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Helicobacter pylori and gastric cancer prevention is possible
Cancer Detection and Prevention 28 (2004) 392–398 www.elsevier.com/locate/cdp
Review
Helicobacter pylori and gastric cancer prevention is possible Francis Me´graud MD*, Philippe Lehours PharmD Universite´ Victor Segalen Bordeaux 2, National Reference Center for Campylobacters and Helicobacters, Laboratoire de Bacte´riologie, Universite´ Victor Segalen Bordeaux 2, 33076 Bordeaux Cedex, France Accepted 27 July 2004
Abstract Epidemiological data gathered during the past few years have shown an association between Helicobacter pylori infection and gastric carcinoma. This association is considered to be causal because of its biological plausibility and the existence of an animal model, even though the positive consequences of eradication on cancer prevention have not yet been definitely proven. The limited proportion of H. pylori infected subjects who develop a gastric cancer can be explained by host factors (certain alleles of IL-1b) and bacterial factors (cag positive strains), and to a lesser extent by environmental factors (diet). Arguments in favor of the prevention of gastric carcinoma by eradicating H. pylori are now stronger than before, given the availability of simple and accurate diagnostic tests (serology) and treatment follow-up (urea breath test), as well as a 7-day treatment which is usually sufficient for eradication. # 2004 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved. Keywords: Helicobacter pylori; Eradication; Gastric carcinoma; Risk factors
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
393
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The role of Helicobacter pylori infection in the development of gastric cancer . 2.1. Association and temporal relationship . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Pathophysiological mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Effect of an intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Animal model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3.
Risk 3.1. 3.2. 3.3.
factors for gastric carcinoma Environmental factors . . . . Host factors . . . . . . . . . . . Bacterial factors . . . . . . . .
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4.
How 4.1. 4.2. 4.3.
can gastric carcinoma be prevented in 2004?. . . . . Arguments for doing nothing . . . . . . . . . . . . . . . Arguments in favor of taking preventive measures Who should therefore be treated? . . . . . . . . . . . .
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* Corresponding author. Tel.: +33 5 56795910; fax: +33 5 56796018. E-mail address: [email protected] (F. Me´graud). 0361-090X/$30.00 # 2004 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.cdp.2004.07.005
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1. Introduction
Table 2 Time interval between serum collection and diagnosis of gastric cancer [8]
The most common gastric cancer (adenocarcinoma) is still widespread. A study published on worldwide mortality in 1990 put gastric cancer in the fourteenth position, with 750,000 deaths, making it the second major cause of cancer mortality after respiratory tract cancers [1]. Furthermore, the mortality rate linked to this form of cancer parallels its incidence, with a less than 25% survival rate after 5 years. Incidence data adjusted for age show an important decrease for this cancer from the beginning of the 20th century. Due to the aging population throughout the world, the number of cancer cases is nevertheless increasing in absolute value [2]. In this article, we will review the role of Helicobacter pylori infection in the etiology of gastric carcinoma and consider the risk factors which lead to cancer in patients infected with H. pylori, before discussing preventive measures. Low grade B cell MALT lymphoma, which is another good example of a cancer of infectious etiology, will not be part of this review since it is a much rarer disease.
Interval (years)
OR [95% CI]
>10 10–14 >14
2.2 [1–5] 4.4 [1.8–13] 8.7 [2.7–44.7]
OR: odds ratio, CI: confidence interval.
There are two histological types of distal cancers: (1) intestinal cancers which are the most frequent and in which the mucosal aspect evolves over decades towards intestinal metaplasia and dysplasia, and (2) diffuse cancers which apparently develop independently of this histological evolution [5], while at the molecular level they show intestinalization as well [6]. However, the two types have the same link with H. pylori infection. The association between cancer and an H. pylori infection, acquired during childhood and essentially a lifelong infection, was officially recognized in 1994 by a group of experts gathered at the International Center for Cancer Research, a WHO agency, on the basis of several case-control studies nested on cohorts in two countries, England and the United States, and in the latter in California and Hawaii [7]. Long term follow-up on large cohorts of subjects with biological samples obtained at the onset of the studies have allowed the assessment of potential risk factors for the development of gastric carcinomas. Hence, it has been possible to evaluate the strength of association between H. pylori and gastric cancer while demonstrating a temporal relationship between H. pylori infection and gastric carcinogenesis. This point is important because the discovery of concomitant H. pylori infection and gastric cancer does not predict the direction of causality. Furthermore, in those cases in which H. pylori infection is not evident at the time of cancer diagnosis, the presence of a previous sample demonstrating infection is necessary to suggest a relationship between H. pylori infection and gastric cancer. Three studies published before the WHO consultation (Table 1) [7] showed that H. pylori infection increases the risk for gastric carcinoma [odds ratio (OR): 2.8–6] with statistically significant confidence intervals (CI). In addition, all three studies demonstrated a direct relationship between the time interval from the diagnosis of the infection and the development of cancer (Table 2) [8]. Case-control studies
2. The role of Helicobacter pylori infection in the development of gastric cancer An interesting approach to studying the relationship between two different phenomena, e.g. H. pylori infection and gastric carcinoma, is to employ B. Hill’s criteria of causality, designed in the first instance to show a causal relationship between smoking and lung cancer, which have been used and improved by epidemiologists since then. These criteria concern, first, an association and temporal relationship between the two phenomena; secondly, the biological plausibility, i.e. the pathophysiological mechanisms which support the association; and finally the evaluation of an intervention aimed at eliminating the suspected cause [3]. 2.1. Association and temporal relationship It is well known that the association between H. pylori infection and gastric carcinoma only concerns distal cancers, and not proximal cancers (cardia) which represent 20% of the gastric cancer cases in Western Europe and are more similar to esophageal cancers [4].
