 (25–96)
Characteristic
\0.0001
T stage
70 (27–94)
0.5
\0.0001
Ethnicity
White non-Hispanic
P
Smoker
Nonsmoker
T1
173 (42%)
126 (44%)
T2
137 (33%)
92 (32%)
T3
94 (23%)
67 (23%)
T4
6 (2%)
4 (1%)
179 (62%)
0.97
336 (82%)
198 (69%)
N stage
White Hispanic
23 (6%)
22 (7%)
N0
251 (61%)
Asian
22 (5%)
46 (16%)
N1
108 (26%)
71 (25%)
African American
25 (6%)
19 (7%)
N2
43 (11%)
24 (8%)
4 (1%)
4 (1%)
N3
8 (2%)
15 (5%)
154 (38%)
115 (40%)
242 (59%)
167 (58%)
14 (3%)
7 (2%)
Unknown/other
Diabetes
Yes
No
Unknown
0.57
59 (14%)
43 (15%)
350 (85%)
246 (85%)
1 (\ 1%)
C1
No
–
Not reported
Performance status
0
0.06
97 (34%)
72 (18%)
35 (12%)
No
243 (59%)
180 (62%)
23 (6%)
13 (5%)
Not reported
Smoker
Nonsmoker P
0.006
82 (28%)
Body
66 (23%)
84 (20%)
143 (35%) 129 (45%)
15 (4%)
12 (4%)
Lauren classification
0.099
171 (42%) 131 (45%)
Diffuse
93 (23%)
73 (25%)
Mixed
32 (8%)
25 (9%)
114 (28%)
60 (21%)
Not reported
0.57
144 (35%)
Gastroesophageal junction/cardia 168 (41%)
Intestinal
Perineural invasion
Yes
Site
Other
0.63
254 (88%)
TABLE 2 Tumor characteristics
Antrum
0.10
338 (82%)
Data are presented as n (%) or median (range)
Characteristic
Vascular invasion
Yes
difference in vascular or perineural invasion between the
smokers and nonsmokers.
P
significantly associated with worse gastric cancer–specific
survival in multivariate analysis (Table 4). Patients with a
smoking history had a 43% higher rate of death due to
gastric cancer when compared to never smokers. Similarly,
when DSS was analyzed with deaths of unknown cause
excluded or attributed to gastric cancer if they occurred
before 5 years (n = 26), the adverse association of cancerspecific survival and tobacco use remained independently
significant; HR 1.39 (95% CI 1.02–1.19, P = 0.036) when
deaths of unknown cause were excluded and HR 1.43 (95%
CI 1.07–1.93, P = 0.017) when deaths of unknown cause
within 5 years of surgery were attributed to disease. When
patients with unknown causes of death were not attributed
to gastric cancer and were censored at the time of their
death, the association of tobacco and DSS demonstrated a
HR of 1.28 (95% CI 0.94–1.75, P = 0.11).
Tobacco and Disease-free Survival
Tobacco and Gastric Cancer DSS
At a median follow-up of 76 months, 311 deaths had
occurred, 44% of the entire patient cohort. A total of 204
(66%) of these deaths were due to gastric cancer, 62 (20%)
were not due to gastric cancer (cardiopulmonary (n = 30),
stroke (n = 4), other malignancy (n = 13), postoperative
complication (n = 10), other (n = 5), and 45 (14%) were
of unknown cause. In univariate analysis, tobacco use was
associated with an increased risk of gastric cancer-specific
death with hazard ratio (HR) 1.49 [95% confidence interval
(CI) 1.15–1.94, P = 0.003], and remained independently
Disease free survival at 5 years was investigated as a
secondary outcome. A total of 453 patients (65%) were
alive 5 years after curative-intent gastric cancer surgery
and 246 patients (35%) had died, 186 (27%) of recurrent
gastric cancer, 34 (5%) of other cause, and 26 (4%) of
unknown cause. Eleven patients (1.5%) had experienced
disease recurrence but not died within 5 years from surgery. Univariate analysis demonstrated the smoking related
