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Keywords:

  • diabetes;
  • esophageal adenocarcinoma;
  • gastric adenocarcinoma;
  • case–control study;
  • polychotomous logistic regression

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Diabetes has been consistently associated with an increased risk of liver, pancreas and endometrial cancer and has been implicated as a risk factor for esophageal and gastric cancers, although this association has been less well studied. We sought to determine the role of diabetes in the etiology of esophageal, gastric cardia and distal gastric adenocarcinomas (DGAs). This analysis included patients with esophageal adenocarcinoma (EA) (n = 209), gastric cardia adenocarcinoma (GCA) (n = 257) and DGA (n = 382), and 1,309 control participants from a population-based case–control study conducted in Los Angeles County. The study included non-Hispanic whites, African Americans, Hispanics and Asian Americans. The association of diabetes with the three tumor types was estimated using polytomous logistic regression. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated. Nine percent of control participants and 13% of the case patients reported a history of diabetes. After adjustment for age, gender, race, birthplace, education, cigarette smoking status and body mass index, diabetes was associated with an increased risk of EA (OR, 1.48; 95% CI, 0.94–2.32; p = 0.089) and DGA (OR, 1.47; 95% CI, 1.01–2.15; p = 0.045), but was not associated with risk of GCA (OR, 0.96; 95% CI, 0.59–1.55; p = 0.87). However, the association between diabetes and risk of DGA was statistically significant only among patients for whom we interviewed their next of kin. Our study further investigated the association between diabetes and adenocarcinomas of the esophagus and distal stomach.

The prevalence of diabetes has been increasing globally; rates in North America are among the highest.1 In 2010, 25.6 million or 11.3% of Americans ages 20 years or older had diabetes,2 with an estimated 1.9 million new cases diagnosed each year. Diabetes has been consistently associated with an increased risk of cancers of the liver, pancreas and endometrium3; however, for many other cancers, data are limited. Over 18 studies have investigated the risk of esophageal and gastric cancer in relation to history of diabetes.4–22 However, to our knowledge, only five studies distinguished adenocarcinomas from squamous carcinoma of the esophagus17–20, 23 and only two studies18, 23 specifically evaluated risk patterns of gastric cardia cancer. In this report, we have investigated whether diabetes is associated with risk of esophageal and gastric adenocarcinoma using data from a large population-based case–control study conducted among residents of Los Angeles County.24

The association between diabetes and cancer risk may be mediated via direct effects of hyperglycemia, insulin resistance and hyperinsulinemia3 or indirectly via risk factors common to both diabetes and cancer, such as obesity, diet and tobacco smoking. In the Los Angeles case–control study, cigarette smoking,24 body size,24 history of reflux25 and fiber intake26 have been significantly associated with esophageal and gastric adenocarcinoma. Thus, we have also explored whether the association between diabetes and risk of esophageal and gastric adenocarcinoma is modified by age, body mass index (BMI), fiber intake, reflux symptoms and cigarette smoking.

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Study population

The details of the study population and design have been described previously.24–32 Briefly, cases for our study were men and women, ages 30–74 years with histologically confirmed, incident esophageal adenocarcinoma (EA; International Classification of Disease for Oncology code C15.0–C15.9), gastric cardia adenocarcinoma (GCA; International Classification of Disease for Oncology code C16.0) or distal gastric adenocarcinoma (DGA; International Classification of Disease for Oncology codes C16.1–C16.6 and C16.8–C16.9) diagnosed between 1992 and 1997. They were identified by the Los Angeles County Cancer Surveillance Program, the population-based cancer registry covering Los Angeles County, a member of the National Cancer Institute's Surveillance, Epidemiology, and End Results program and the statewide California Cancer Registry. Control participants were subjects without a diagnosis of gastric or esophageal cancer. They were individually matched to each case patient on sex, race, age (±5 years) and neighborhood of residence. A systematic algorithm based on the address of the case patient was used to recruit control subjects.25 To increase the study's statistical power, we sought two control participants for each case patient whenever possible.

