Laryngeal Cancer and Gastroesophageal Reflux Disease: A Case-Control Study
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The American Journal of Medicine (2006) 119, 768-776
CLINICAL RESEARCH STUDY
AJM Theme Issue: GI and Nutrition
Laryngeal Cancer and Gastroesophageal Reflux Disease:
A Case-Control Study
Michael F. Vaezi, MD, PhD, MSepi,a Mohammed A. Qadeer, MD,a Rocio Lopez, MS, MPH,b Natalie Colabianchi, PhDc
a
Department of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tenn; and bQuantitative Health Sciences, Cleveland
Clinic Foundation, cDepartment of Epidemiology, Case Western Reserve University, Cleveland, Ohio.
ABSTRACT
PURPOSE: Gastroesophageal reflux disease (GERD) is common in patients with laryngeal cancer.
However, the role of GERD in laryngeal cancer remains controversial because of poor matching and
selection of inappropriate control groups in prior studies. We aimed to better understand this relationship
by conducting a matched case-control study.
METHODS: This study was based in a single tertiary care center over a 2-year period. Cases included all
patients with a diagnosis of new laryngeal cancer presenting to the otolaryngology clinics. Two controls,
derived from the internal medicine clinics, were matched to the cases on an individual basis for age (within
1 year), gender, ethnicity, and time of first visit to the institution (within 1 month). Data were extracted by
chart review. Conditional logistic regression was used to assess the relationship between laryngeal cancer
and GERD, tobacco, and alcohol consumption.
RESULTS: A total of 96 cases were matched to 192 controls. On univariable analysis, the significant risk
factors were current smoking, odds ratio (OR) 5.46 (95% confidence interval [CI], 2.59-11.50); alcohol,
OR 1.97 (CI, 1.19-3.26); and GERD, OR 1.79 (CI ,1.03-3.11). On multivariable analysis, only smoking
and GERD continued to be significantly associated with laryngeal cancer, OR 6.08 (CI, 2.82-13.10) and
OR 2.11 (CI, 1.16-3.85), respectively.
CONCLUSIONS: Smoking and GERD are significant risk factors for laryngeal cancer and may have an
independent incremental risk for laryngeal carcinogenesis. © 2006 Elsevier Inc. All rights reserved.
KEYWORDS: Laryngeal cancer; GERD; Smoking
Laryngeal cancer is the most common head and neck cancer in tracted attention as a possible etiologic factor.14-20 In a
the United States with an annual incidence of approximately meta-analysis of the effect of GERD on laryngeal cancer,
10,000 new cases.1-6 The 5-year mortality from this cancer is we recently reported a pooled odds ratio (OR) of 2.37 (95%
reported to be 40%.7 Identification and reduction of the risk confidence interval [CI], 1.38-4.08) for GERD in patients
factors might decrease the incidence of this cancer. However, with cancer.21 However, prior studies assessing the role of
although some causal factors are well established, the role of GERD in laryngeal cancer suffer from potential bias and
others is still controversial. Among the former group are smok- confounding. For example, despite published data on age,
ing1-6 and, to a certain extent, alcohol use, whereas the latter gender, and ethnic predilection in patients with laryngeal
group include genetic,8 environmental,9 certain occupa- cancer,3,22,23 no study has matched the subjects on these
tions,10,11 viral infections,12 and dietary factors.13 variables. Matching may be especially important in this
Gastroesophageal reflux disease (GERD), because of its disease because the same demographic variables (age, gen-
high prevalence in patients with laryngeal cancer, has at- der, and ethnicity) also may have an effect on GERD diag-
nosis.24 In addition, prior controlled studies have been crit-
Requests for reprints should be addressed to Michael F. Vaezi, MD,
PhD, MSepi, Department of Gastroenterology, Vanderbilt University Med-
icized for the choice of controls not being representative of
ical Center, 1501 TVC, 1301 22nd Ave. South, Nashville, TN 37232-5280. the general population, possibly decreasing the reliability
E-mail address: Michael.vaezi@vanderbilt.edu. and generalizability of the study results.