Table 1 Seroprevalence of Helicobacter pylori infection in three nested case-control studies in prospective cohorts of patients with gastric cancer and paired controls [7] Country
Case No.
UK 29 US (California) US (Hawaii)
29 109 109
Control H. pylori infected No.
Percent
20 92 103
69 84 94
OR: odds ratio, CI: confidence interval.
No.
116 109 109
OR
95% CI
Average follow-up (years)
2.8 3.6 6.0
1.0–8.0 1.8–7.3 2.1–17
6 14 13
H. pylori infected No.
Percent
54 66 83
47 61 76
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Table 3 Results of a meta-analysis on case-control studies associating Helicobacter pylori infection and gastric carcinoma [9] Group
No.
OR
95% CI
All of the studies together Proximal (cardia) Distal Intestinal type Diffuse type Early cancer Advanced cancer
19 7 10 10 10 3 3
1.9 1.2 3 2.5 2.6 6.3 2.1
1.3–2.8 0.6–2.7 1.8–5.3 1.4–4.4 1.4–4.5 1.9–21.5 0.4–10.7
OR: odds ratio, CI: confidence interval.
considered together in a meta-analysis (Table 3) show a weak (x2) but significant global OR for developing gastric carcinoma in the presence of an H. pylori infection. These studies confirm that H. pylori infection is associated with distal gastric cancers. Other data have confirmed the association between H. pylori infection and distal gastric cancer. It is well known that many distal gastric cancers develop on an inflamed mucosa (aside from rare families with known genetic abnormalities) which is frequently the result of H. pylori infection (95% of the cases in the Eurohepygast study) [9]. A Japanese study in which 526 patients were followed for an average of 7.8 years showed that only the H. pylori infected subjects developed distal gastric cancer (Fig. 1) [10]. A graphic representation of the prevalence of H. pylori infection according to age in case and control subjects is shown on Fig. 2 [11]. When gastric cancers diagnosed in young subjects were grouped together, the OR for developing gastric cancer in the setting of H. pylori infection reached 15 [12]. In addition, the diagnosis of the infection is made by a global ELISA test, using a pool of antigens. Moreover, when H. pylori infection was assessed using anti-CagA antibodies rather than pooled antigens, the relative risk for distal gastric carcinoma adjusted for age and gender increased from 2.2 [95% CI: 1.4–3.6] to 21 [65% CI: 8.3–53.4] [13]. Therefore, there is a strong association between infection with specific H. pylori strains and the subsequent development of gastric cancer.
Fig. 1. Evolution towards gastric carcinoma according to the Helicobacter pylori status of 526 patients followed over an average period of 7.8 years in Japan [11].
Fig. 2. Prevalence of Helicobacter pylori infection in case and control patients according to their age when cancer was diagnosed [9].
2.2. Pathophysiological mechanism H. pylori induces an inflammatory response in the gastric mucosa [14]. This reaction which persists throughout the patient’s lifetime is presumed to result in carcinogenesis via apoptosis, compensatory epithelial cell proliferation, and an increase in the risk of genetic mutations. The contact of bacteria with the gastric epithelial cells induces chemokines, in particular interleukin 8 (IL-8), which attract and activate the polymorphs and macrophages. Furthermore, H. pylori increases the permeability of the mucosa [15], allowing the passage of antigens such as urease which will also activate the polymorphs and macrophages. Proinflammatory cytokines, e.g. TNFa and IFN-g, are then released. This latter cytokine originates from the Th1 lymphocytes induced by IL-6 and IL-12. Although a Th2 type response may occur (IL-10), a Th1 response is most frequently encountered. This response favors cellular immunity, and may explain the failure in eliminating the bacterium because H. pylori is an extracellular pathogen. The inflammation (chronic gastritis) will, however, be a virtually lifelong affliction, unless an intercurrent eradication is achieved. The evolution of chronic gastritis toward atrophic gastritis was described before the discovery of H. pylori. This sequence termed ‘‘Correa’s cascade’’ is a series of events evolving over several decades that progress through stages of chronic gastritis, mucosal atrophy, intestinal metaplasia, glandular dysplasia, and carcinoma [16]. Several studies showed that apoptosis increases significantly in the event of an H. pylori infection and that eradication brings the apoptotic index back down to the control level [17–19]. A compensatory proliferation of gastric cells also occurs, and is significantly increased in an active gastritis due to H. pylori [20]. It is well known that an increase in cellular proliferation favors mutations. In a model using transgenic mice (Big blue) infected with H. pylori for 6 months, an increase in the rate of mutagenesis comparable to that of positive controls was observed [21].
