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Relationship between dietary factors and cancer development

Question:

Discuss about the Reflux-Inducing Dietary Factors and Risk of Adenocarcinoma of the Esophagus and Gastric Cardia.

Over the last decades, the reported cases of adenocarcinoma of the esophagus amounts to about less than 10% of all the esophageal cancers in the Western population (Zhang, Jin, &Shen,2012). Reflux is the common risk factor associated with the esophageal adenocarcinoma and gastric cardia cancer (Pohl et al., 2013). Moreover, the long term sufferers with severe reflux symptoms, the risk of developing esophageal cancer increases 40-fold (Zhang, Jin, &Shen, 2012; Pohl et al., 2013). The reflux disease common among the Western populations is chronic gastroesophageal reflux (GER) (Zhang, Jin, &Shen, 2012). Western suffers from reflux at least once per week. In Sweden, there is an annual increase of 1.5% of the reflux disease over the tenure of 24 years (Stefanidis et al., 2010). Therefore, identification of the factors responsible for the development of the reflux disease is important for the individuals who are suffering from the discomfort of reflux like heartburn (Kahrilas et al., 2012). Moreover, identification of the disease causing factors will also help towards the development towards esophageal cancer prevention steps. There are multiple foods, which are known to relax the lower esophageal sphincter (LES) and thus promoting reflux. These reflux promoting food includes dietary fat, mints, chocolate, coffee, citrus food, tomato and onions (Gonsalves et al., 2012). Not only this, dietary fat consumed in diet retards the process of gastric emptying (Gonsalves et al., 2012) and this further increases the possibility of GER. The principle aim of the study, conducted by Paul Terry et al.,2000, is to explore the unaddressed parts in the esophageal carcinoma that is the effect of diet in development of disease susceptibility. Their research question was whether observation of specific reflux-provoking diet imparts any amount of risk towards the development of susceptibility of adenocarcinoma of the esophagus and gastric cardia. The study also tries to elucidate the effect of meal size and time of meal consumption (that is bedtime) on esophageal adenocarcinoma.

There lays a strong association between the severity and frequency of reflux and risk factor for developing esophageal and gastric cardia adeno carcinomas. The findings suggest that consumption of reflux promoting food is not a concern of public health for the general population as dietary factors are not related with the threats of developing adenocarcinoma of the esophagus or gastric cardia.

Importance of identifying factors causing reflux disease

No significant trends were observed towards the development of the esophageal adeno carcinoma upon consumption of the reflux promoting food. Moreover there was a presence of non-significant, decreased risk of the disease development with the greater consumption of leeks, onions and garlic. Not only this, there was no relation between the development of squamous cell carcinoma and consumption of reflux causing food (however, data was not shown in this case). The size and the time of the meal also turned out to be non-significant in relation to the risk of the disease development, as elucidated via statistical analysis. The additional adjustments like the presence or severity of the reflux symptoms showed no significant alteration in the findings.

The study was done via analyzing the affect of intake of LES-relaxing foods in a nationwide population based case control study, which was done in Sweden. The study also tried to elucidate dietary habits of these people and the subsequent affect on the predisposition of esophagealadenocarcinoma. The study on done based on two core pillars of biology, histology and anatomy. The histological slides were analysed by the pathologist. Based on the histological and anatomical classification, the patients of cardia cancer and adenocarcinoma were separated. Cardia cancer was isolated based as adenocarcinoma when the centre was with the 2 cm proximal end and 3 cm from the distal end in comparison to the gastroesophageal junction (Yan, Wistuba, Emmert-Buck & Erickson, 2011). If there was visible appearance of Barrett's metaplasia, it was classified as esophageal, even if the presence is within the cardia (Zhang, 2013).

All the subjects of the focus group gave a face-to-face interview, which was conducted by a group of professional interviewers from Statistics Sweden and the entire process of interview was computer oriented. A structured food frequency questionnaire containing 63 different items of food and beverage was utilised to evaluate the dietary habits of from the date of interview to 2 decades back. The questions mostly encompasses the rate of consumption of food, the number of servings (per day, month or annually), the time of dinner, average size of the meals and it was assessed by photographs of 4 different proportion of 7 common Swedish dishes. The reflux symptoms are classified on the basis of presence or absence of heart burn, its duration, frequency and severity. A severity index of the heart burn was also created based on the nature and frequency of reflux.

Food items known to promote reflux

The analysis of the data was done via statistical analysis via using Spearman correlation co-efficient. Unconditional logistic regression was used based on multivariable model. This multi-variable model include gender, BMI, total intake of energy, energy adjusted intake of alcohol, intake of total fruits and vegetables and degree of cigarette smoking.