0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2006.01.019
Vaezi et al Laryngeal Cancer and GERD 769
Thus, we aimed to perform a case-control study evalu- of the department medical records by using International
ating the risks of smoking, alcohol, and GERD in the de- Classification of Diseases, 9th Revision (ICD-9) codes
velopment of laryngeal cancer and overcome these limita- (161.0-161.9). The diagnosis of cancer required patho-
tions by matching cases and controls for the 3 significant logic confirmation. Patients presenting with recurrent
demographic variables (age, gender, and ethnicity) and se- cancers were excluded.
lecting appropriate controls for Controls were selected from the
each subject with laryngeal large database of internal medicine
cancer. clinics. Two controls were matched
CLINICAL SIGNIFICANCE
to a single case on an individual
METHODS ● The role of GERD in laryngeal cancer is basis as follows: The first step was
The study design was reviewed and uncertain due to disparate studies. to identify a group of potential con-
approved by the institutional review trols who were matched to the case
● Age, gender, and ethnicity are the three by age, within 1 year. Gender, eth-
board of The Cleveland Clinic
Foundation, Cleveland, Ohio. important determinants for GERD, which nicity, and time of first clinic visit
were controlled in our study but not in (within 1 month) also were matched
Study Population previous studies. to cases. The time of the first visit to
This study was conducted in a the institution in controls was deter-
● We found that the risk of laryngeal can-
single tertiary care center with a mined on the basis of the unique
large referral base from north- cer was highest among patients who institutional identifying number for
east Ohio. The cases in this study smoked and had GERD. each patient. The institutional iden-
included all the adult patients tifying numbers of the controls were
(age ⬎21 years) who presented first placed in the ascending order,
to our Head and Neck Institute and were first diagnosed and then two controls with institutional identifying numbers
with laryngeal cancer between January 1, 2002, and De- closest to the case after matching for age, gender, and ethnicity
cember 31, 2003. They were identified from the database were selected (Figure 1).
Figure 1 Flowchart depicting the process of patient selection.
770 The American Journal of Medicine, Vol 119, No 9, September 2006
Table 1 Univariable Associations with Laryngeal Cancer
Cases Controls Odds Ratio
Characteristics (n ⫽ 96) (n ⫽ 192) (95% CI)
Age (y) median (25th, 75th percentiles) 61.0 (53.9-71.3) 61.5 (54.0-70.8) 0.94 (0.36-2.67)
Females 21 (21.9%) 42 (21.9%) 1.00 (0.56-1.83)
Ethnicity
Whites 86 (89.6%) 172 (89.6%) 1.00 (0.29-3.08)
Blacks 7 (7.3%) 14 (7.3%)
Others 3 (3.1%) 6 (3.1%)
Alcohol 60 (62.5%) 85 (45.3%) 1.97 (1.19-3.26)
Smoking
Never 18 (18.8%) 80 (41.9%) 1.00
Ex-smokers 34 (35.4%) 70 (36.7%) 2.03 (0.99-4.15)
Current 44 (45.8%) 41 (21.5%) 5.46 (2.59-11.50)
Years of smoking 30.0 (15.0-40.0) 0.0 (0.0-30.0) 1.23 (1.12-1.34)
Median (25th, 75th percentiles) n* ⫽ 90 n* ⫽ 147
Packs per day 0.0 (0.0-1.0) 0.0 (0.0-0.0) 3.86 (2.26-6.57)
Median (25th, 75th percentiles) n* ⫽ 96 n* ⫽ 188
Years of smoking cessation 0.0 (0.0-8.0) 7.0 (0.0-20.0) 0.77 (0.65-0.92)
Median (25th, 75th percentiles) n* ⫽ 78 n* ⫽ 111
GERD (Any criteria) 37 (38.5%) 52 (27.1%) 1.79 (1.03-3.11)
Symptomatic GERD† 13 (13.5%) 11 (5.7%) 2.58 (1.11-6.10)
GERD diagnosis by ICD-9 codes 12 (12.5%) 39 (20.3%) 0.52 (0.24-1.09)
Long-term acid-suppressive therapy‡ 27 (28.1%) 36 (18.8%) 1.81 (0.97-3.36)
GERD ⫽ gastroesophageal reflux disease; CI ⫽ confidence interval; n ⫽ number of patients with this variable; ICD-9 ⫽ International Classification of
Diseases, 9th Revision.