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In addition, H. pylori is capable of altering of DNA repair mechanisms at the epithelial cell level. This was shown at the transcription level as well as at the expression level of the genes involved. An accumulation of mutations could hence be the result of the DNA replication [22]. 2.3. Effect of an intervention The definitive and formal proof of the causal role of H. pylori infection in gastric carcinogenesis would be the beneficial effect of an intervention, i.e. the eradication of the bacteria. This proof is not available and probably never will be, because tens of thousands of subjects would have to be included in a placebo trial where cancer would be the endpoint and then be followed for several years. For practical, ethical and economic reasons, such a study has little chance of being carried out and, therefore, one must be satisfied with indirect proof. However, a randomized controlled trial of this kind was carried out in a region of China with high risk gastric cancer but this study had limited power because the sample size was relatively small: 1630 subjects, who were followed during 7.5 years. Only 18 new cases of gastric cancer occurred during this period, with no significant difference between those having received the eradication treatment (n = 7) or the placebo (n = 11) (p = 0.3). Interestingly, in the subgroup of subjects with no precancerous lesions on presentation, which received eradication treatment none developed gastric cancer vs. 6 for those receiving the placebo (p = 0.02) highlighting the existence of a point of no return when mutations are present in the precancerous lesions [23]. Another intervention trial involved patients with an early gastric cancer followed by surgery who were subjected or not to an eradication treatment. The 65 patients who received an eradication treatment remained healthy during the 60 months of an average follow-up, while 9 (13%) of the 67 patients without treatment had a cancer recurrence (Fig. 3) [24]. This promising trial nevertheless has its limits because it was not a randomized, double-blind study. Several studies, in which the endpoint of H. pylori infection is not the development of cancer but the impact on precancerous lesions, are being carried out in different countries, mainly in Asia, but with great difficulty when a placebo study is proposed.
Fig. 4. Pathological lesions observed in Mongolian gerbils infected with Helicobacter pylori according to time [24].
2.4. Animal model In addition to the epidemiological criteria reviewed above, the existence of an animal model is a very strong argument in favor of causality. The model was first described in 1998, and consists of a Mongolian gerbil infected with H. pylori which develops the same lesions as man. A chronic gastritis appears very quickly in all of the animals, precancerous lesions of intestinal metaplasia are present after 26 weeks in 2/3 of the animals and in virtually all of them at the end of their life. A carcinoma is also observed in 1/4 of the animals when they are sacrificed at 54 weeks (Fig. 4) [25].
3. Risk factors for gastric carcinoma The preceding data point out the essential role of H. pylori infection in the development of a gastric carcinoma. However, it is accepted that less than 1% of the infected subjects develop a cancer. This proportion may have been underestimated because it has been reported that up to 5% of infected subjects might develop gastric cancer for 10 years in Japan [10]. Whatever the percentage is, it indicates that although the infection is necessary, it is not sufficient. As is the case for any disease, other factors are involved, including environmental factors, host factors and probably, in this case, characteristics the infecting strain. 3.1. Environmental factors
Fig. 3. Effect of Helicobacter pylori eradication or failure of eradication after mucosectomy on cancer relapse [23].
These factors are essentially related to diet. The current belief is that food preservation methods have had an impact on the incidence of gastric cancer. In the past, food was treated by smoking or salting or preserved using various other methods, whereas for the last 50 years refrigeration is more common. A meticulous study on nutritional factors carried out in Italy confirmed that there was a higher risk of gastric cancer when the diet was rich in animal proteins and nitrites, and a
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protective effect when fruit and fresh vegetables containing ascorbic acid and tocopherol were consumed [26]. Other studies have also shown the role of salt in the development of gastric atrophy. Nonetheless, the impact of these dietary factors on the cancer risk is quite limited. Smoking is another risk factor [OR: 2.3, 95% CI: 1.1–4.7] [27].
It is likely that an infection by a strain which has particular virulence factors like cag PI, in a host with a particular IL-1b genotype, increases the risk of developing a cancer by very important proportions [OR: 24, 95% CI: 7– 72] [36].
3.2. Host factors
4. How can gastric carcinoma be prevented in 2004?
An important discovery of these last years is to have found a biological basis for host susceptibility, which had always been suspected. Certain alleles of the interleukin 1b gene (IL-1b-5110 2 et 310 2 as well as IL-1 RN 2/2 gene) lead to an elevated production of this cytokine. In addition to its proinflammatory property, IL-1b has a strong inhibitory effect on acid secretion. El Omar et al. [28,29] showed that, when an H. pylori infection is present, the risk of gastric cancer increased in the patients harboring these alleles. They also noted that hypochlorhydria and gastric atrophy were present only in family members of gastric cancer patients with an H. pylori infection and not in family members without H. pylori infection, nor in the controls, whether they were infected or not [30]. Consequently the first degree relatives of distal gastric carcinoma patients constitute the first group of subjects at risk. The topographic evolution of the infection, by affecting the body of the stomach and achlorhydria rather than by the presence of an antral gastritis alone, seems to be determined by the host’s genetic characteristics.
4.1. Arguments for doing nothing The decrease in gastric cancer has paralleled the decrease in the prevalence of H. pylori infection, probably since the end of the 20th century. The rapid drop in prevalence observed since 1945 indicates that the incidence of cancer will become negligible for the generations born after World War II. The formal proof of the impact of eradication on the incidence of gastric carcinoma is lacking. This proof is absolutely necessary. The systematic eradication of H. pylori would lead to an overconsumption of antibiotics which would not only be expensive but would also have a negative ecological impact on bacterial resistances of H. pylori and other pathogenic bacteria, not to mention serious complications (pseudomembranous colitis) which may be an adverse event of taking antibiotics. A vaccine is therefore needed. Eradicating H. pylori could have negative consequences on gastroesophageal reflux disease, or even on cancer of the esophagus and the cardia which are on the rise.