The study was designed on the native population of Sweden and included people who were less than 80 years old as on 1st December 1994 to 31st December 1997. All the people who were recently diagnosed with esophageal adenocarcinoma (n = 216) and gastric cardia (n = 313) were considered suitable for this study. The patients, who were suffering from the squamous cell carcinoma of the esophagus and were under 80 years of age, were excluded from the study. This is due to the fact squamous cell carcinoma and esophagaladenocarcinoma has different disease mechanism all together (Agrawal et al., 2012). Moreover, the risk of the squamous cell carcinoma is unrelated with GER.

The exclusion criteria or the non-participation among the esophagealadeno carcinoma was 21.5 % (n = 27) and the cardia cancer patients was 16.3% (n = 51). So the total number of the non-participations amounted to 84.6% (n=66). This non-participation is based on the poor clinical condition of the patients or death, immediately after the diagnosis. Moreover non-participation among the control group (n=308 or 27%) was attributed due to unwillingness to participate. 7 subjects were excluded from the analysis due to their poor total energy intake, indicating erroneous dietary questions responses. 3 subjects were excluded because of the lack of information of the Body Mass Index (BMI). The other 2 subjects were excluded from the study due to poor response of the dietary questions. After implementing all the exclusion criteria there were 185 participants under esophagealadenocarcinoma, 258 participants of cardiaadenocarcinoma and 815 participants were used a placebo group or control.

The food, which have shown positive effects in the development of temporary GER or relaxed LER in previous laboratory experiments, may not taken in significant quantity. Moreover, the development of the temporary reflux caused by the exposure of food as elucidated in previous laboratory study might be qualitatively different. As proposed by this study, such disease may be different from inflammation-causing reflux characteristic of GER. Another possible explanation given by the researchers of this study behind the non-dependence of the food habit on the development of the GERD and subsequent esophagealadeno carcinoma is people who suffers from GERD feels fuller due to lack of appetite and hence consume small servings of food(Bohdjalian et al., 2010). Moreover, the reflux promoting foods like tomato, citrus food, onions and garlic are rich on anti-carcinogenic content and hence can be claimed to be related with the development of GERD linked esophagealadeno carcinoma (Steevens, Schouten, Goldbohm& van den Brandt, 2011).

Background of the study and study design

The findings to this study are completely different from the other previous findings. Previous findings showed that the consumption of the reflux initiating food is associated with the development of GERD, promoting the increase in the susceptibility of esophagusadeno carcinoma. However, the research carried out by Terry et al., showed no significant association with the dietary habits with the disease development. Future research scope will be thus directed towards the further refinement of the research in order to strengthen of the findings. This refinement of the research must be done via choosing a different population group in the western population apart from the Swedish population. The refinement of the results obtained can also be done via testing the validity of the research on potent reflux generating food which scores zero in the amount of anti-carcinogenic content like the carbonated beverages.

Confounding

The results are likely to be affected by the biases including cofounding. The cofounding will arise as a result of the baseline characteristic of the study subjects. The median age of the controls (68 years) and the target group (67 years) was not kept same; there exist a one year difference between the two. Apart from these minor biases, there also exists some significant bias factor in this study done by Terry et al., (2000). The target Swedish population, which was selected for the study lacks equality in gender. Here the men comprised of 86% of the cases with 83% attributing for the control group. Moreover, the proportion of the tobacco smoking subjects was kept lower in the placebo group and comparatively higher among the target group upon which the study was conducted. Moreover, the BMI scale was also lower among the placebo group than that of the target group. This significant variation in the selection parameter among the placebo and the target group is bound to attribute for biases.

In this study, the results are obtained via conducting the study with a large group of Swedish population and hence there are a high chance of generation of chance variation in the Statistical analysis. Moreover, chance variance of chance error is an error common in any statistical model of data analysis and this statistical model in not an exception (Busk &Marascuilo, 2015). Moreover, the chance variation is also attributed over the statistical model for several other factors. The first is a multi variative model was used to study. The energy adjusted alcohol intake is converted into grams of pure alcohol based on per week of consumption. However, alcohol intake is associated with the increase chance of development of esophageal adenocarcinoma (Hardikar et al., 2013). Hence, the consideration of the alcohol intake in the energy parameter of the daily food intake may have lead to the generation of chance error in the statistical analysis. The significant influence of alcohol might have manipulated the effect of other reflux causing diet on the disease prognosis.

Analysis of the data via statistical models

However, the questions related with the dietary habits are based on the last 20 years data. Such a long span of food habit is difficult to memorise by a person who is above 60 years old (67-68 years) this thus lead to chance of biases and variance in data representation. Moreover, the size of the meal as answered by the participants was based on the eye estimation on only 7 popular Swedish. This eye- estimation of hampers the clear representation of data.