*Number of patients in whom the data from the corresponding variable were available.
†Symptomatic GERD included heartburn or acid regurgitation.
‡In the absence of other known gastrointestinal disorders.
Data Collection smokers, ex-smokers, and lifetime nonsmokers. For cur-
Data collected from the computerized archives of patients rent smokers, information was obtained regarding the
included demographics (date of birth, gender, and eth- intensity (packs per day) and duration (in years) of smok-
nicity), date of cancer diagnosis, GERD-related symp- ing. For ex-smokers, time since smoking cessation also
toms, presence of other gastrointestinal disorders, use of was recorded. Alcohol use was divided into 2 groups:
acid-suppressive medications, and smoking and alcohol consumers (including both current and former consum-
history. The presence of other factors, including exposure ers) and nonconsumers (lifetime nonconsumers). As with
to radiation and family history of laryngeal cancers also smoking, information about the intensity (drinks per day)
was noted. The results of investigations performed for and duration of consumption, and time since cessation (if
GERD, such as esophagoscopy, barium swallow, and pH former drinker) also were recorded.
monitoring were noted. Diagnosis of GERD was established by ICD-9 codes and
presence of symptoms (heartburn or acid regurgitation),
Definition of Variables esophagitis ⫾ Barrett’s epithelium, abnormal pH monitor-
For evaluation of smoking, all of the subjects were as- ing, hiatal hernia, reflux on barium swallow, or presence of
signed to one of three mutually exclusive groups: current long-term acid-suppressive medications (in the absence of
Table 2 Conditional Logistic Regression Model for the Association of Gastroesophageal Reflux Disease and Smoking with
Laryngeal Cancer
Factor Level Odds Ratios 95% Lower Limit 95% Upper Limit
GERD No 1.00 — —
Yes 2.11 1.16 3.85
Smoking Never 1.00 — —
Quitter 2.02 0.98 4.18
Current smoker 6.08 2.82 13.10
GERD ⫽ gastroesophageal reflux disease.
Vaezi et al Laryngeal Cancer and GERD 771
Figure 2 Smoking duration and risk of developing laryngeal cancer. LL ⫽ lower limit of 95% confidence interval; OR ⫽ odds ratio;
UL ⫽ upper limit of 95% confidence interval.
other known gastrointestinal disorders). The presence of RESULTS
any one of these findings established the diagnosis of A total of 96 patients with newly diagnosed laryngeal can-
GERD. cer were identified over the 2-year study period. Some 192
matched controls from a total of 88,508 patients visiting the
Statistical Analysis internal medicine outpatient clinics were randomly selected.
Matching was successful for age, gender, and ethnicity
Bivariable analysis was performed on all variables (de-
(Table 1). The median age of cases was 61.0 years (25th and
mographics, GERD symptoms, tobacco, and alcohol use).
75th percentiles: 53.9-71.3) compared with 61.5 years (25th
Frequencies of laryngeal cancer for each level were cal-
and 75th percentiles: 54.0-70.8) in controls. Females con-
culated, and ORs were estimated. Multivariable analysis stituted 21.9% of cases and controls, 89.6% of subjects were
using conditional logistic regression was next performed white, 7.3% were black, and 3.1% were of other ethnicity.
to estimate the odds of disease as a function of presence
of GERD, tobacco, and alcohol consumption, and the Laryngeal Cancer and Smoking
interaction terms between them (GERD*smoking,
Smoking tobacco was significantly associated with laryn-
GERD*alcohol, and smoking*alcohol). Conditional lo- geal cancer; 45.8% of patients with laryngeal cancer were
gistic regression was used because the data were current smokers compared with 21.5% of controls
matched. Final models were chosen with a backward (P ⬍ .0001) (Table 1). By using nonsmokers as the refer-
elimination method. This method started with a model ence, the odds of developing cancer in current smokers were
containing all of the factors mentioned above and elim- 5.46 (95% CI, 2.59-11.50) (Table 1). The multivariable
inated the least significant terms among the included model also suggested a significant (P ⬍ .001) association
factors one at a time until all variables remaining in the between smoking and laryngeal cancer (OR 6.08; 95% CI,
model had a significance level lesser than .05. A type I 2.82-13.10) (Table 2).