3.3. Bacterial factors 4.2. Arguments in favor of taking preventive measures It is well known that certain H. pylori strains which possess a cag pathogenicity island (PI) are often associated with the development of gastric carcinoma, both diffuse and intestinal types [31]. This may be due to the fact that the cag PI induces the production of important quantities of the proinflammatory cytokine IL-8 by the epithelial cells, via the nuclear factor Kappa B pathway [32]. However, the possibility of a direct carcinogenic action by certain strains, although unproven as yet, cannot be excluded. In fact, the example of this cag PI shows that H. pylori is capable of introducing molecules inside the epithelial cell by a type IV secretion system [33]. One of the molecules introduced is the CagA protein which disturbs actin polymerization and provokes a cytoskeleton rearrangement, which in turn most likely contributes to the apoptosis [34]. Via another pathway which is still not fully understood, the CagPAI activates the NF-KB which stimulates IL-8 production by the cell. Other molecules with a direct carcinogenic effect may also be involved. The genomes of three H. pylori strains have been sequenced but the function of many genes is still unknown. Furthermore, the proportion of genes which varies from one strain to another is 20–30% [35]. This macrodiversity leaves room for the possible existence of specific carcinogenic genes.
As mentioned before, the incidence of gastric cancer is on the decline and will become negligible, but not before 20 years or so, i.e. when the pre-war generation whose members still have a high prevalence of infection is no longer with us. The proof is provided by the stable number of new cases detected in Western Europe. In the meantime, it may seem abnormal to do nothing to stop a cancer with such a poor prognosis. We currently have sufficient evidence to foresee that the eradication of H. pylori will have a beneficial effect, perhaps not for all patients but for the majority, as long as intervention on early gastric cancer has shown its efficacity [23]. Furthermore, most of the studies targeting preneoplastic lesions have shown that eradication at least prevents the progression of the lesions even if no regression has been noted [37]. This example indeed brings us to the limits of evidence-based medicine. It is probable that the impact of thousands of treatments on bacterial resistance will not be negligible but will be largely counterbalanced by the beneficial effects. However, the impact of an increased consumption of certain antibiotics might be appreciated in the light that only half of all antibiotics are used in human medicine. Although
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vaccines are being developed, the difficulty in obtaining an effective one means that there will be a waiting period of at least 10 years. Therefore, one should not count too much on this form of prevention. H. pylori eradication is not the cause of reflux which is primarily due to an abnormality of the sphincter. Only in certain cases of H. pylori pangastritis can eradication cause an increase in gastric acidity which, in the presence of a reflux, will aggravate the symptoms. Moreover, even though cases of esophageal cancer are on the rise, they are still much less frequent than stomach cancer and should not hamper the prevention of the latter. Although there is a negative association between H. pylori infection and reflux, one could hypothesize that, in the event of high gastric acidity, the implantation of H. pylori would be difficult. There is no evidence in the literature that these diseases increase after eradication treatment. 4.3. Who should therefore be treated? The recent recommendation of a group of international experts was to propose a detection and treatment for all patients presenting themselves at health facilities. The French Helicobacter Study Group adopted this recommendation. In the same fashion as, during a doctor’s visit, the doctor offers to take the patient’s blood pressure and eventually treat hypertension to eliminate this risk factor for cardiovascular disease, he could also offer a serological test for the detection of H. pylori; in the event of a positive result, he could prescribe an eradication treatment, followed by confirmation of a successful eradication using a urea breath test. These detection tests and eradication follow-up tests are available in many countries and are very reliable [38,39]. A 7-day treatment is effective in at least 75% of the cases and a second treatment results in less than 5% of the patients remaining positive. This approach seems preferable to detection by targeting precancerous lesions which would then necessitate additional tests, either endoscopy or a determination of the pepsinogen I/III ratio and gastrin 17 level, as their predictive values are not ideal. However, a systematic prevention in the general population is not foreseeable without the existence of a vaccine. This prevention should nonetheless target families of gastric cancer patients who have a highly increased risk. In summary, it has been firmly established that H. pylori infection constitutes a major risk factor for gastric cancer. Contrary to many other risk factors for chronic disease, it is possible to eliminate this risk factor, which is found in fifth place in the hierarchy of risk factors of all cancers combined, and with relative ease by administering a 1-week treatment. Furthermore, the efficacity of the treatment can be easily confirmed. At this point in time when cancer prevention is a priority in many developed countries, it seems incredible and indeed shocking to ignore this major risk factor.
