Is Opium a Real Risk Factor for Esophageal Cancer or Just a Methodological Artifact? Hospital and Neighborhood Controls in Case-Control Studies

Background: Control selection is a major challenge in epidemiologic case-control studies. The aim of our study was to evaluate using hospital versus neighborhood control groups in studying risk factors of esophageal squamous cell carcinoma (ESCC). Methodology/Principal Findings: We compared the results of two different case-control studies of ESCC conducted in the same region by a single research group. Case definition and enrollment were the same in the two studies, but control selection differed. In the first study, we selected two age- and sex-matched controls from inpatient subjects in hospitals, while for the second we selected two age- and sex-matched controls from each subject's neighborhood of residence. We used the test of heterogeneity to compare the results of the two studies. We found no significant differences in exposure data for tobacco-related variables such as cigarette smoking, chewing Nass (a tobacco product) and hookah (water pipe) usage, but the frequency of opium usage was significantly different between hospital and neighborhood controls. Consequently, the inference drawn for the association between ESCC and tobacco use did not differ between the studies, but it did for opium use. In the study using neighborhood controls, opium use was associated with a significantly increased risk of ESCC (adjusted OR 1.77, 95% CI 1.17–2.68), while in the study using hospital controls, this was not the case (OR 1.09, 95% CI 0.63–1.87). Comparing the prevalence of opium consumption in the two control groups and a cohort enrolled from the same geographic area suggested that the neighborhood controls were more representative of the study base population for this exposure. Conclusions/Significance: Hospital and neighborhood controls did not lead us to the same conclusion for a major hypothesized risk factor for ESCC in this population. Our results show that control group selection is critical in drawing appropriate conclusions in observational studies

Esophageal Cancer in Iran: A Review

Esophageal cancer is the second and third most common malignancy in Iranian malesand females, respectively, claiming lives of approximately 5800 Iranians each year.Squamous cell carcinoma (SCC) is presently the most common type accounting forabout 90% of all esophageal cancers in Iran. Recent studies have shown that there isa gradual increase in the incidence of adenocarcinoma of the distal esophagus alongwith gastric cardia adenocarcinoma. Thirty-five years ago, the age standardizied rate (ASR) of esophageal SCC in thecity of Gonbad (Golestan Province, northeast of Iran) was found to be one of the highestrates for any single cancer that had been reported worldwide (ASR >100/105/year).Recent studies have shown that the incidence of SCC in Gonbad has declined to lessthan half of what it was in the past. This decline in the incidence of esophageal SCCparallels an improvement in the socioeconomic situation of people living in thisregion. According to recent cancer registry data in Iran there is still an obviousintracountry variability between the incidence of esophageal cancer in the south withan ASR of 3 for males and 2 for females in Kerman and 43 and 36 in the northeasternprovince of Golestan. The reasons for this very high rate of SCC in northeastern Iranhave been the subject of several studies during the past 35 years. According to resultsof these studies the suspected risk factors are: low intake of fruits and vegetables, drinkinghot tea, consumption of opium products and tobacco, H.pyloriinfection in the stomach,using unhealthy drinking water from cisterns and genetic susceptibility. The mainsuspected mutagens are polycyclic aromatic hydrocarbons (PAH) and N-nitrosocompounds. In order to embark primary and secondary prevention of this fatal cancer,further prospective studies are presently underway in the region. The Golestanesophageal cancer cohort study which follows of 50,000 subjects is on going. We expectsimple and feasible evidence based preventive strategies to be implemented in the futureaccording to the results of this study

Cigarette use and risk of ESCC in cases and controls in the two phases of the Golestan Case-Control Study of ESCC in Golestan Province, Iran.

*<p>Adjusted for opium, nass, hookah, ethnicity, education and place of residence.</p>**<p>Median of control group in each set.</p>***<p>Cumulative = duration×amount.</p

Nass use and risk of ESCC in cases and controls in the two phases of the Golestan Case-Control Study of ESCC in Golestan Province, Iran.

*<p>Adjusted for cigarette smoking, opium and hookah consumption, ethnicity, education and place of residence.</p>**<p>Median of control group in each set.</p>***<p>Cumulative = duration×amount.</p

Opium use and risk of ESCC in cases and controls in the two phases of the Golestan Case-Control Study of ESCC in Golestan Province, Iran.

*<p>Adjusted for cigarette smoking, nass, hookah, ethnicity, education and place of residence.</p>**<p>Median of control group in each study.</p

Determinants of opium use in hospital and neighborhood controls in the two phases of the Golestan Case-Control Study in Golestan Province, Iran.

*<p>Model includes all the variables in the table except source of controls;</p>**<p>model includes all the variables in the table.</p><p>OR: odds ratio; CI: Confidence interval;</p>†<p>p<0.05;</p>‡<p>p<0.01;</p>¶<p>p<0.001.</p

Hookah use in cases and controls of the two phases of the Golestan Case-Control Study of ESCC in Golestan Province, Iran.

*<p>Adjusted for cigarette smoking, opium, nass, ethnicity, education and place of residence.</p>**<p>Median of control group in each study.</p>***<p>Cumulative = duration×amount.</p