error rate of 0.05 was used for all analyses. SAS 9.1 The risk of developing laryngeal cancer in smokers
software (SAS Institute, Cary, NC) was used to carry out seemed to be incremental and a function of the duration of
all analyses. smoking as it increased by 23% for every 5 years of smok-
772 The American Journal of Medicine, Vol 119, No 9, September 2006
Figure 3 Smoking intensity and risk of laryngeal cancer. LL ⫽ lower limit of 95% confidence interval; OR ⫽ odds ratio; UL ⫽ upper limit
of 95% confidence interval.
ing (OR 1.23; CI, 1.12-1.34) (Figure 2). The cancer risk was Laryngeal Cancer and Gastroesophageal Reflux
also related to the intensity of smoking increasing by ap- Disease
proximately 4 times for every additional pack of smoking GERD was significantly associated with laryngeal cancer in
(OR 3.86; 95% CI, 2.26-6.57) (Figure 3). Furthermore, both both the univariable and multivariable models: OR 1.79
duration and intensity of smoking had an additive affect on (95% CI, 1.03-3.11) and OR 2.11 (95% CI, 1.16-3.85),
laryngeal cancer development (Figure 4). Smoking cessa- respectively (Tables 1 and 2). Significantly more cases
tion diminishes the likelihood of developing laryngeal can- (38.5%) than controls (27.1%) had GERD. Furthermore,
cer. The risk of developing cancer decreases by approxi- symptomatic GERD also was significantly higher in patients
mately 23% with every 5 years of smoking cessation (OR with cancer compared with controls, 13.5% versus 5.7%,
0.77; 95% CI, 0.65-0.92) (Figure 5). The maximum risk respectively (OR 2.58; 95% CI, 1.11-6.10). However, the
reduction was noted in the first 15 years of smoking cessa- numeric superiority of long-term acid suppression did not
tion, but the risk did not disappear completely (Figure 5). reach statistical significance in cases compared with con-
trols (OR 1.81; CI, 0.97-3.36). For any given level of smok-
Laryngeal Cancer and Alcohol Consumption ing, the presence of GERD increased the probability of
History regarding alcohol consumption was not consistently developing laryngeal cancer (Figure 7). There was no in-
detailed in patients’ medical records. Nonetheless, the effect teraction between smoking and GERD (P ⫽ .4), alcohol and
of alcohol was more modest compared with smoking (Table GERD (P ⫽ .2), and smoking and alcohol (P ⫽ .1).
1). The univariable model suggested an increased risk for
laryngeal cancer with an OR of 1.97 (95% CI, 1.19-3.26).
The intensity (volume) of drinking also was an associated DISCUSSION
risk factor (OR 1.17; CI, 1.01-1.35) with approximately a In this study, we found that the risk of laryngeal cancer
17% increased risk of laryngeal cancer with one additional was highest in patients who smoked and had GERD.
drink of alcohol per day (Figure 6). However, the multiva- Tobacco use was the single most important risk factor in
riable model did not identify alcohol use as a significant risk developing laryngeal cancer. Presence of GERD alone
factor for laryngeal cancer (OR 1.22; 95% CI, 0.67-2.20). also increased the risk for laryngeal cancer significantly
Vaezi et al Laryngeal Cancer and GERD 773 Figure 4 Relationship between duration and intensity of smoking and laryngeal cancer development. OR ⫽ odds ratio; ppd ⫽ packs per day. irrespective of smoking. Alcohol use, although signifi- may be an important possible cause. Although smoking cant in the univariable model, was not significantly as- prevalence has decreased, the prevalence of GERD has sociated with laryngeal cancer when adjusting for GERD increased over the past 3 decades.27 and tobacco consumption. Thus, our data suggest that The association of GERD with laryngeal cancer was first tobacco and GERD may have independent associations suggested in 1983 by Olson,14 who identified laryngeal with laryngeal cancer development. cancers in a series of patients with GERD. Since then, Several prior studies have suggested an association be- several studies have reported a high prevalence of GERD in tween smoking and laryngeal cancer,1,4,5,6,25 which is also patients with laryngeal cancer.15-21 However, these studies confirmed in our matched case-control study. We also con- were not well matched and were criticized for selection of firmed prior observations4,25 on the longitudinal effect of inappropriate control population. African Americans are smoking on laryngeal cancer. Our data also suggest that the more likely to have laryngeal cancer than whites,23 females intensity of smoking may carry a far greater risk than are more susceptible to this cancer than males,22 and pa- duration of smoking. However, unlike other studies finding tients aged more than 60 years are more likely to