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[31] Queiroz DMM. Mendes EN, Rocha GA, et al. cagA-positive Helicobacter pylori and risk for developing gastric carcinoma in Brazil. Int J Cancer 1998;78:135–9. [32] Censini S, Lange C, Xiang Z, et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Acad Sci 1996;93:14648–53. [33] Odenbreit S, Puls J, Sedlmaier B, et al. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 2000;287:1497–500. [34] Higashi H, Tsutsumi R, Muto S, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 2002;295:683–6. [35] Salama N, Guillemin K, McDaniel TK, et al. A whole-genome microarray reveals genetic diversity among Helicobacter pylori strains. Proc Natl Acad Sci USA 2000;97:14668–73. [36] Figueiredo C, Machado JC, Pharoah P, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 2002;94:1662–3. [37] Zivny J, Wang TC, Yantiss R, Kim KH, Houghton J. Role of therapy or monitoring in preventing progression to gastric cancer. J Clin Gastroenterol 2003;36:S50–60. [38] Monteiro L, de Mascarel A, Sarrasqueta AM, et al. Diagnosis of Helicobacter pylori infection: noninvasive methods compared to invasive methods and evaluation of two new tests. Am J Gastroenterol 2001;96:353–8. [39] Versalovic J. Helicobacter pylori. Pathology and diagnostic strategies. Am J Clin Pathol 2003;119:403–12.
Review
Helicobacter pylori and gastric cancer prevention is possible Francis Me´graud MD*, Philippe Lehours PharmD Universite´ Victor Segalen Bordeaux 2, National Reference Center for Campylobacters and Helicobacters, Laboratoire de Bacte´riologie, Universite´ Victor Segalen Bordeaux 2, 33076 Bordeaux Cedex, France Accepted 27 July 2004
Abstract Epidemiological data gathered during the past few years have shown an association between Helicobacter pylori infection and gastric carcinoma. This association is considered to be causal because of its biological plausibility and the existence of an animal model, even though the positive consequences of eradication on cancer prevention have not yet been definitely proven. The limited proportion of H. pylori infected subjects who develop a gastric cancer can be explained by host factors (certain alleles of IL-1b) and bacterial factors (cag positive strains), and to a lesser extent by environmental factors (diet). Arguments in favor of the prevention of gastric carcinoma by eradicating H. pylori are now stronger than before, given the availability of simple and accurate diagnostic tests (serology) and treatment follow-up (urea breath test), as well as a 7-day treatment which is usually sufficient for eradication. # 2004 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved. Keywords: Helicobacter pylori; Eradication; Gastric carcinoma; Risk factors
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
393
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The role of Helicobacter pylori infection in the development of gastric cancer . 2.1. Association and temporal relationship . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Pathophysiological mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Effect of an intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Animal model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3.
Risk 3.1. 3.2. 3.3.
factors for gastric carcinoma Environmental factors . . . . Host factors . . . . . . . . . . . Bacterial factors . . . . . . . .
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4.
How 4.1. 4.2. 4.3.
can gastric carcinoma be prevented in 2004?. . . . . Arguments for doing nothing . . . . . . . . . . . . . . . Arguments in favor of taking preventive measures Who should therefore be treated? . . . . . . . . . . . .
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* Corresponding author. Tel.: +33 5 56795910; fax: +33 5 56796018. E-mail address: [email protected] (F. Me´graud). 0361-090X/$30.00 # 2004 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.cdp.2004.07.005
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393
1. Introduction
Table 2 Time interval between serum collection and diagnosis of gastric cancer [8]
The most common gastric cancer (adenocarcinoma) is still widespread. A study published on worldwide mortality in 1990 put gastric cancer in the fourteenth position, with 750,000 deaths, making it the second major cause of cancer mortality after respiratory tract cancers [1]. Furthermore, the mortality rate linked to this form of cancer parallels its incidence, with a less than 25% survival rate after 5 years. Incidence data adjusted for age show an important decrease for this cancer from the beginning of the 20th century. Due to the aging population throughout the world, the number of cancer cases is nevertheless increasing in absolute value [2]. In this article, we will review the role of Helicobacter pylori infection in the etiology of gastric carcinoma and consider the risk factors which lead to cancer in patients infected with H. pylori, before discussing preventive measures. Low grade B cell MALT lymphoma, which is another good example of a cancer of infectious etiology, will not be part of this review since it is a much rarer disease.
Interval (years)
OR [95% CI]
>10 10–14 >14
2.2 [1–5] 4.4 [1.8–13] 8.7 [2.7–44.7]
OR: odds ratio, CI: confidence interval.
There are two histological types of distal cancers: (1) intestinal cancers which are the most frequent and in which the mucosal aspect evolves over decades towards intestinal metaplasia and dysplasia, and (2) diffuse cancers which apparently develop independently of this histological evolution [5], while at the molecular level they show intestinalization as well [6]. However, the two types have the same link with H. pylori infection. The association between cancer and an H. pylori infection, acquired during childhood and essentially a lifelong infection, was officially recognized in 1994 by a group of experts gathered at the International Center for Cancer Research, a WHO agency, on the basis of several case-control studies nested on cohorts in two countries, England and the United States, and in the latter in California and Hawaii [7]. Long term follow-up on large cohorts of subjects with biological samples obtained at the onset of the studies have allowed the assessment of potential risk factors for the development of gastric carcinomas. Hence, it has been possible to evaluate the strength of association between H. pylori and gastric cancer while demonstrating a temporal relationship between H. pylori infection and gastric carcinogenesis. This point is important because the discovery of concomitant H. pylori infection and gastric cancer does not predict the direction of causality. Furthermore, in those cases in which H. pylori infection is not evident at the time of cancer diagnosis, the presence of a previous sample demonstrating infection is necessary to suggest a relationship between H. pylori infection and gastric cancer. Three studies published before the WHO consultation (Table 1) [7] showed that H. pylori infection increases the risk for gastric carcinoma [odds ratio (OR): 2.8–6] with statistically significant confidence intervals (CI). In addition, all three studies demonstrated a direct relationship between the time interval from the diagnosis of the infection and the development of cancer (Table 2) [8]. Case-control studies
2. The role of Helicobacter pylori infection in the development of gastric cancer An interesting approach to studying the relationship between two different phenomena, e.g. H. pylori infection and gastric carcinoma, is to employ B. Hill’s criteria of causality, designed in the first instance to show a causal relationship between smoking and lung cancer, which have been used and improved by epidemiologists since then. These criteria concern, first, an association and temporal relationship between the two phenomena; secondly, the biological plausibility, i.e. the pathophysiological mechanisms which support the association; and finally the evaluation of an intervention aimed at eliminating the suspected cause [3]. 2.1. Association and temporal relationship It is well known that the association between H. pylori infection and gastric carcinoma only concerns distal cancers, and not proximal cancers (cardia) which represent 20% of the gastric cancer cases in Western Europe and are more similar to esophageal cancers [4].