In-person interviews were conducted with participants. Next of kin (NOK) were interviewed when case patients were unable to be interviewed due to death or illness. Although it was not feasible to blind interviewers to case (or NOK) or control status, interviewers and study participants were not aware of the study hypotheses. Written informed consent was obtained from each study participant before interview. A total of 947 case patients were interviewed, representing 77% of the 1,230 eligible patients who were approached (77% for EA, 74% for GA and 78% for DGA). Among them, 528 were matched to one control participants and 382 to two or more control participants; 37 had no eligible control participants identified. NOK interviews accounted for 271 (66 EA, 85 GCA and 120 DGA) of the interviews with case patients. We excluded 99 case patients and 47 control subjects because of extreme caloric intake or missing data on diabetes or BMI. A total of 848 case patients (209 with EA, 257 with GCA and 382 with DGA) and 1,309 control participants were included in the current analyses.

Data collection

Cases and their matching controls were interviewed by the same interviewer in almost all instances. A reference date was defined as 1 year before the date of diagnosis of the case patient; this same reference date was used for each case patient's matched control subject(s). A structured questionnaire designed specifically for our study was administered during the in-person interview, obtaining data up to the reference date. The interview queried demographic information, smoking history, lifetime use of all types of alcoholic beverages, usual diet, weight at ages 20 and 40 years and on the reference date (referred to as current weight) and height. In addition, we asked detailed questions regarding personal history of conditions of esophagus and gastrointestinal tract and other medical conditions. Specifically, participants were asked if they had diabetes diagnosed by a doctor before the reference date. If the response was yes, participants were then asked age at first diagnosis, treatment received and duration of treatment.

Statistical analysis

Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated. To maximize statistical power, we report results from unconditional polytomous logistic regression with adjustment for the matching variables26 including age (≤49, 50–59, 60–69, ≥70 years), sex (male/female) and race (non-Hispanic white, African American, Hispanic and Asian). Birth place (US born and non-US born), level of education (<high school, high school, some college, college graduate or higher), cigarette smoking status (never smoker, former smoker and current smoker) and BMI at reference age (in quartiles) were also included as covariates in the analyses. Results remained materially unchanged if we further adjusted for the duration and intensity of cigarette smoking. We previously showed26 that this approach provided more precise estimates of the ORs, whereas the magnitude of the estimated ORs was consistent with those obtained in separate conditional logistic regression analyses that preserved the original case–control match within each cancer site. Similar results were also observed when we evaluated the effect of diabetes.

One degree of freedom likelihood ratio test was used to assess the homogeneity of diabetes' effect by potential effect modifiers including age, BMI, fiber intake, reflux history, cigarette smoking status and respondent type. We conducted these analyses separately for each type of cancer using unconditional logistic regression.

To perform a meta-analysis33, 34 of the studies that examined EA specifically, we identified studies by a computerized search in MEDLINE (January 1960 to June 2011) of all English language and human subject articles. The reference lists of the relevant publications were also reviewed to identify additional studies. Study-specific adjusted estimates of relative risk were obtained from the original study publications and pooled according to the DerSimonian and Laird random effects model35 to allow for variation in true associations across studies. Forest plot was prepared using the Forest Plot Viewer software version 1.00 (The National Toxicology Program, Research Triangle Park, NC). Between-study heterogeneity was tested by the Cochran's Q test36 for statistical significance and quantified by I2, which was estimated using the equation:

  • equation image

All reported test significance levels (p values) are two sided. Meta-analysis was performed using STATA 11 (StataCorp, College Station, TX) and all other analyses were performed using the SAS 9.2 statistical software (SAS Institute, Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Characteristics of the study participants have been described in details previously.25, 32 Diabetes was diagnosed in 9% of control participants and 13% of case patients. As shown in Table 1, the prevalence of diabetes among control participants increased with age (p trend = 0.018), BMI (p trend < 0.001) and fiber intake (p trend = 0.035). Diabetes among controls was more prevalent among Hispanics and African Americans than non-Hispanic whites, although the differences by race were not statistically significant (p = 0.25). The prevalence of diabetes also did not differ by sex (p = 0.14) or cigarette smoking status (p = 0.69).

