TITLE: Atitudes No Diagnóstico E Tratamento Das Lesões Precursoras Do Cancro Gástrico

TITLE: Management of premalignant lesions of gastric cancer: a survey of the main options applied by European Gastroenterologists

AUTHORS: Silva AJ, Carvalho A, Laranja C A, Leite C, Oliveira D, Silva F, Sousa H, Matos J, Cardoso J, Vale L, Santiago M, Morais P, Ramos R, Loureiro R, Salazar T. Supervisors: Dinis- Ribeiro M, Santos R.

Class 16 – 1st year of Integrated Master’s Degree in Medicine, Faculty of Medicine, University of Porto, Porto, Portugal. [email protected]

ABSTRACT Gastric cancer is a worldwide health problem. It has considerable morbidity and mortality rates and diverse etiologies, of which the most important are gastric cancer premalignant lesions. Timely detection and treatment of these lesions thus becomes of the outmost importance. However, there is no consensus, within the scientific and medical communities, on what methods and techniques to use to achieve these purposes. This observational, cross-sectional and quantitative research project was devised to contribute to the solution for this problem. The innovative character of this paper arises from its ambition to identify and compile the main options for diagnosis and treatment of premalignant lesions of gastric cancer currently being used by European gastroenterologists. Using an unique European Gastroenterology Centre database – the first one ever made – created specifically for the purposes of this paper, but with foreseeable applications in many other studies, online queries were sent to several medical practitioners of this field. Although there are no statistical results yet, the results obtained will be the object of a statistical analysis, which will be published online and culminated in the establishment of eventual reference guidelines for clinical cases of premalignant gastric lesions.

KEY-WORDS: signs and symptoms, digestive, diagnostic techniques and procedures, therapy, stomach neoplasms INTRODUCTION: BACKGROUND AND JUSTIFICATION

Gastric Cancer, a current day disease, is also something that has affected Mankind since ancient times. The first large scale statistical analysis of cancer incidence and mortality, made from 1760 to 1839, was carried out in Verona, Italy and the gastric variety already appeared as the most common and lethal of all kinds of cancer. [1] Until the 1980’s, gastric cancer was the leader in the world ranking of cancer related causes of death. Nowadays, the first place concerning diagnosed cases belongs to lung, breast and colorectal cancer, but in terms of mortality it can be verified that the numbers for stomach cancer are only surpassed by lung cancer [2], i.e., less diagnosed cases, but higher mortality. Today’s statistical results are alarming due to the scope of what they represent – according to an estimate of the National Cancer Institute, an american governmental organization for cancer related issues, for the current year of 2008, appearance of 21500 new cases of cancer is predicted, resulting in the death of 10880 patients, in that country alone. [3] Portugal is the European country with the most deaths due to stomach cancer, with stable mortality rates in recent years, going against the world tendency. In 2005 (most recent available data) 2500 Portuguese people died with the disease, this is, 8 people a day. [4] The decline in the number of diagnosed cases of gastric cancer in recent years is related with several factors (improvement of health conditions and access to medical treatment on the part of the general population, spread of diagnostic techniques and advances of those techniques), one of the most important causes being the recognition of the existence of some risk factors (endogenous, environmental, dietetic, bacteriological) that function as precursors for the appearance of the disease. The recognition by the “International Agency for Research on Cancer”, an organism of the World Health Organization, in 1994, that infection by Helicobacter pylori has a causal relation with gastric carcinogenesis, being definitively considered a carcinogen for man is especially important. [5] The problem is spread worldwide, as it is estimated that this bacteria infects the gastric mucosa of 50% of the world population, of whom approximately 1% may develop some kind of tumour. [6]

Premalignant lesions of gastric cancer

The gastric adenocarcinoma can occur in two forms: diffuse (undifferentiated) and intestinal. The intestinal type represents the majority of all gastric cancers and is generally preceded by lesions such as atrophic gastritis, intestinal metaplasia and dysplasia. [5] Environmental factors such as

Multistep model for the progression of gastric cancer 0 a diet rich in salt or biological factors, such as Helicobacter pylori, have a known causal relation with gastric cancer, acting, the latter, as a trigger and increasing in more than six times the risk of appearance of gastric cancer. [7] Among premalignant lesions, atrophic gastritis is placed at the beginning of the neoplastic cascade of premalignant gastric lesions [7]. It consists of a loss of glandular structures of the gastric mucosa, associated with a loss of specialized cells and consequent reduction of gastric secreting ability. Intestinal metaplasia occurs when there is a replacement of the cells of gastric mucosa by other intestinal morphologies. Gastric dysplasia is characterized by the variation of the size, shape and orientation of the epithelial, increase of atypia of the nucleus and distortion of the normal glandular array. These lesions are more frequently found on the atrium of the stomach. [7]