Table 1 Seroprevalence of Helicobacter pylori infection in three nested case-control studies in prospective cohorts of patients with gastric cancer and paired controls [7] Country
Case No.
UK 29 US (California) US (Hawaii)
29 109 109
Control H. pylori infected No.
Percent
20 92 103
69 84 94
OR: odds ratio, CI: confidence interval.
No.
116 109 109
OR
95% CI
Average follow-up (years)
2.8 3.6 6.0
1.0–8.0 1.8–7.3 2.1–17
6 14 13
H. pylori infected No.
Percent
54 66 83
47 61 76
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Table 3 Results of a meta-analysis on case-control studies associating Helicobacter pylori infection and gastric carcinoma [9] Group
No.
OR
95% CI
All of the studies together Proximal (cardia) Distal Intestinal type Diffuse type Early cancer Advanced cancer
19 7 10 10 10 3 3
1.9 1.2 3 2.5 2.6 6.3 2.1
1.3–2.8 0.6–2.7 1.8–5.3 1.4–4.4 1.4–4.5 1.9–21.5 0.4–10.7
OR: odds ratio, CI: confidence interval.
considered together in a meta-analysis (Table 3) show a weak (x2) but significant global OR for developing gastric carcinoma in the presence of an H. pylori infection. These studies confirm that H. pylori infection is associated with distal gastric cancers. Other data have confirmed the association between H. pylori infection and distal gastric cancer. It is well known that many distal gastric cancers develop on an inflamed mucosa (aside from rare families with known genetic abnormalities) which is frequently the result of H. pylori infection (95% of the cases in the Eurohepygast study) [9]. A Japanese study in which 526 patients were followed for an average of 7.8 years showed that only the H. pylori infected subjects developed distal gastric cancer (Fig. 1) [10]. A graphic representation of the prevalence of H. pylori infection according to age in case and control subjects is shown on Fig. 2 [11]. When gastric cancers diagnosed in young subjects were grouped together, the OR for developing gastric cancer in the setting of H. pylori infection reached 15 [12]. In addition, the diagnosis of the infection is made by a global ELISA test, using a pool of antigens. Moreover, when H. pylori infection was assessed using anti-CagA antibodies rather than pooled antigens, the relative risk for distal gastric carcinoma adjusted for age and gender increased from 2.2 [95% CI: 1.4–3.6] to 21 [65% CI: 8.3–53.4] [13]. Therefore, there is a strong association between infection with specific H. pylori strains and the subsequent development of gastric cancer.
Fig. 1. Evolution towards gastric carcinoma according to the Helicobacter pylori status of 526 patients followed over an average period of 7.8 years in Japan [11].
Fig. 2. Prevalence of Helicobacter pylori infection in case and control patients according to their age when cancer was diagnosed [9].
2.2. Pathophysiological mechanism H. pylori induces an inflammatory response in the gastric mucosa [14]. This reaction which persists throughout the patient’s lifetime is presumed to result in carcinogenesis via apoptosis, compensatory epithelial cell proliferation, and an increase in the risk of genetic mutations. The contact of bacteria with the gastric epithelial cells induces chemokines, in particular interleukin 8 (IL-8), which attract and activate the polymorphs and macrophages. Furthermore, H. pylori increases the permeability of the mucosa [15], allowing the passage of antigens such as urease which will also activate the polymorphs and macrophages. Proinflammatory cytokines, e.g. TNFa and IFN-g, are then released. This latter cytokine originates from the Th1 lymphocytes induced by IL-6 and IL-12. Although a Th2 type response may occur (IL-10), a Th1 response is most frequently encountered. This response favors cellular immunity, and may explain the failure in eliminating the bacterium because H. pylori is an extracellular pathogen. The inflammation (chronic gastritis) will, however, be a virtually lifelong affliction, unless an intercurrent eradication is achieved. The evolution of chronic gastritis toward atrophic gastritis was described before the discovery of H. pylori. This sequence termed ‘‘Correa’s cascade’’ is a series of events evolving over several decades that progress through stages of chronic gastritis, mucosal atrophy, intestinal metaplasia, glandular dysplasia, and carcinoma [16]. Several studies showed that apoptosis increases significantly in the event of an H. pylori infection and that eradication brings the apoptotic index back down to the control level [17–19]. A compensatory proliferation of gastric cells also occurs, and is significantly increased in an active gastritis due to H. pylori [20]. It is well known that an increase in cellular proliferation favors mutations. In a model using transgenic mice (Big blue) infected with H. pylori for 6 months, an increase in the rate of mutagenesis comparable to that of positive controls was observed [21].
