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Likewise, other prior research has reported conflict- ing results. A European case-control study of 1,774 HNSCC cases found no association between heartburn and specific HNSCC tumor sites, except for an inverse association with hypopharyngeal cancer (OR 5 0.64; 95% CI 0.44, 0.93). 13 Another epidemiologic study (1,303 cases) reported that ever-smoker/ever-drinker HNSCC subjects were not more likely to have had a history of GERD than never-smoker/never-drinker HNSCC patients. 14 A small case-control study (120 cases) exam- ined associations between H. pylori infection, a cause of GERD, and odds of laryngopharyngeal cancer but found no association (OR 5 1.53; 95% CI 0.69, 3.41). 15 Studies of the etiologic role of GERD in laryngeal cancer have arrived at different conclusions. A meta- analysis concluded that GERD was associated with an increased odds of laryngeal cancer (OR 5 2.21; 95% CI 1.53, 3.19) but not pharyngeal cancer, although the pharynx OR was extremely imprecise. 16 A literature review that was not a meta-analysis could not conclude that GERD caused laryngeal cancer, but noted that con- founding by alcohol and tobacco consumption were inad- equately controlled. 17 A large case-control study conducted in the Veterans Health Administration system (14,449 cases) found no association between GERD and laryngeal cancer (OR 5 1.01; 95% CI 0.92, 1.12). 18 An important strength of our study was examina- tion of two different measures of GERD exposure: 1) self-reported history of symptoms and medical diagnosis and 2) development of HNSCC. A medical diagnosis of GERD is more likely to indicate substantial GERD mor- bidity than a self-reported history of having had fre- quent heartburn, resulting in less misclassification. Second, our analysis was based on a large, population- based case-control study, making it representative of a well-defined source population and increasing the preci- sion of the effect estimates. Third, CHANCE has detailed information on alcohol and tobacco consump- tion, important causes of HNSCC not well measured in a number of previous studies that examined relation- ships between GERD and HNSCC. 17 This enabled us to appropriately control for the effects of tobacco and alcohol. In terms of limitations, our assessment of GERD by self-report was not as accurate as an objective measure- ment such as pH monitoring would be, 5 even when the self-reported measure was medical diagnosis of GERD rather than self-assessment of GERD symptoms. Medi- cal diagnosis of GERD was ascertained by asking sub- jects whether they were ever diagnosed with GERD by a doctor rather than abstracting the information from medical records. Furthermore, even among self-reported measures of GERD, our simple one-question assessment might not be as accurate or reliable as validated multi- question instruments such as the Reflux Symptom Index. 19 However, alternative measures of self-reported GERD were not available in CHANCE. There is the pos- sibility of misclassification of the history of GERD, espe- cially if subjects are not aware of the criteria for frequency and severity of symptoms used to diagnose GERD. 20 For example, subjects who are not aware of

frequency criteria and assume that their symptoms do not occur frequently enough to warrant being considered a medical diagnosis could falsely report not having had GERD exposure, thereby possibly attenuating estimates of an association between GERD and HNSCC. Future research on GERD and HNSCC must con- sider the differing study designs and inconsistent find- ings of results reported to date. A larger study may be beneficial to further elucidate this association. Such a study would need to provide adequate control for tobacco and alcohol consumption as well as obesity, as was done here. 5 It would be informative to compare the effect of GERD when measured by self-report, medical diagnosis as ascertained by medical records, and by pH monitoring or another objective measurement. Multiple measures of self-reported GERD could be used for purposes of com- parison, including questionnaires such as the Reflux Symptom Index. 19 Because a few of our site-specific associations suggested greater risk, estimates of the association of GERD with HNSCC should be conducted for both overall HNSCC as well as individual tumor sites, as was done here. CONCLUSION In summary, we find no general pattern of associa- tion between GERD and the development of HNSCC. Subgroup analysis of subjects who were neither heavy drinkers nor heavy smokers does not show an associa- tion between GERD and the development of laryngo- pharyngeal cancer, a finding that conflicts with prior research. However, whereas none of our associations is statistically significant, the patterns of some point esti- mates, such as the larynx result, are suggestive and should be further investigated in future larger studies. Such additional work would help to resolve the inconsis- tencies observed in this literature. BIBLIOGRAPHY 1. Spechler SJ. Clinical manifestations and esophageal complications of GERD. Am J Med Sci 2003;326:279–284. 2. Williams JL. Gastroesophageal reflux disease: clinical manifestations. Gas- troenterol Nurs 2003;26:195–200. 3. Kapoor H, Agrawal DK, Mittal SK. Barrett’s esophagus: recent insights into pathogenesis and cellular ontogeny. Transl Res 2015;166:28–40. doi: 10.1016/j.trsl.2015.01.009. 4. Wang RH. From reflux esophagitis to Barrett’s esophagus and esophageal adenocarcinoma. World J Gastroenterol 2015;21:5210–5219. 5. Herbella FA, Neto SP, Santoro IL, Figueiredo LC. Gastroesophageal reflux disease and nonesophageal cancer. World J Gastroenterol 2015;21:815– 819. 6. Langevin SM, Michaud DS, Marsit CJ, et al. Gastric reflux is an inde- pendent risk factor for laryngopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2013;22:1061–1068. 7. Johnston N, Dettmar PW, Strugala V, Allen JE, Chan WW. Laryngophar- yngeal reflux and GERD. Ann N Y Acad Sci 2013;1300:71–79. 8. Kuo CL, Chen YT, Shiao AS, Lien CF, Wang SJ. Acid reflux and head and neck cancer risk: A nationwide registry over 13 years. Auris Nasus Lar- ynx 2015;42:401–405. doi: 10.1016/j.anl.2015.03.008. 9. Johnston N, Yan JC, Hoekzema CR, et al. Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells. Laryngoscope 2012;122:1317– 1325. 10. Kelly EA, Samuels TL, Johnston N. Chronic pepsin exposure pro- motes anchorage-independent growth and migration of a hypophar- yngeal squamous cell line. Otolaryngol Head Neck Surg 2014;150: 618–624. 11. Divaris K, Olshan AF, Smith J, et al. Oral health and risk for head and neck squamous cell carcinoma: the Carolina Head and Neck Cancer Study. Cancer Causes Control 2010;21:567–575. 12. Stingone JA, Funkhouser WK, Weissler MC, Bell ME, Olshan AF. Racial differences in the relationship between tobacco, alcohol, and squamous

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