Assessment of the efficacy of anti-Helicobacter therapy in patients operated on for gastric cancer

The dissertation is devoted to evaluating the effectiveness of anti-Helicobacter pylori therapy in patients who have undergone surgical treatment for gastric cancer. The work considers the epidemiology of gastric cancer, the role of Helicobacter pylori and its individual strains, in particular cagA-positive ones, in the development of precancerous changes and tumor recurrence after resection. The study aims to compare bismuth-based and PPI-based eradication regimens in patients with chronic gastritis of the gastric stump after distal subtotal resection. The dynamics of morphological and endoscopic data, the frequency of gastric cancer recurrence over a three-year period, and criteria for differentiated monitoring aimed at the early diagnosis of malignant neoplasm recurrence are analyzed.

Relevance of the Problem

Gastric cancer is one of the pressing problems of clinical medicine in general and oncology in particular due to the unsatisfactory results of its diagnosis and treatment, despite the fact that in recent years a steady decline in morbidity has been observed in economically developed countries (Verdecchia A. et al., 2003). At present, gastric cancer is the second most common form of human malignant neoplasms. Every year, 798 thousand new cases of gastric cancer and 628 thousand deaths from this nosological form are registered worldwide, which accounts for 9.9% in the structure of morbidity and 12.1% in the structure of mortality from malignant neoplasms.

In Russia, gastric cancer occupies the third place in the structure of malignant neoplasm morbidity (10.2%), and the mortality rate in the first year after diagnosis reaches 56% (Chissov V.I. et al., 2004). At present, gastric cancer is regarded as the result of a long, multistage, and multifactorial process in which cellular changes are caused by disturbances of the microenvironment, in which H. pylori plays one of the leading roles. The pathogenetic cascade triggered by H. pylori, which through stages of atrophy, metaplasia, and dysplasia leads to the development of gastric cancer, has been well studied (Aruin L.I. et al., 1998; Ivashkin V.T., Inozemtsev S.A., 2002). In this regard, the International Agency for Research on Cancer has included H. pylori in the list of carcinogens. The prevalence of H. pylori in the population of developed countries is 80–90%, and the proportion of gastric cancer cases associated with the presence of this bacterium is estimated at 42% (Eurogast Study Group, 1993; Troost E. et al., 2003).

The scientific recognition that H. pylori is the causative agent of chronic gastritis, and through it of gastric cancer, has revealed to clinicians a completely new picture of the emergence of pathological processes and new, previously unrevealed mechanisms of interaction between the micro- and macro-organism (Kuipers E.J., 1998; Rad R. et al., 2003). The prevention of gastric cancer has now come to be regarded as a problem whose solutions may be associated with the eradication of H. pylori (Ivashkin V.T., 2002; Malfertheiner P. et al., 2003). However, the question of the significance of different H. pylori strains, especially cagA-positive ones, in the development of gastric cancer remains open. Thus, according to some literature data, it is the presence of these H. pylori strains that determines an increased risk of gastric adenocarcinoma (Holton J. et al., 1998; Parsonnet J. et al., 1997).

H. pylori-associated gastritis of the gastric stump after resection for cancer, as a recommendation for H. pylori eradication, was first considered by the II Maastricht Consensus (2000) and included in the group of mandatory indications for eradication therapy with a high level of evidence. First of all, such treatment should be considered as prophylactic, given that the gastric stump after resection is at high risk of developing a recurrence of the malignant neoplasm (Matsukura N. et al., 2003). Thus, according to Borie F. (2003), the frequency of tumor recurrence after radical resections for early gastric cancer reaches 18%.

Among gastroenterologists there is no consensus on the effectiveness of using different eradication therapy regimens in patients with H. pylori-associated gastritis of the gastric stump operated on for cancer that meet such requirements as high effectiveness, safety, and cost-efficiency. In accordance with the II Maastricht Consensus (2000), the use of a PPI in combination with two antibacterial drugs is recommended as first-line eradication therapy. However, there are also works indicating that the effectiveness of treatment regimens based on bismuth preparations, which are widely available for economic reasons, is equivalent to that of PPI-based regimens (De Boer W.A., 1999; Unge P., 1996; Wang W.H. et al., 2000). It is also known that patients operated on for gastric cancer with distal subtotal resection are prone to developing hypo- and anacidic conditions (Ivanov M.A. et al., 2002; Kuipers E.J., 1998). In this regard, it can be assumed that in this category of patients the use of reserve regimens based on bismuth preparations is preferable.

Thus, the majority of practical and theoretical issues related to the treatment and adequate monitoring of gastric cancer patients who have undergone surgical treatment remain not fully resolved. The limited experience of using eradication therapy both in the primary prevention of gastric cancer and in the prevention of tumor recurrence, as well as the inconsistency of the results of conducted studies, testify to the relevance of this problem (Ivashkin V.T., 2002; Isakov V.A. et al., 2003; Ohkusa T. et al., 2001; Matsukura N. et al., 2003; Tomonaga K. et al., 2003; Troost E. et al., 2003). It is obvious that the question of the appropriateness of H. pylori eradication in patients operated on for gastric cancer requires further study.