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In addition, H. pylori is capable of altering of DNA repair mechanisms at the epithelial cell level. This was shown at the transcription level as well as at the expression level of the genes involved. An accumulation of mutations could hence be the result of the DNA replication [22]. 2.3. Effect of an intervention The definitive and formal proof of the causal role of H. pylori infection in gastric carcinogenesis would be the beneficial effect of an intervention, i.e. the eradication of the bacteria. This proof is not available and probably never will be, because tens of thousands of subjects would have to be included in a placebo trial where cancer would be the endpoint and then be followed for several years. For practical, ethical and economic reasons, such a study has little chance of being carried out and, therefore, one must be satisfied with indirect proof. However, a randomized controlled trial of this kind was carried out in a region of China with high risk gastric cancer but this study had limited power because the sample size was relatively small: 1630 subjects, who were followed during 7.5 years. Only 18 new cases of gastric cancer occurred during this period, with no significant difference between those having received the eradication treatment (n = 7) or the placebo (n = 11) (p = 0.3). Interestingly, in the subgroup of subjects with no precancerous lesions on presentation, which received eradication treatment none developed gastric cancer vs. 6 for those receiving the placebo (p = 0.02) highlighting the existence of a point of no return when mutations are present in the precancerous lesions [23]. Another intervention trial involved patients with an early gastric cancer followed by surgery who were subjected or not to an eradication treatment. The 65 patients who received an eradication treatment remained healthy during the 60 months of an average follow-up, while 9 (13%) of the 67 patients without treatment had a cancer recurrence (Fig. 3) [24]. This promising trial nevertheless has its limits because it was not a randomized, double-blind study. Several studies, in which the endpoint of H. pylori infection is not the development of cancer but the impact on precancerous lesions, are being carried out in different countries, mainly in Asia, but with great difficulty when a placebo study is proposed.
Fig. 4. Pathological lesions observed in Mongolian gerbils infected with Helicobacter pylori according to time [24].
2.4. Animal model In addition to the epidemiological criteria reviewed above, the existence of an animal model is a very strong argument in favor of causality. The model was first described in 1998, and consists of a Mongolian gerbil infected with H. pylori which develops the same lesions as man. A chronic gastritis appears very quickly in all of the animals, precancerous lesions of intestinal metaplasia are present after 26 weeks in 2/3 of the animals and in virtually all of them at the end of their life. A carcinoma is also observed in 1/4 of the animals when they are sacrificed at 54 weeks (Fig. 4) [25].
3. Risk factors for gastric carcinoma The preceding data point out the essential role of H. pylori infection in the development of a gastric carcinoma. However, it is accepted that less than 1% of the infected subjects develop a cancer. This proportion may have been underestimated because it has been reported that up to 5% of infected subjects might develop gastric cancer for 10 years in Japan [10]. Whatever the percentage is, it indicates that although the infection is necessary, it is not sufficient. As is the case for any disease, other factors are involved, including environmental factors, host factors and probably, in this case, characteristics the infecting strain. 3.1. Environmental factors
Fig. 3. Effect of Helicobacter pylori eradication or failure of eradication after mucosectomy on cancer relapse [23].
These factors are essentially related to diet. The current belief is that food preservation methods have had an impact on the incidence of gastric cancer. In the past, food was treated by smoking or salting or preserved using various other methods, whereas for the last 50 years refrigeration is more common. A meticulous study on nutritional factors carried out in Italy confirmed that there was a higher risk of gastric cancer when the diet was rich in animal proteins and nitrites, and a
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protective effect when fruit and fresh vegetables containing ascorbic acid and tocopherol were consumed [26]. Other studies have also shown the role of salt in the development of gastric atrophy. Nonetheless, the impact of these dietary factors on the cancer risk is quite limited. Smoking is another risk factor [OR: 2.3, 95% CI: 1.1–4.7] [27].
It is likely that an infection by a strain which has particular virulence factors like cag PI, in a host with a particular IL-1b genotype, increases the risk of developing a cancer by very important proportions [OR: 24, 95% CI: 7– 72] [36].
3.2. Host factors
4. How can gastric carcinoma be prevented in 2004?
An important discovery of these last years is to have found a biological basis for host susceptibility, which had always been suspected. Certain alleles of the interleukin 1b gene (IL-1b-5110 2 et 310 2 as well as IL-1 RN 2/2 gene) lead to an elevated production of this cytokine. In addition to its proinflammatory property, IL-1b has a strong inhibitory effect on acid secretion. El Omar et al. [28,29] showed that, when an H. pylori infection is present, the risk of gastric cancer increased in the patients harboring these alleles. They also noted that hypochlorhydria and gastric atrophy were present only in family members of gastric cancer patients with an H. pylori infection and not in family members without H. pylori infection, nor in the controls, whether they were infected or not [30]. Consequently the first degree relatives of distal gastric carcinoma patients constitute the first group of subjects at risk. The topographic evolution of the infection, by affecting the body of the stomach and achlorhydria rather than by the presence of an antral gastritis alone, seems to be determined by the host’s genetic characteristics.
