Controversies surrounding body mass, reflux, and risk of oesophageal adenocarcinoma

doi:10.1016/S1470-2045(06)70660-X

The Lancet Oncology

Volume 7, Issue 4, April 2006, Pages 347-349

https://doi.org/10.1016/S1470-2045(06)70660-X Get rights and content

Summary

At first the association between body mass, reflux, and oesophageal adenocarcinoma might seem easily interpreted, but a more thorough assessment of the published work shows that several factors are missing. Reflux and obesity are established risk factors for oesophageal adenocarcinoma, particularly when they occur in combination. However, the interplay between these and other factors with regard to oesophageal adenocarcinoma is uncertain. Moreover, the contribution of these risk factors in explaining the increasing incidence of oesophageal adenocarcinoma is unclear, because the trends in prevalence of reflux and obesity do not match those of incidence of oesophageal adenocarcinoma. Moreover, none of these factors contribute strongly to the striking predominance of oesophageal adenocarcinoma in men. Thus, several factors that can explain the development of oesophageal adenocarcinoma need to be addressed.

Introduction

Adenocarcinomas of the distal oesophagus and gastric cardia share several epidemiological characteristics, but also have important differences;¹ therefore, these tumours should be regarded as separate diseases. Furthermore, distinguishing between adenocarcinoma of the distal oesophagus and of the gastric cardia is commonly difficult in clinical practice.² Similarly, gastric-cardia adenocarcinoma and proximal-gastric adenocarcinoma are often misclassified.³ Thus, many gastric-cardia adenocarcinomas are probably misclassified, and tumours in this site might be a mixture of adenocarcinoma of the oesophagus and stomach. Therefore, I have not included adenocarcinoma of the gastric cardia in this essay, but have focused on oesophageal adenocarcinoma.

Section snippets

Body mass, reflux, and oesophageal adenocarcinoma: the simple interpretation

The interplay between body mass, gastro-oesophageal reflux, and oesophageal adenocarcinoma (figure 1) might seem easily interpreted. Gastro-oesophageal reflux and body mass are established as strong, severity-dependent risk factors for oesophageal adenocarcinoma.4, 5, 6, 7, 8, 9, 10, 11, 12 Reflux is also associated with high body mass.12, 13, 14 Moreover, exposure to both reflux and obesity seems to increase the risk of oesophageal adenocarcinoma in a multiplicative way.¹⁵ Apart from old age

Gastro-oesophageal reflux and oesophageal adenocarcinoma

The biological association between reflux and oesophageal adenocarcinoma is the development of Barrett's oesophagus, a columnar-lined epithelium that replaces the healthy squamous-cell epithelium of the distal oesophagus.²⁴ Barrett's oesophagus is caused by chronic and long-term reflux, but the extent to which the components of the refluxate contribute to carcinogenesis is uncertain.²⁴ Some data show that the acidic gastric juice is the most important risk factor, whereas other data show that

Obesity and oesophageal adenocarcinoma

An increase in body mass has been shown to be positively and probably causally associated with risk of developing oesophageal adenocarcinoma, an association that seems to be independent of reflux.8, 9, 10, 11, 12 Several biological mechanisms have been proposed that might explain this association, but none has yet been established.¹ Some data suggest that the combination of reflux and increased body mass has a multiplicative effect in the development of oesophageal adenocarcinoma,¹⁵ adding

Gastro-oesophageal reflux and obesity

The biological mechanisms for the relation between obesity and reflux include increased intra-abdominal pressure, long-term gastric emptying, decreased sphincter pressure in the lower oesophagus, and increased occurrence of transient sphincter relaxations.¹² However, the link between body mass and reflux is much stronger in women than in men, at least in the few studies that did sex-specific analyses.14, 38, 39 Moreover, the association between body mass and reflux in women is augmented by high

Conclusion

After reviewing the initially seemingly simple equation between body mass, reflux, and oesophageal adenocarcinoma in more detail, several factors seem to be missing. Although reflux and obesity are risk factors for oesophageal adenocarcinoma, the interplay between these two factors and other factors with regard to oesophageal adenocarcinoma is uncertain and several inconsistencies remain. The contribution of these risk factors to the increasing incidence of oesophageal adenocarcinoma remains

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Cited by (27)