HR for 5-year DFS to be 1.51 (95% CI 1.18–1.94, P =
0.001). In multivariate analysis, the HR for smoking in
association with 5 year DFS was 1.46 (95% CI 1.13–2.08,
E. C. Smyth et al.
TABLE 4 Multivariate
analysis of gastric cancer DSS
Variable
Continuous variable
95% CI
P
Yes
1.44
1.02–2.04
0.041
Performance status
C1
1.27
0.91–1.76
0.157
1.08–1.90
0.014
0.0002
Smoking
Yes
1.43
T stage
T1
1.00
T2
2.05
1.40–3.01
Site
a
HR
Diabetes
N-Stage
Multivariate analysis including
tumor stage, location, diabetes,
gender, and age. Unknown
causes of death were treated as
events
Subcategory
T3
4.64
3.13–6.88
\0.001
T4
3.84
1.63–9.05
0.002
N0
1.00
N1
1.88
1.34–2.58
N2
4.18
2.83–6.18
\0.001
N3
12.58
7.31–21.64
\0.001
Antrum
0.0001
1.00
Body
0.96
0.67–1.37
0.809
Gastroesophageal
junction/cardia
1.38
1.01–1.87
0.042
Other
1.50
0.75–3.01
0.248
Age at surgerya
–
1.01
1.00–1.02
0.043
Sex
F
0.79
0.59–1.06
0.120
P = 0.007). In this analysis, neither ECOG performance
status nor diabetes mellitus were significantly independently associated with DFS, whereas T and N stage and age
at the time of surgery remained independent predictors of
outcome.
Tobacco Use and OS
TABLE 5 Pack-year tobacco use and outcome
Smoking status
Survival
95% CI
P
Disease Specific Survival
Never
1.0
0–20 pack-years
1.71
1.22–2.41
0.0021
C20 pack-years
1.41
0.94–2.13
0.09
5-year Disease Free Survival
Tobacco use was significantly associated with worse
OS. In univariate analysis, the HR for smoking was 1.57
(95% CI 1.24–1.98, P = 0.0002), and in multivariate
analysis, the HR for OS was 1.48 (95% CI 1.15–1.92,
P = 0.003). OS was also significantly and independently
associated with stage at resection, performance status, site
of the primary tumor, age at the time of surgery, and a
diagnosis of diabetes mellitus.
Never
1.0
0–20 pack-years
2.04
1.43–2.91
\0.0001
C20 pack-years
1.69
1.11–2.59
0.0151
1.42–2.81
1.19–2.61
\0.0001
0.005
Overall Survival
Never
1.0
0–20 pack-years
C20 pack-years
2.0
1.76
All unknown causes of deaths were treated as events
Tobacco Pack-year Analysis and Patient Outcome
We also examined the influence of cigarette dose on
patient outcome. Of the 410 patients who reported current
or previous smoking history, the use of tobacco was
quantified in 227 patients (55%). Together with the 289
nonsmokers, 516 patients (74% of the total population)
patients were included in this analysis. We defined light
smoking (\20 pack-years) or heavy smoking (C20 packyears) as variables, along with no smoking history. Light
smokers had a significantly worse gastric cancer DSS (HR
1.71, 95% CI 1.22–2.41, P = 0.002), whereas for heavy
smokers, the HR for DSS was 1.41 (95% CI 0.94–2.13,
P = 0.09). In addition, light and heavy smokers both
demonstrated a significantly decreased DSS at 5 years after
resection and OS (Table 5).