acquire a decline in the cancer risk for the general population after this cancer.4,22 GERD symptoms, diagnosis, and treatment 15 years of cessation,4 we found that the risk reduction also have ethnic and gender predilection.24 Thus, demo- might be much slower. Increased risk might last up to 40 to graphic variability may have played an important confound- 45 years. ing role in prior studies of GERD and laryngeal cancer. Our Lifelong nonsmokers were more prevalent in our study matched case-control study, however, continues to support (19%) than in prior reports (5%-10%).4,25 The reason for an association between GERD and laryngeal cancer. this discrepancy is not entirely clear. Differences in patient Selection of inappropriate control groups in the past has population may be one reason. It also may be the result of resulted in conflicting reports regarding association of declining smoking prevalence in the U.S. population.26 GERD with laryngeal cancer. For example, in a study by With the decreasing tobacco consumption, increasing laryn- Chen et al.,28 who chose cases and controls from the ear, geal cancer prevalence in the US population may need to be nose, and throat clinics, concluded no association between explained by other causes. Our study suggests that GERD GERD and laryngeal cancer. However, El-Serag et al.20
774 The American Journal of Medicine, Vol 119, No 9, September 2006 Figure 5 Smoking cessation and the likelihood of developing laryngeal cancer. LL ⫽ lower limit of 95% confidence interval; OR ⫽ odds ratio; UL ⫽ upper limit of 95% confidence interval. reported a significant association based on a Veterans Af- that patients with occasional heartburn in the past could fairs patient population. Because laryngeal cancer develops have been coded as having GERD. Such a misclassification in the general population, the appropriate control group would have decreased the likelihood of GERD association would also need to be selected from this population. We with cancer. The differing practices of diagnosing GERD chose controls from the internal medicine clinics because between the otolaryngology and internal medicine physi- this group of patients most closely resemble the general cians may also be a cause for potential misclassification in population than those presenting to specialty clinics. As a our study. These misclassification biases assume added im- verification of this contention, GERD prevalence of 27% in portance because the 95% CI for GERD barely crossed our control group closely resembles the GERD prevalence significance. However, the increased significance of GERD previously reported in the general population (20%-40%).29 on inclusion of smoking in the logistic regression model Important shortcomings of our study may include the suggests that there might be an interaction between the two presence of misclassification bias and inability to address risk factors, which was not detected because of the study the issue of reverse causality. The misclassification bias sample size. becomes evident because of non-uniformity of the GERD Another deficiency of our study was a failure to assess diagnosis. For example, GERD diagnosis in the patients the effect of reverse causality. Given the limited data on the with laryngeal cancer was more commonly established on duration of GERD in cases and controls, evaluation of this the basis of the presence of GERD symptoms. Thus, GERD phenomenon was not possible. Thus, it is possible that classification in this group could have been overestimated if laryngeal cancer may increase the prevalence of GERD, and symptoms were not attributable to GERD and if acid sup- our current observation of increased GERD prevalence in pression was administered for non-GERD reasons. Such a laryngeal cancer may be a case of reverse causality. There misclassification would increase the likelihood of finding an are currently no data suggesting that laryngeal cancer can association between GERD and laryngeal cancer. In addi- induce GERD; however, this possibility will need to be tion, more of the control group were diagnosed with GERD addressed in future clinical studies. Other potential biases, by ICD-9 codes. Because ICD-9 codes are not indicative of which could not have been controlled for may include the severity and current activity of the disease, it is possible Berkson’s bias, referral bias, and length bias. Berkson’s bias
Vaezi et al Laryngeal Cancer and GERD 775
Figure 6 Alcohol intake (drinks per day) and risk of laryngeal cancer. LL ⫽ lower limit of 95% confidence interval; OR ⫽ odds ratio;
UL ⫽ upper limit of 95% confidence interval.
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