Most frequent symptoms associated to gastric cancer

In patients on an early stage of the disease there are no symptoms or, when present, they are not specific. [7] However, some patients can present symptoms related not only with the metastasis of the gastric cancer, specifically in the liver, but also with advanced and high degree of malignancy. This includes weight loss, anorexia and nausea. Around 80% of the patients present epigastric pain which resembles to a start of gastric ulcer.[8]

Frequent treatments

As we referred before, there are multiple precursor lesions of gastric cancer. Among them, the most common are atrophic gastritis and intestinal metaplasia. Atrophic gastritis, that is mainly caused by Helicobacter pylori can also appear from autoimmune cause, and has several approaches/treatments. One of the most common includes a proton pump inhibitor for 7 days conjugated with two antibiotics which can be, amoxicillin, clarithomycin and metrodinazole. If this stage fails, according to this protocol, the treatment should advance to a therapeutic involving tetracycline, metronidazole and bismuth combined with the proton pump inhibitor. Intestinal metaplasia can be a consequence of atrophic gastritis, or other gastric diseases caused by Helicobacter pylori. So it is easy to understand that the treatment in these cases would be similar, because the cause of lesion is the same. This is one of the several approaches/interventions that are used all over the world in the treatment of this kind of lesions. However, and due to the absence of a protocol fully accepted by all, it is urgent that guidelines for the intervention on these lesions be defined not just at regional or national level but at global level. [9]

Importance of guidelines

Nowadays, premalignant lesions of gastric cancer are frequently ignored, because they are already part of the routine in endoscopic biopsy, or because they originate a large role of clinical decisions concerned with the surveillance and treatment of these patients. This fact results from the lack of effective guidelines that could work as a guide on the treatment and follow-up of these symptoms. The importance of the establishment of these guidelines should be emphasized because they could, eventually, prevent some unnecessary deaths. [7,10]

Considering this, the research question which was in the base of our study and that guided us was: Which are the main options concerning diagnosis, monitoring and treatment of premalignant lesions of gastric cancer that are being taken by European Gastroenterologists?

To answer this question and all the issues surrounding it, the following aims have been outlined: - To assess the practice in terms of diagnosis, monitoring and treatment of premalignant lesions of gastric cancer - To compile these management options into a database

PARTICIPANTS AND METHODS

Study Participants: The target population of this study was composed of all European Gastroenterologists that perform research in gastric cancer area. Their identification was done through a Pubmed research on articles in this area and with defined keywords (intestinal neoplasm, precancerous conditions, adenocarcinoma, atrophic gastritis, metaplasia), where the centres and the authors involved were identified. Our inclusion criteria included, besides the referred keywords, only european articles, published after 2007 in which the author/department contact was present. Our exclusion criteria was to eliminate every article which did not comply to any of the inclusion criteria. So, that was a non randomized sample. Study Design: This was an observational, cross-sectional and quantitative study. It began with a research of the major gastric diseases that could be a background for stomach neoplasms and the best methods of diagnosis and treatment. This research resulted from the compilation and analysis of the present legis artis related to this thematic which supplied the study. Then the data analyzed was used for background and justification of the study. Next, a database of all European Gastroenterologists was made according to a research on Pubmed for published articles, according to inclusion and exclusion criteria. After that, an on-line query regarding options in diagnosis and treatment of gastric cancer premalignant lesions, given to us by specialists, was analysed, rewritten according to our aims and sent to those centres. The collected data was inserted into SPSS and analysed. The results will be published on-line.

Data collection methods: For the choice of the data collection instruments, we took into account the objectives and characteristics of the study. We chose a questionnaire which was divided into two parts: the first had closed-answer questions that were focus mainly on the centre’s choice in terms of diagnostic tests, follow-up conducts and therapeutics. The second part contained some open-answer questions where centres were able to add information they found relevant for the study. Some questions about the characteristics of the centre were also included in the first part of the questionnaire. Our objective was to minimize the disadvantages associated with each type of questionnaire (both closed-answer and open-answer questions), like the possibility of omitting important answers and information (in closed-answers) or make data management and analysis too complicated (in open- answers). After the ethical and formal procedures, such as agreement by the author to be included in the study, we will create a specific page on the internet for this study, where any information about the research can be found, as well as the questionnaire itself. So as to obtain a database with the contacts of the Europeans Gastroenterologists two different strategies were adopted, aiming to the highest possible success when referring to quantity and validity of data in our database. A research on PubMed was developed with the purpose of a revision of the scientific production developed by European scientists or by European Centres partners in the area in study. Thus, the keywords for the study were defined. They were “atrophic chronic gastritis”, “atrophy”, “adenocarcinoma metaplasia intestinal”, “precancerous lesions”, “gastric” and the associated MeSH terms (“gastritis, atrophic”, “atrophic”, “metaplasia”, “intestinal neoplasms”, “precancerous conditions”, “adenocarcinoma”). A research of European published articles was in PubMed from which we obtained 1200 papers to be examined. These were distributed fairly by all the elements of the group and each one identified from a paper: the authors, the European Centre to which they are associated and the respective contact. The articles corresponding to not European authors or centres were excluded and in doubt of the origin of the authors, the papers were included. The data relative to email, telephone and address were collected and organized in a database of European Gastroenterologists. The results obtained both were inserted in a database allowing the elimination of repeated centres, without redundancy that also allowed us to validate the contacts found. The referred database of the contacts of European Gastroenterologists was used for sending the questionnaire. The questionnaire that was sent to the authors, allowing the identification of options of diagnosis and treatment of the premalignant lesions of gastric cancer, was obtained through the consultation of specialists in the area and their supply of a previously elaborated questionnaire. This was subject to an analysis and modified in accordance with the objective of the study. Then a first attempt of contact with the gastroenterology authors was made via e-mail. The mail included the questionnaire on-line, through an especially developed program for the retraction of data through on-line questionnaires. The questionnaires were sent twice so that we could have an upper response rate. This process made possible the collection of the data in fault, later to be compiled and analyzed.