DISCUSSION
This study found that for patients with resected gastric
cancer, the risk of dying of gastric cancer was significantly
worse in those with a smoking history. We examined a
large cohort of consecutively resected patients with localized gastric cancer over a 15-year period at a single
academic institution. All patients had no evidence of
metastatic disease at the time of surgery and underwent
resection with curative intent, all with microscopically
Smoking and Gastric Cancer Recurrence
negative (R0) resection margins. The exclusion of patients
who received adjuvant therapy resulted in a relatively
uniform study population enriched for early stage gastric
cancer and removed any potential source of bias with
respect to selection for, response to, or tolerance of perioperative treatment based on physical condition and
smoking history. In this population, we found that smokers
had 43% higher risk of death due to recurrent gastric cancer
after resection than those who had never smoked.
Although the majority of patients were followed closely
for recurrent disease or complications from surgery, their
follow-up evaluation was not prospectively defined and
thus is subject to bias. However, for the primary end point
of DSS, the cause of death was attributable for 86% of
patients. Furthermore, within 5 years of surgery at which
point the vast majority of deaths from gastric cancer would
have occurred, the cause of death was attributable in 90%
of patients. In addition, both sensitivity analyses in which
unknown causes of death were excluded or in which
unknown causes of death were attributed to disease if the
death occurred within 5 years of resection demonstrated
consistent results of a significant independent increased
risk of dying of gastric cancer–specific survival after
resection amongst smokers (HR 1.39–1.43, P \ 0.05 for
each). The sensitivity analysis least likely to reflect the
course of disease, in which all patients with an unknown
cause of death were censored at the date of death, irregardless of when the patient died, was also supportive of
the association of tobacco and worse gastric cancer biology
with borderline significance (HR 1.28, P = 0.11).
Importantly, the potential clinical effect of smoking
history on gastric cancer disease biology has not been
previously reported. Cigarette smoke contains more than
4500 biologically active compounds within its gaseous and
particulate phases.16 Laboratory studies suggest possible
mechanisms to explain the effects of tobacco use on the
biological behavior of malignancy. Nicotine, although not
carcinogenic by itself, induces proliferation and angiogenesis in several preclinical models.17–19 Nicotine
induced increase in cell motility is associated with
decreased E-cadherin expression, and in gastric cancer, this
appears to be associated with perturbation of the epithelialmesenchymal transition (EMT) mediated by the Erk/
5-LOX signaling pathway.20,21 Additional factors may play
a role including the interaction between Helicobacter
pylori infection and tobacco use, which clinically have an
additive interaction for the risk of gastric cancer (HR 4.9
for H. pylori and tobacco use together).22 Because many
patients in our study received empiric therapy for upper
gastrointestinal symptoms before their cancer diagnosis,
the true prevalence of H. pylori in our population is
unknown. Because H. pylori eradication is negatively
affected by tobacco and alcohol use, it is possible that
smokers in our cohort could have an increased risk of
H. pylori–related cancer.23,24 However, there is no evidence that gastric cancer developing in the setting of
H. pylori infection is associated with worse DFS or OS.25
Additionally, the effect of tobacco on the immune system has been well documented. Current and former
smokers have demonstrated lower levels of natural killer
(NK) cells than never smokers; this depletion may continue
for up to 20 years after tobacco cessation.26 Tobacco
related defects in NK mediated immune surveillance may
lead to an increased risk of metastasis. Lu et al. demonstrated that in a murine lung metastasis model, tobacco
exposed mice injected with B16-MO5 melanoma cells
developed significantly more lung metastases than those
who were not exposed to tobacco smoke.27 Tobacco
exposed animals demonstrated both decreased NK cell
activation, as measured by CD69 expression, and compromised cytotoxic T-lymphocyte mediated cell lysis, with
fewer apoptotic and dead YAC-1 target cells seen after
incubation with NK cells taken from smoke exposed mice.
Thus, it is possible that both tumor and host factors may
contribute to the association between tobacco and gastric
cancer–specific survival seen in this study.