The Aim of the Work is to evaluate the effectiveness of eradication therapy regimens and to monitor patients with H. pylori-associated gastritis of the gastric stump operated on for distal gastric cancer.

Objectives of the Study

1. To determine the frequency of infection with different H. pylori strains in patients with distal gastric cancer and the severity of morphological changes in the gastric mucosa before treatment.

2. To evaluate the effectiveness of bismuth-based eradication therapy in patients with chronic H. pylori-associated gastritis of the gastric stump after radical distal subtotal gastric resection for gastric cancer.

3. To evaluate the effect of bismuth-based eradication therapy on the severity of morphological changes in the gastric stump mucosa and on the frequency of tumor recurrence in patients operated on for distal gastric cancer infected with H. pylori.

4. To establish criteria for effective differentiated monitoring of patients with chronic H. pylori-associated gastritis of the gastric stump operated on for distal gastric cancer, aimed at the early diagnosis of malignant neoplasm recurrence.

Scientific Novelty

For the first time, the frequency of H. pylori infection in patients with distal gastric cancer, the degree of gastric mucosa colonization by H. pylori, and the detection rate of cagA-positive strains have been shown. For the first time, H. pylori eradication therapy regimens based on bismuth subcitrate potassium and reserve antibacterial drugs have been considered in patients operated on for gastric cancer with distal subtotal gastric resection, and their effectiveness in the treatment of H. pylori-associated gastritis of the gastric stump has been evaluated.

The three-year dynamics of morphological changes in the gastric stump mucosa and the frequency of gastric cancer recurrence have been studied in patients who received and did not receive eradication therapy, depending on the degree of colonization and the H. pylori genotype. The prognostic significance for the development of gastric cancer recurrence of such factors as the degree of H. pylori colonization, the severity of morphological changes in the gastric stump mucosa, and the presence of the cagA gene has been established.

For the first time, a program for monitoring patients operated on for gastric cancer has been proposed, aimed at the early diagnosis of malignant neoplasm recurrence.

Practical Significance

The results of the study have shown that in patients with distal gastric cancer operated on with distal subtotal gastric resection, identification and genotyping of H. pylori and the administration of eradication therapy using bismuth-based regimens upon confirmation of H. pylori infection are indicated for the purpose of preventing tumor recurrence.

Factors of increased risk of malignant neoplasm recurrence have been established in patients with H. pylori-associated gastritis of the gastric stump operated on for distal gastric cancer, taking into account which recommendations for monitoring this category of patients have been given.

Main Provisions Submitted for Defense

1. The majority of patients with distal gastric cancer are infected with H. pylori. At the same time, the presence of a pronounced degree of gastric mucosa colonization by H. pylori, a high degree of inflammatory activity, and dysregenerative changes in the gastric mucosa reliably correlates with infection by cagA-positive H. pylori strains.

2. Eradication therapy regimens based on bismuth preparations and reserve antibacterial drugs have shown reliable effectiveness in the treatment of H. pylori-associated gastritis of the gastric stump in patients operated on for gastric cancer. At the same time, a reliable decrease in the degree of gastritis activity in the gastric stump mucosa has been revealed.

3. H. pylori eradication prevents the progression of preneoplastic changes in the gastric stump mucosa in patients operated on for gastric cancer infected with H. pylori, and reduces the risk of gastric cancer recurrence.

4. In patients with distal gastric cancer, in the case of a combination of a pronounced degree of gastric mucosa colonization by cagA-positive H. pylori strains and pronounced morphological changes in the gastric mucosa, there is an increased risk of tumor recurrence after surgical treatment; therefore, this category of patients should undergo more frequent examination (every 3 months).

Implementation of the Research Results

The results of the study have been implemented in the practice of the Oncology Center, the Gastroenterological and Therapeutic Departments of Central Clinical Hospital No. 2 named after N.A. Semashko of JSC «RZD», and the Therapeutic Department of Medical Unit No. 33 in Moscow. The obtained results have been incorporated into the work of the Department of Oncology, Propaedeutics of Internal Diseases, and Gastroenterology of MGMSU and are used in lectures, seminars, and practical classes with students, postgraduate students, and physicians.

Approval of the Work

The main provisions of the dissertation research were presented and discussed on February 1, 2005, at a joint scientific and practical conference of the staff of the Departments of Oncology and Internal Diseases and Gastroenterology of the State Educational Institution of Higher Professional Education «MGMSU» of Roszdrav, the staff of the departments of oncological and therapeutic profiles of Central Clinical Hospital No. 2 named after N.A. Semashko of JSC «RZD», and Medical Unit No. 33 in Moscow (Moscow, 2005).

Publications

On the topic of the dissertation, 8 printed works have been published.

Volume and Structure of the Dissertation

The dissertation is presented on 138 pages of typewritten text and consists of an introduction, 3 chapters of the author's own research, a conclusion, conclusions, and practical recommendations. The bibliography comprises 96 domestic and 155 foreign sources. The work is illustrated with 21 tables and 36 figures.