Cancer of the esophagus and gastroesophageal junction: Evolution of surgical management
2011, Bulletin de l'Academie Nationale de Medecine
La stratégie thérapeutique du cancer de l’œsophage a subi de profonds changements depuis vingt ans. Les progrès dans les traitements néo adjuvants et l’optimisation de la prise en charge péri-opératoire se sont traduits par une amélioration des résultats postopératoires et de la survie. Le but de notre travail était d’analyser l’expérience d’un centre expert dans la prise en charge chirurgicale des cancers de l’œsophage au cours des vingt dernières années, afin de vérifier la réalité de ces évolutions. Les patients opérés d’un cancer de l’oesophage ou de la jonction oeso-gastrique entre 1988 et 2008 ont été inclus (n = 1153). Quatre périodes d’études (P) ont été définies : P1 : 1988–1993, P2 :1994–1998, P3 : 1999–2003, et P4 :2004– 2008. Les données démographiques, de suivi post-opératoire et de survie ont été recueillies en prospectif. Une comparaison rétrospective des quatre périodes d’étude a été réalisée. Parmi les 1153 cancers de l’œsophage, 77,4 %étaient de type histologique épidermoïde. Au cours de la période d’étude, le ratio épidermoïde/adénocarcinome est passé de 12,0 à 1,3 (P1 vs. P4, P < 0,001). Les taux de mortalité et de morbidité post-opératoire étaient respectivement de 5,6 % et 39 %, et sont restées stables au cours de la durée de l’étude. Le taux de survie à cinq ans après résection est passé de 24,3 %à 42,7 %(P1 vs. P4, P < 0,001). Le taux de résection complète R0 était de 80.7 % et a augmenté au fil du temps (P1: 74,1 % vs. P4: 82,1 %, P < 0.05). Chez ces patients opérés à visée curative, la survie à cinq ans est s’est améliorée au cours de la période d’étude(P1:32.7 %vs.P4:52.3 %,P < 0.001). La proportion de patients ayant bénéfice d’un traitement néoadjuvant (essentiellement radiochimiothérapie) est passée de 46,8 % à 66,5 % (P1 vs. P4). La réponse histologique à la radiochimiothérapie était corréllée au pronostic. La survie à cinq ans des patients en réponse histologique complète, partielle ou absente était respectivement de 52,1 %,24.8 % et 10,0 %. Les résultats postopératoires se sont peu modifiés au cours des quatre périodes étudiées ; ils sont conformes à ceux observés dans les centres experts. L’amélioration significative de la survie à long terme est probablement le reflet d’une meilleure évaluation de l’extension tumorale, d’une meilleure sélection des malades avec un taux plus élevé de chirurgie compléte, et de l’utilisation la radiochimiothérapie néoadjuvante pour les cancers localement avancés. Les espoirs de progrès pour l’avenir concernent la prédiction de la chirurgie complète R0 et une évaluation optimisée de la réponse à la chimio radiothérapie afin de pouvoir administrer un traitement « à la carte » adapté à chaque patient.
Management of esophageal cancer has evolved markedly in the last two decades. Advances in neoadjuvant treatment combined with refinements in surgical techniques and perioperative care have resulted in better postoperative outcomes and long-term survival. We investigated trends in the outcome of esophagectomy for esophageal cancer over the past 20 years at our high-volume institution. We studied patients who underwent surgery for primary cancer of the esophagus or gastroesophageal junction from 1988 through 2008 (N = 1153). Four study periods (P) were compared: 1988–1993 (P1), 1994–1998 (P2), 1999–2003 (P3) and 2004– 2008 (P4). Demographic parameters, tumor characteristics, post-operative morbidity, in-hospital mortality and long-term survival were recorded prospectively and the four periods were compared retrospectively. Squamous cell carcinoma accounted for 77.4 % of the 1153 malignancies. The ratio of squamous cell carcinoma to adenocarcinoma fell from 12.0 to 1.3 during the study period (P1 vs P4, P < 0.001), with a parallel increase in the number tumors of the lower esophagus or gastroesophageal junction. The post-operative mortality and morbidity rates were respectively 5.6 % and 42.7 % overall and remained stable during the study period. The five-year survival rate among all resected patients improved significantly, from 24.3 %to 42.7 % (P1 vs P4, P < 0.001). The complete (R0) resection rate was 80.7 %overall and increased from 74.1 % to 82.1 %(P1 vs P4, P < 0.05). The five-year survival rate improved significantly among R0-resected patients, from 32.7 % to 52.3 % (P1 vs P4, P < .0001). The proportion of patients who received neoadjuvant treatment (mainly chemoradiotherapy) rose from 46.8 % to 66.5 %. The completeness of the pathologic response after neoadjuvant chemoradiotherapy correlated with long-term survival (P < 0.001): five-year survival rates among pathologically complete, partial and non responders were 52.1 %, 24.8 % and 10 %, respectively. Short-term outcomes after resection remained stable during the study period and compared favorably with those reported by other high-volume institutions. Long-term survival improved significantly. Advances in staging methods and surgical management, combined with more stringent patient selection and use of neoadjuvant chemoradiation, may explain this progress. More reliable predictors of complete R0 resection and of the response to chemoradiation therapy are needed in order to tailor management to the individual patient.
Association of Helicobacter pylori Infection With Reduced Risk for Esophageal Cancer Is Independent of Environmental and Genetic Modifiers
2010, Gastroenterology
Infection with Helicobacter pylori is associated with reduced risk of esophageal adenocarcinoma (EAC), but it is not clear whether this reduction is modified by genotype, other host characteristics, or environmental factors. Furthermore, little is known about the association between H pylori and adenocarcinomas of the esophagogastric junction (EGJAC) or squamous cell carcinomas (ESCC). We sought to measure the association between H pylori infection and esophageal cancer and identify potential modifiers.
In an Australian, population-based, case-control study, we compared the prevalence of H pylori seropositivity and single nucleotide polymorphisms in interleukin (IL)-1B (–31, –511) and tumor necrosis factor (TNF)-α (–308, –238) among 260 EAC, 298 EGJAC, and 208 ESCC patients and 1346 controls. To estimate relative risks, we calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable logistic regression in the entire sample and within strata of phenotypic and genotypic risk factors.
H pylori infection was associated with significantly reduced risks of EAC (OR, 0.45; 95% CI: 0.30–0.67) and EGJAC (OR, 0.41; 95% CI: 0.27–0.60) but not ESCC (OR, 1.04; 95% CI: 0.71–1.50). For each cancer subtype, risks were of similar magnitude across strata of reflux frequency and smoking status. We found no evidence that polymorphisms in IL-1B or TNF-α modified the association between H pylori and EAC or EGJAC.