Table 1. Prevalence of diabetes by demographic and lifestyle characteristics among control subjects
inline image

Diabetes was statistically significantly associated with an increased risk of DGA in a model that adjusted for age, sex, race, smoking status and BMI (OR, 1.47; 95% CI, 1.01–2.15). A similar pattern was observed for EA (OR, 1.48; 95% CI, 0.94–2.32), although this finding was only marginally statistically significant (Table 2). No association was observed between diabetes and GCA. We also investigated the time interval between the diagnosis of diabetes and the diagnosis of the patient's cancer (for control participants, the date of diagnosis of their matched case was used). Diabetes that had been diagnosed less than 10 years before these dates was associated with an elevated risk for all three tumor types; this finding was statistically significant for DGA (p = 0.028). Diabetes that had been diagnosed more than 10 years before these dates was not associated with an increased risk of any tumor type.

Table 2. Adjusted odds ratios (and 95% confidence intervals) for esophageal and gastric adenocarcinoma in relation to diabetes
inline image

Table 3 presents the stratified analyses of diabetes's effect by age, BMI, fiber intake, reflux symptoms, cigarette smoking and respondent type. The diabetes-EA or diabetes-DGA association was more pronounced among older participants, NOK respondents, those with a low BMI (<25 kg/m2) and those without a prior history of reflux but these results were not statistically significantly different. However, the association between diabetes and risk of DGA was statistically significant only among patients for whom we interviewed NOK.

Table 3. Adjusted odds ratios (and 95% confidence intervals) for esophageal and gastric adenocarcinoma in relation to diabetes by subgroups of interest
inline image

Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Results from this population-based case–control study from Los Angeles County provide further support that diabetes may be associated with an increased the risk of EA and DGA.

A history of diabetes was reported by 9% of our control subjects, a rate comparable with published figures in the US.37 Consistent with previous reports,2, 38 we also found higher prevalence rates of diabetes among control participants who were Hispanic or African American and those with higher BMI, lending further support to the reliability of our exposure assessment by self-report. The observation of a higher level of fiber intake among diabetic control participants is not surprising because these individuals may have changed their dietary habits to improve glucose tolerance after the diagnosis of diabetes.

Four case–control studies17–20 and one prospective cohort study23 have investigated the diabetes-EA association (Supporting Information Table 1). Three of the five studies showed a positive association; this included females in England and Scotland17 (OR, 7.00; 95% CI, 0.86–56.89), veterans in Portland, US20 (OR, 2.78; 95% CI, 1.38–5.62) and men and women in Australia18 (OR, 1.32; 95 CI, 0.85–2.05). No association was found in the NIH-AARP Diet and Health study (HR, 0.90; 95% CI, 0.67–1.20).23 Similarly, no association was found when distal EA was examined in combination with GCA among 10,465 veterans with GERD identified within the US Veterans Affairs National Patient Care Datasets (OR, 1.1; 95% CI, 0.8–1.5).19 Limitations of these studies include small sample sizes,17, 20 nonpopulation-based,19, 20 use of medical records for exposure assessment19, 20 and lack of information on the duration of diabetes.17, 19, 20, 23 A random-effects meta-analysis33, 34 of the four prior studies17, 18, 20, 23 that examined EA specifically as well as our result on EA risk produced a combined OR of 1.48 (95% CI, 0.96–2.28; p = 0.077; test for heterogeneity: p = 0.011, I2 = 69%). Supporting Information Figure 1 shows the forest plot for this meta-analysis.