4.1. Arguments for doing nothing The decrease in gastric cancer has paralleled the decrease in the prevalence of H. pylori infection, probably since the end of the 20th century. The rapid drop in prevalence observed since 1945 indicates that the incidence of cancer will become negligible for the generations born after World War II. The formal proof of the impact of eradication on the incidence of gastric carcinoma is lacking. This proof is absolutely necessary. The systematic eradication of H. pylori would lead to an overconsumption of antibiotics which would not only be expensive but would also have a negative ecological impact on bacterial resistances of H. pylori and other pathogenic bacteria, not to mention serious complications (pseudomembranous colitis) which may be an adverse event of taking antibiotics. A vaccine is therefore needed. Eradicating H. pylori could have negative consequences on gastroesophageal reflux disease, or even on cancer of the esophagus and the cardia which are on the rise.
3.3. Bacterial factors 4.2. Arguments in favor of taking preventive measures It is well known that certain H. pylori strains which possess a cag pathogenicity island (PI) are often associated with the development of gastric carcinoma, both diffuse and intestinal types [31]. This may be due to the fact that the cag PI induces the production of important quantities of the proinflammatory cytokine IL-8 by the epithelial cells, via the nuclear factor Kappa B pathway [32]. However, the possibility of a direct carcinogenic action by certain strains, although unproven as yet, cannot be excluded. In fact, the example of this cag PI shows that H. pylori is capable of introducing molecules inside the epithelial cell by a type IV secretion system [33]. One of the molecules introduced is the CagA protein which disturbs actin polymerization and provokes a cytoskeleton rearrangement, which in turn most likely contributes to the apoptosis [34]. Via another pathway which is still not fully understood, the CagPAI activates the NF-KB which stimulates IL-8 production by the cell. Other molecules with a direct carcinogenic effect may also be involved. The genomes of three H. pylori strains have been sequenced but the function of many genes is still unknown. Furthermore, the proportion of genes which varies from one strain to another is 20–30% [35]. This macrodiversity leaves room for the possible existence of specific carcinogenic genes.
As mentioned before, the incidence of gastric cancer is on the decline and will become negligible, but not before 20 years or so, i.e. when the pre-war generation whose members still have a high prevalence of infection is no longer with us. The proof is provided by the stable number of new cases detected in Western Europe. In the meantime, it may seem abnormal to do nothing to stop a cancer with such a poor prognosis. We currently have sufficient evidence to foresee that the eradication of H. pylori will have a beneficial effect, perhaps not for all patients but for the majority, as long as intervention on early gastric cancer has shown its efficacity [23]. Furthermore, most of the studies targeting preneoplastic lesions have shown that eradication at least prevents the progression of the lesions even if no regression has been noted [37]. This example indeed brings us to the limits of evidence-based medicine. It is probable that the impact of thousands of treatments on bacterial resistance will not be negligible but will be largely counterbalanced by the beneficial effects. However, the impact of an increased consumption of certain antibiotics might be appreciated in the light that only half of all antibiotics are used in human medicine. Although
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vaccines are being developed, the difficulty in obtaining an effective one means that there will be a waiting period of at least 10 years. Therefore, one should not count too much on this form of prevention. H. pylori eradication is not the cause of reflux which is primarily due to an abnormality of the sphincter. Only in certain cases of H. pylori pangastritis can eradication cause an increase in gastric acidity which, in the presence of a reflux, will aggravate the symptoms. Moreover, even though cases of esophageal cancer are on the rise, they are still much less frequent than stomach cancer and should not hamper the prevention of the latter. Although there is a negative association between H. pylori infection and reflux, one could hypothesize that, in the event of high gastric acidity, the implantation of H. pylori would be difficult. There is no evidence in the literature that these diseases increase after eradication treatment. 4.3. Who should therefore be treated? The recent recommendation of a group of international experts was to propose a detection and treatment for all patients presenting themselves at health facilities. The French Helicobacter Study Group adopted this recommendation. In the same fashion as, during a doctor’s visit, the doctor offers to take the patient’s blood pressure and eventually treat hypertension to eliminate this risk factor for cardiovascular disease, he could also offer a serological test for the detection of H. pylori; in the event of a positive result, he could prescribe an eradication treatment, followed by confirmation of a successful eradication using a urea breath test. These detection tests and eradication follow-up tests are available in many countries and are very reliable [38,39]. A 7-day treatment is effective in at least 75% of the cases and a second treatment results in less than 5% of the patients remaining positive. This approach seems preferable to detection by targeting precancerous lesions which would then necessitate additional tests, either endoscopy or a determination of the pepsinogen I/III ratio and gastrin 17 level, as their predictive values are not ideal. However, a systematic prevention in the general population is not foreseeable without the existence of a vaccine. This prevention should nonetheless target families of gastric cancer patients who have a highly increased risk. In summary, it has been firmly established that H. pylori infection constitutes a major risk factor for gastric cancer. Contrary to many other risk factors for chronic disease, it is possible to eliminate this risk factor, which is found in fifth place in the hierarchy of risk factors of all cancers combined, and with relative ease by administering a 1-week treatment. Furthermore, the efficacity of the treatment can be easily confirmed. At this point in time when cancer prevention is a priority in many developed countries, it seems incredible and indeed shocking to ignore this major risk factor.
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