H pylori infection is inversely associated with risks of EAC and EGJAC (but not ESCC); the reduction in risk is similar across subgroups of potential modifiers.
Postmenopausal Hormone Therapy as a Risk Factor for Gastroesophageal Reflux Symptoms Among Female Twins
2008, Gastroenterology
Citation Excerpt :
A paradox that still remains to be explained is that while obesity and reflux symptoms are almost equally common in men and women, the complications of gastroesophageal reflux such as Barrett’s esophagus and esophageal adenocarcinoma are much more common in men. One hypothesis suggests that this could be due to sex differences in fat distribution, with abdominal obesity being more common in men.44 If our findings are confirmed in future research, the clinical implications of the findings might be considered.
Background & Aims: Female sex hormones have been suggested to increase the risk of gastroesophageal reflux symptoms via a relaxing effect on the lower esophageal sphincter. We investigated the relationship of oral contraceptives and postmenopausal hormone therapy (HT) to risk of reflux symptoms, controlling for genetic factors and body mass. Methods: Information on exposures and reflux symptoms was obtained by telephone interviews conducted in 1998–2002 among women in the Swedish Twin Registry. Use of oral contraceptives was also assessed in 1973 by questionnaires. Both cross-sectional and prospective nested case-control designs were used, each with external control analysis. The cross-sectional design was further submitted to monozygotic co-twin control analysis. Results: The cross-sectional study design comprised 4365 twins with reflux and 17,321 without. In ever users of estrogen HT, the risk of reflux symptoms was increased by 32% (odds ratio, 1.32; 95% confidence interval, 1.18–1.47). This association remained in the nested case-control analyses and increased slightly with higher body mass index. A similar pattern was observed for the use of progestin in the cross-sectional design, but no association remained in the nested case-control analysis. Use of oral contraceptives was not associated with an increased risk of reflux symptoms. Generally, the risk estimates remained virtually unchanged after adjustments for potential confounding factors, including genetic factors. Conclusions: This population-based twin study indicates that estrogen HT is an independent risk factor for reflux symptoms, while the influence of progestin HT and oral contraceptives is less consistent.
Impact of obesity on outcomes in the management of localized adenocarcinoma of the esophagus and esophagogastric junction
2007, Journal of Thoracic and Cardiovascular Surgery
Citation Excerpt :
The explanation for this association is unclear. One possible mechanism links the typical male central adiposity with chronic gastroesophageal reflux disease, both of which are independently associated with adenocarcinoma of the esophagus and junction.28 In addition to a mechanical link, the pleiotropic properties of the adipocyte have come under scrutiny, because adipocytes from central fat may have endocrine, paracrine, and immunologic properties.29
Obesity trends in the Western world parallel the increased incidence of adenocarcinoma of the esophagus and esophagogastric junction. The implications of obesity on standard outcomes in the management of localized adenocarcinoma, particularly operative risks, have not been systematically addressed.
This retrospective analysis of prospectively collected data included 150 consecutive patients (36 [24%] obese [body mass index > 30] and 114 nonobese), of whom 43 were normal weight (body mass index 20–25) and 71 were overweight (body mass index 25–30). Eighty-one patients underwent multimodal therapy. The primary end points were in-hospital mortality and morbidity, and median and overall survivals.
Thirty of 36 obese patients (84%) had a body mass index from 30 to 35. Compared with those of the nonobese cohort, obese patients had significantly increased respiratory complications (P = .037), perioperative blood transfusions (P = .021), anastomotic leaks (P = .009), and length of stay (P = .001), but no difference in mortality (P = .582) or major respiratory complications (P = .171). Median and overall survivals were equivalent (P = .348) in both groups.
Obesity was associated with increased respiratory complications and anastomotic leak rates but not with major respiratory complications, mortality, or survival. These outcomes suggest that the added risks of obesity on standard outcomes in esophageal cancer surgery are modest and should not independently have a significant impact on risk assessment in esophageal cancer management.
Central Adiposity and Risk of Barrett's Esophagus
2007, Gastroenterology
Citation Excerpt :
These results suggest that the large relative risks found for the association between BMI and EA in population-based, case-control studies may be largely driven by abdominal obesity.5,41 It has been hypothesized that obesity in general, and abdominal obesity in particular, could play a role in the development of BE by increasing intragastric pressure, which tends to promote gastroesophageal reflux.19,42 However, direct evidence for this pathway is surprisingly weak.
Background & Aims: Aside from chronic reflux, the etiology of Barrett’s esophagus (BE) remains largely unknown. This case-control study investigated body mass index (BMI), central adiposity, and cigarette smoking and risk of BE. Methods: Washington residents newly diagnosed with specialized intestinal metaplasia on at least 1 of 4 esophageal biopsy specimens taken at community gastroenterology clinics (cases [n = 193]) were compared with matched population controls (n = 211). Case subgroups included those with any visible columnar epithelium (visible BE) and those with at least 2 cm of columnar epithelium (long-segment BE [LSBE]). Interviewers conducted personal interviews and took anthropometric measurements. Results: All measures of central adiposity were strongly related to BE risk, particularly for LSBE. For the high category of waist-to-hip ratio (WHR), the adjusted odds ratios were 2.4 (95% confidence interval [CI]: 1.4–3.9) for all cases, 2.8 (95% CI: 1.5–5.1) for visible BE, and 4.3 (95% CI: 1.9–9.9) for LSBE. In contrast, the associations with BMI were weaker. When BMI and WHR were modeled simultaneously, the associations with BMI were greatly attenuated, whereas those with WHR remained strong. Further adjustment for frequency of heartburn did not change these results. Cigarette smoking moderately increased risk but with no evidence of a dose-dependent response or increasing strength by case group. Conclusions: These observations indicate the importance of identifying the mechanisms underlying obesity’s role in BE and esophageal adenocarcinoma, and suggest that weight loss might be a fruitful approach to the prevention of these diseases.
Adiposity and risk of oesophageal cancer subtypes in the Million Women Study
2023, International Journal of Epidemiology