Although over 13 studies4–16, 22 have investigated the association between gastric cancer and diabetes, only few18, 19, 23 have evaluated this by gastric cancer subtype (Supporting Information Table 1). Rubenstein et al.19 examined GCA in combination with distal EA and did not find any evidence of an association with diabetes. Neale et al.18 observed that individuals with GCA were more likely than controls to report a history of diabetes and the association was stronger for diabetes that had been diagnosed > 10 years (OR, 2.16; 95% CI, 1.16–4.04). Using data from the NIH-AARP Diet and Health study, Lin et al.23 recently reported a significant association between diabetes and risk of GCA, but no significant association of diabetes with risk of gastric noncardia adenocarcinoma. Contrary to Lin et al., in this study, we did not find any association between GCA and diabetes; however, an increased risk of DGA was observed among those with diabetes. The inconsistency observed among the current limited data highlights the need for additional research on diabetes, including information on age at diagnosis and treatment for diabetes.

Several mechanisms have been proposed to explain associations between diabetes and cancer. Metabolic abnormalities associated with diabetes, such as insulin resistance, compensatory hyperinsulinemia, the elevated levels of bioactive insulin-like growth factor and/or chronic inflammation, can stimulate cancer cell mitogenesis, proliferation, invasion and metastasis, therefore enhance the promotion and progression of cancer cells.3 Hyperinsulinemia has been shown to increase bioavailable estrogen and testosterone,39 sex hormones which have been suggested to play a role in the development of EA and GCA.40 In addition, early evidence suggests that some diabetes treatments may also affect cancer risk.3 Specific to the esophagus and stomach, it has also been reported that diabetic patients frequently suffer from delayed gastric emptying,41 which has been associated with an increased risk of reflux symptoms,42 a known risk factor for esophageal cancer in the current and previous studies.25 In our study, the diabetes-EA/DGA associations were more pronounced among participants without a prior history of reflux, suggesting that delayed gastric emptying is unlikely to explain our observation. It is also possible that the associations between diabetes and cancer are not causal, instead may be due to shared common risk factors such as aging and obesity. We controlled for a number of known risk factors including age, BMI and cigarette smoking in our analyses; further, the associations we observed between diabetes and EA and GCA did not differ by age and appeared to be more pronounced among subjects with low BMI (<25). Therefore, it is unlikely that the effect of diabetes was mediated by these shared risk factors.

Our study represents one of the few large population-based studies that have investigated the role of diabetes in the etiology of adenocarcinoma of the esophagus and stomach. However, our study has a number of limitations that warrant consideration in interpreting the results. Information on diabetes were based on self-report, although we considered only physician-diagnosed disease and asked extensive questions regarding diabetes (e.g., age at diagnosis, treatment). Another limitation is the relatively small number of individuals with diabetes, particularly in the subgroup analyses, increasing the likelihood of spurious associations. Despite the significant association between diabetes and DGA, our analysis did not reveal a trend toward increasing cancer risk among individuals with longer duration of diabetes. Also, our observed association between diabetes and DGA was more pronounced when restricted to patients for whom we interviewed their NOK. This may be because these patients were more susceptible to diabetes-induced complications. As individuals with diabetes are at a higher risk of cardiovascular diseases and mortality,43 these susceptible individuals were also more likely to be ill or deceased and consequently participate in the study through next of kin interviews. This was supported by the higher rate of next of kin interview among diabetic cases (41%) than that among nondiabetic cases (26%) in our study.

In summary, our data suggest that diabetes may be associated with an increased risk of EA and DGA. Future studies with larger sample sizes are needed to confirm our findings, further examine timing of diabetes (age at diagnosis of diabetes, interval between age at diagnosis of diabetes and cancer) and explore possible mechanisms by which diabetes may increase the risk of these tumor types.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

We thank all study participants and the data collection team for their contributions. Incident cancer cases for our study were collected by the USC Cancer Surveillance Program (CSP), which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program.

References

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
IJC_27390_sm_SuppFig1.gif15KSupporting Information Figure 1
IJC_27390_sm_SuppTab1.doc45KSupplemental Table 1. Previous studies of diabetes and risk of adenocarcinoma of the esophagus and stomach.

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.