Laryngeal Cancer and Gastroesophageal Reflux Disease: A Case-Control Study

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Laryngeal Cancer and Gastroesophageal Reflux Disease: A Case-Control Study
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
Laryngeal Cancer and Gastroesophageal Reflux Disease: A Case-Control Study
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.
Laryngeal Cancer and Gastroesophageal Reflux Disease: A Case-Control Study
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.
Laryngeal Cancer and Gastroesophageal Reflux Disease: A Case-Control Study
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-
Laryngeal Cancer and Gastroesophageal Reflux Disease: A Case-Control Study
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
Laryngeal Cancer and Gastroesophageal Reflux Disease: A Case-Control Study
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.

would have not been substantial in this study because both                4. Wynder EL, Stellman SD. Comparative epidemiology of tobacco-
the cases and controls were evaluated and diagnosed as                       related cancers. Cancer Res. 1977;37:4608-4622.
                                                                          5. Muir C, Weinland L. Upper aerodigestive tract cancers. Cancer. 1995;
outpatients. Referral bias was unavoidable given the fact
                                                                             75:147-153.
that the study was conducted in a tertiary referral center.               6. Spitz MR, Fueger JJ, Goepfert H, et al. Squamous cell carcinoma of
However, both cases and controls were from the same                          the upper aerodigestive tract. A case comparison analysis. Cancer.
institution. Length bias may have existed if the patients with               1988;61:203-208.
more severe laryngeal cancer died before being evaluated.                 7. Berrino F, World Health Organization, International Agency for Re-
                                                                             search on Cancer, Commission of the European Communities. Sur-
                                                                             vival of cancer patients in Europe: the EUROCARE-2 study. Lyon:
CONCLUSION                                                                   International Agency for Research on Cancer; 1999 IARC scientific
In this matched case-control study, smoking and GERD were                    publications no. 151.
independent risk factors for laryngeal cancer development. To             8. Copper MP, Jovanovic A, Nauta JJP, et al. Role of genetic factors in
                                                                             the etiology of squamous cell carcinoma of the head and neck. Arch
reduce the risk of laryngeal cancer, physicians should educate
                                                                             Otolaryngol. 1995;121:157-160.
patients on complete cessation of smoking and treat GERD in               9. Wynder EL, Convey LS, Mabuchi K, et al. Environmental factors in
symptomatic patients. Future studies are needed to assess the                cancer of larynx: a second look. Cancer. 1976;38:1591-1601.
role of reverse causality and prospective assessment of GERD             10. Brown LM, Mason TJ, Pickle LW, et al. Occupational risk factors for
in controls and in patients with laryngeal cancer.                           laryngeal cancer on the Texas Gulf Coast. Cancer Res. 1988;48:1960-
                                                                             1964.
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Figure 7      Estimated probability of laryngeal cancer based on tobacco consumption and GERD status. GERD ⫽ gastroesophageal reflux
disease.

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