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EssayControversies surrounding body mass, reflux, and risk of oesophageal adenocarcinoma

Summary

Introduction

Section snippets

Body mass, reflux, and oesophageal adenocarcinoma: the simple interpretation

Gastro-oesophageal reflux and oesophageal adenocarcinoma

Obesity and oesophageal adenocarcinoma

Gastro-oesophageal reflux and obesity

Conclusion

Clin Gastroenterol Hepatol

Am J Med

Gastroenterology

Lancet

Control Clin Trials

Endocrinol Metab Clin North Am

Evaluating gastric cancer misclassification: a potential explanation for the rise in cardia cancer incidence

J Natl Cancer Inst

The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia

JAMA

Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma

N Engl J Med

Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer

Cancer Causes Control

Risk of adenocarcinomas of the oesophagus and gastric cardia in patients hospitalised for asthma

Br J Cancer

Hiatal hernia, reflux symptoms, body size, and risk of esophageal and gastric adenocarcinoma

Cancer

Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia

J Natl Cancer Inst

Association between body mass and adenocarcinoma of the esophagus and gastric cardia

Ann Intern Med

Body mass, tobacco and alcohol and risk of esophageal, gastric cardia, and gastric non-cardia adenocarcinoma among men and women in a nested case-control study

Cancer Causes Control

Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications

Ann Intern Med

Obesity and estrogen as risk factors for gastroesophageal reflux symptoms

JAMA

Utility of endoscopic screening for upper gastrointestinal adenocarcinoma

JAMA

Essay
Controversies surrounding body mass, reflux, and risk of oesophageal adenocarcinoma