Statistical methods fail to establish a causal relationship. The significance of causal association depends on the matter of judgment that goes beyond any statement of statistical probability. There is no stronger association between the risk factor and the outcome. Here the risk factor is dietary intake of reflux causing diet and the outcome is the development of esophageal adenocarcinoma. The specificity of the association means relationship between cause and outcome, however, there is no association of relationship. There is however, temporal sequence of outcome as the exposure of the reflux causing diet precede no disease outcome, the relationship is thus inverse. The biological plausibility behind the possible outcome is, people with reflux disease consume less diet hence negative or no effect on the disease development and the presence of anti-carcinogenic factor in the reflux causing diet like citrus fruits and onions have prevented the development of GERD induced esophagealadeno carcinoma. There is no coherence because the relationship obtained from this study has no degree of resemblance with the current knowledge of the biology of the adeno carcinoma and its prognosis upon reflux causing diet. The removal of the exposure is expected to alter the frequency of the outcomes as shown by the placebo group. Thus overall, there is a lack of causal relationship.

Application to source population

Here the source population is the Swedish population. But the majority of the epidemiological analysis was done over males who were 67-68 years old. Thus the final results though significant with this specific population group, may extract different results altogether when applied over females who are suppose 50 to 55 years (or more than that). Here the population taken for the study smokes tobacco and consumes alcohol and hence the results may be different when applied to a Swedish population of same age group and gender but are non-smokers.

The external validity of the study is determined by the fact that how it can be successfully implemented over other relevant population. The present research uses population based case-control study, Swedish population. The external validity will be established when other western populations, apart from Sweden, produce same results on the disease pre-disposition and effects of dietary intake. However, the criteria, which have been undertaken for sampling and for separating the placebo group from the target group must also be maintain or applied to other population. The criteria taken for sampling is not generalised and hence the relevancy of external validity is questionable.

References

Agrawal, N., Jiao, Y., Bettegowda, C., Hutfless, S. M., Wang, Y., David, S., ...& Wang, L. D. (2012). Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. Cancer discovery, 2(10), 899-905.

Bohdjalian, A., Langer, F. B., Shakeri-Leidenmühler, S., Gfrerer, L., Ludvik, B., Zacherl, J., &Prager, G. (2010). Sleeve gastrectomy as sole and definitive bariatric procedure: 5-year results for weight loss and ghrelin. Obesity surgery, 20(5), 535-540.

Busk, P. L., &Marascuilo, L. A. (2015). Statistical Analysis in Single-Case Research. Single-Case Research Design and Analysis (Psychology Revivals): New Directions for Psychology and Education, 159.

Gonsalves, N., Yang, G. Y., Doerfler, B., Ritz, S., Ditto, A. M., & Hirano, I. (2012). Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology, 142(7), 1451-1459.

Hardikar, S., Onstad, L., Blount, P. L., Odze, R. D., Reid, B. J., & Vaughan, T. L. (2013). The role of tobacco, alcohol, and obesity in neoplastic progression to esophageal adenocarcinoma: a prospective study of Barrett's esophagus. PloS one, 8(1), e52192.

Kahrilas, P. J., Jonsson, A., Denison, H., Wernersson, B., Hughes, N., &Howden, C. W. (2012). Regurgitation is less responsive to acid suppression than heartburn in patients with gastroesophageal reflux disease. Clinical Gastroenterology and Hepatology, 10(6), 612-619.

Pohl, H., Wrobel, K., Bojarski, C., Voderholzer, W., Sonnenberg, A., Rösch, T., &Baumgart, D. C. (2013).Risk factors in the development of esophageal adenocarcinoma. The American journal of gastroenterology, 108(2), 200-207.

Steevens, J., Schouten, L. J., Goldbohm, R. A., & van den Brandt, P. A. (2011).Vegetables and fruits consumption and risk of esophageal and gastric cancer subtypes in the Netherlands Cohort Study. International journal of cancer, 129(11), 2681-2693.

Stefanidis, D., Hope, W. W., Kohn, G. P., Reardon, P. R., Richardson, W. S., Fanelli, R. D., & SAGES Guidelines Committee. (2010). Guidelines for surgical treatment of gastroesophageal reflux disease. Surgical endoscopy, 24(11), 2647-2669.

Terry, P., Lagergren, J., Wolk, A., &Nyrén, O. (2000).Reflux-Inducing Dietary Factors and Risk ofAdenocarcinoma of the Esophagus and Gastric Cardia. Nutrition and cancer, 38(2), 186-191.

Yan, W., Wistuba, I. I., Emmert-Buck, M. R., & Erickson, H. S. (2011).Squamous cell carcinoma–similarities and differences among anatomical sites. American journal of cancer research, 1(3), 275.

Zhang, H. Z., Jin, G. F., &Shen, H. B. (2012).Epidemiologic differences in esophageal cancer between Asian and Western populations. Chinese journal of cancer, 31(6), 281.

Zhang, Y. (2013). Epidemiology of esophageal cancer. World journal of gastroenterology: WJG, 19(34), 5598.

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