The retrospective assessment of tobacco use and lack of
data regarding alcohol use provides another potential
source of bias in this study. As alcohol intake was not
formally quantified, it was not formally assessed in our
predictive model. Misclassification of tobacco use in
patients with cancer may occur when smoking history is
collected in an indirect manner due to recall bias and social
desirability issues.28 When an exposure is considered either
a personal threat to health, or socially undesirable, as with
tobacco consumption in the setting of cancer, underreporting of usage may occur.29 Although both light and
heavy smokers appeared to have an adverse association
with patient outcome, we did not demonstrate a dose–
response effect with tobacco use in this study. This may be
due to the unavailability of pack-year data on a significant
minority of patients who reported a smoking history,
potential biases associated with the mode of data collection, or because a dose–response relationship does not
exist. Between 5% and 12% of never smokers are misclassified in epidemiologic studies.30,31 In our study,
individuals who may have been misclassified as never
smokers would likely only dilute the perceived effects of
tobacco usage on DSS.
Tumors of the gastric antrum were significantly more
common in the group of never smokers, and cardia/gastroesophageal junction tumors in the group of prior or
current smokers (45% vs. 35% and 41% vs. 28%, respectively; P = 0.006). Although tobacco consumption
increases the risk of development of both antral and proximal tumors, our data support the previous finding that the
E. C. Smyth et al.
relationship appears to be stronger for tumors of the cardia/
gastroesophageal junction. In a meta-analysis of 32 epidemiologic studies examining the effect of tobacco on gastric
cancer occurrence, Ladeiras-Lopes et al. found that the
effect of tobacco consumption on the risk of malignancy
was higher for cardia cancers when compared to antral
tumors (relative risk of 3.14 vs. 1.60, respectively).3 This
was also seen in a large Korean prospective cohort study of
669,570 men in whom the risk for proximal gastric cancer
was increased by 90% for former smokers and 120% for
current smokers, compared to increases in antral gastric
cancer of only 40% for both current and former smokers.32
Notably, neither study examined the association of tobacco
use and gastric cancer–specific survival.
There are several examples of tobacco-related molecular
differences that may account for unique tobacco-specific
tumor biology. Similar to non–small cell lung cancer, in
which tobacco-associated disease is molecularly distinct
from non-tobacco-related lung cancer, recently published
data suggest differences in the molecular profile of colorectal cancer in smokers and nonsmokers. In a study of
more than thirty-seven thousand women, Limsui et al.
demonstrated that although the HR for colorectal cancer for
ever smokers was consistent with the literature (HR 1.19,
95% CI 1.05–1.35), the incidence of cancers with high
microsatellite instability, those with a highly methylated
CpG island phenotype, and those with BRAF mutations
were significantly more common in ever smokers.33 The
presence of either a hypermethylated CpG island phenotype in proximal colon tumors or a BRAF mutation in
colorectal cancer have each been associated with an
increased risk of disease recurrence in curatively resected
patients with colon cancer.34,35 Thus, in another gastrointestinal malignancy, tobacco use appears to be associated
with a distinct molecular phenotype of malignancy, and
that prior smoking may in fact specifically influence disease biology, thereby affecting patient survival. Also in
common with the work of Meyerhardt et al. on colorectal
cancer, we demonstrated that a diagnosis of diabetes mellitus may also be associated with an increased risk of
gastric cancer recurrence.36
In this study, we found that tobacco use was associated
with a worse DSS after curative-intent resection for gastric
cancer. Tobacco has already been established as an independent risk factor for the development of gastric cancer,
particularly for gastroesophageal junction/proximal tumors.
Our analysis suggests that gastric cancer that develops in
the setting of tobacco use is associated with a higher risk of
dying of gastric cancer independent of other known prognostic variables. Additional interesting research questions
now arise: is tobacco-related gastric cancer a molecularly
distinct phenotype, or do tobacco-related changes in the
host tumor environment lead to increased risk of disease
recurrence and death? The answers to these questions may
lead to the development of future therapeutic targets, which
are desperately needed in this common and devastating
disease.
ACKNOWLEDGMENT Supported in part by the DeGregorio
Foundation for Gastroesophageal Cancers.
FINANCIAL DISCLOSURES
from any author.
There are no financial disclosures
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