Variables description: Our study presents a set of non numerical variables, meaning that as dependent variables we have the follow-up or not of patients and the different options of diagnosis and treatment taken by the different European gastroenterologists (management options). Also, as independent variables we considered for example the type of lesions in cause (chronic gastritis, intestinal metaplasia, dysplasia), if the answers given reflect the author own practice or his department and place of work. All the variables of the study are categorical (qualitative).

Statistical analysis: The collected data will be organized as a database and will then be subjected to statistical management. This will be done electronically through the SPSS program, using descriptive statistics, based on absolute and relative frequency with 95% confidence interval. The results will be presented in tables and graphs: circular and bar; inferential or analytical statistics based on Chi- square hypothesis’ test and contingence tables to associate our categorical and non-paired variables. The Chi-square is an approximated hypothesis test in which if there are less than 20% of the data less than 5 we can’t apply it so, in alternative, we will use Fisher’s hypothesis test which is a more exact test. In all cases we will take as the critical value of significance of the test results of hypothesis: α = 0.05, rejecting the null hypothesis when the probability of Type I error is less than this value (p <0, 05).

RESULTS, TABLES AND GRAPHICS

At the time this paper was written, we haven’t already any significance statistical results to present. Therefor, for now, we will present what we have at the moment:

Until now, we have had a response rate in about 12%. This number may seems high, but compared to the number of emails sent it is not. We are inputting our data into spss in order to create a database that will help us to do the statistical analysis of data. Our database will contain all variables, which will be associated, allowing us to answer our research question. We will try to assess if there is heterogeneity in the practical attitudes that are being taken by European gastroenterologists concerning premalignant lesions of gastric cancer. As the queries are being answered all responses will be subjected to a descriptive statistical analysis, such as: 0 – Do your answers reflect your own practice or of your departments?

This table in an example of a contingency’s table used to associate non-paired and categorical variables. We will present, for each result, the precision of the point estimated (confidence interval).

REFERENCES

[1] Lockead P, El-Omar EM. Gastric Cancer. Br Med Bull. 2008;85:87-100. [2] Parkin DM, Bray F, Ferlay J, Pisani P..Global cancer statistics, 2002. CA Cancer J Clin. 2005 Mar- Apr;55(2):74-108. [3] Stomach (Gastric) Cancer [Internet]. Bethesda: National Cancer Institute. Available from: http://www.cancer.gov/cancertopics/types/stomach [4] Plano Nacional de Prevenção e Controlo das Doenças Oncológicas 2007/2010, Dezembro 2007. [5] Sugiyama T, Asaka M. Helicobacter pylori infection and gastric cancer. Med Electron Microsc. 2004 Sep;37(3):149-57. [6] Menaker RJ, Sharaf AA, Jones NL. Helicobacter pylori infection and gastric cancer: host, bug, environment, or all three?. Curr Gastroenterol Rep. 2004 Dec;6(6):429-35. [7] de Vries AC, Haringsma J, Kuipers EJ. The detection, surveillance and treatment of premalignant gastric lesions related to Helicobacter pylori infection. Helicobacter 2007; 12: 1-15. [8] Bowles MJ, Benjamin IS. ABC of the upper gastrointestinal tract. Cancer of the stomach and pancreas. BMJ 2001;323:1413–6 [9] Witold Bartnik. Clinical aspects of Helicobacter pylori infection. Pol Arch Med Wewn, 2008; 118 (7- 8): 426-430 [10] M Dinis-Ribeiro, A Costa-Pereira, C Lopes, L Moreira-Dias. Guidelines for surveillance of patients with atrophic chronic gastritis and intestinal metaplasia in stomach would be welcome! Helicobacter . 2007 Feb;12(1):1-15

ACKNOWLEDGEMENTS

We would like to thank Engineer Jorge Jácome for the attention and help that gave us with the statistical treatment and elaboration of the online query through his own created software, MedQuest.