Maastricht iv/ Florence Consensus Report
Yüklə 0,54 Mb. Pdf görüntüsü
|
|
Statement 1: H pylori infection is the most consistent risk factor for gastric cancer. Its elimination is therefore the most promising strategy to reduce the incidence of gastric cancer Evidence level: 1a Grade of recommendation: A Based on unequivocal scienti fic evidence, this statement was first released in the Maastricht 3 consensus report and has since been adopted by several international guidelines, including a recent S3-guideline. 3 170e172 Scienti
fic data collected since then reinforce the statement that H pylori infection is the most common proven risk factor for human non-cardiac gastric cancer.
The evidence is based on epidemiological data, experimental models in vitro and in vivo. There is biological plausibility from clinical observations and in therapeutic trials. 173 174
In the original epidemiological reports the risk for non-cardiac gastric cancer in H pylori infection was estimated to be threefold but based on more accurate methodologies and with proper controls epidemiological studies indicate the risk to be 20-fold or even higher. 84 175
H pylori is confirmed to be a risk factor if the lesion is gastric in nature and to originate from below the cardia. 176
In vivo experimental models have demonstrated the causal role of H pylori infection in the cascade leading to gastric cancer. 40
The transgenic expression of IL-1 b (a proin- flammatory and acid-suppressive cytokine) in parietal cells lead to spontaneous gastritis, mobilisation of myeloid-derived suppressor cells and gastric dysplasia. These lesions progress to carcinoma when infected with Helicobacter felis. 178 In a mouse model of Helicobacter-induced gastric cancer bone marrow- derived cells were implicated as the potential origin for gastric cancer. 179
Observational and controlled trials Eradication treatment is effective in preventing gastric cancer if it is given before preneoplastic conditions/ lesions have had time
to develop.
Intervention studies
completed in Columbia, 180 China
181 and Japan 182 all suggest that H pylori eradication is the most effective approach to gastric cancer prevention, but that it is more effective in those who do not have atrophic gastritis or IM at baseline. A pooled analysis of six studies with a total of 6695 (mostly Asian) participants followed up for 4e10 years showed that the RR for gastric cancer after H pylori eradication was 0.65 (95% CI 0.43 to 0.98). 183
After eradication a signi ficant reduction in cancer incidence was seen only in subjects with normal serum pepsinogen levels. This suggests that cancers developing after eradication are related to the presence of extensive atrophic gastritis present before the eradication treatment was given. H pylori eradication is beneficial in most subjects who have normal serum pepsinogen I and those with only mild atrophy. 184
Early eradication of H pylori in gastric cancer prevention has also been shown to be successful in experimental studies using Mongolian gerbils and mice. 185 186
Statement 2: There is strong evidence that H pylori infection exerts direct mutagenic effects in animal models and cell lines. Evidence level: not quotable Grade of recommendation: C H pylori causes direct mutagenic effects in mice. 187 188
This is related to the duration of infection and the gender of the animal. 189
Genetic instability of nuclear and mitochondrial DNA has also been reported in studies conducted on gastric cell lines. 190 191
H pylori causes preneoplastic lesions and cancer in experimental in vivo models, demonstrating the causal role of H pylori infection in the cascade leading to gastric cancer. The most important single carcinogenic factor of H pylori may be CagA, which is injected by the bacteria into the host mucosal epithelial cells. Recently, transgenic expression of CagA has been shown to lead to carcinoma in the absence of coexisting gastritis in mice. This indicates that CagA is a bacterial oncogene. 192 There is no supportive human evidence to date, mainly because transgenic CagA expression is too arti ficial to be extrapolated into the human situation. Statement 3: The risk for gastric cancer development is influenced by bacterial virulence factors, but no specific bacterial virulence markers can be recommended for clinical practice. Evidence level: 1a Grade of recommendation: A Among bacterial pathogenetic factors that carry an increased risk for gastric cancer, CagA and VacA 75 193 194 are by far the most important. The oncogenic potential of bacterial virulence factors relates to distinct polymorphisms of CagA and VacA. 195e197
EPIYA repeats of CagA enable differentiation to be made between Eastern and Western CagA-positive strains. This work indicates that Eastern strains have a much higher virulence than Western ones. The importance of geographical variability in the onco- genic potential of bacterial virulence is re flected by the difference in cancer incidence. 198 199 Statement 4: The risk of gastric cancer is influenced by host genetic factors but in clinical practice no specific marker can be recommended for genetic testing at present. Evidence level: 1b Grade of recommendation: A The impact of a familial risk driven by the presence of H pylori infection is well established 200
and is associated with host cytokine gene polymorphisms. The first observation of a poly- morphism leading to an increased risk of atrophy and gastric cancer was IL-1 b . Since then other genes have been reported in this context, including tumour necrosis factor a, IL-10, interferon g , IL-8.
201e203 Studies in a variety of geographical areas have shown wide variation in the OR for gastric cancer development that is related to altered gene expression of de fined cytokine haplotypes. 204e206 Also, polymorphisms of immune regulatory genes, including pattern recognition factors initiating the innate immune system, are reported to be associated with an increased risk for gastric cancer. 207
Statement 5: The influence of environmental factors is subordinate to the effect of H pylori infection. Evidence level: 1a Grade of recommendation: A A number of nutritional and environmental elements contribute to the development of gastric cancer to various degrees. They include N-nitroso compounds, sodium and salted foods, tobacco, alcohol and others. 208e213 There is a strong association between smoking and gastric cardia adenocarcinoma. Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084 655 Guidelines In contrast, the association between smoking and gastric non- cardia adenocarcinoma is less consistent. 212 Most studies analysing the relationship between gastric cancer and environ- mental factors have not dealt with the presence or absence of H pylori infection. Some nutritional substrates are claimed to provide some degree of protection against gastric cancer but there is little prospective evidence to support this. 214 215 The essential infor- mation gathered from a more recent European study is that the effect of all nutritional components is strictly dependent on the presence of H pylori infection and that nutrition has only a small contributing role in the absence of the infection. 216 217 In October 2009, the International Agency for Research on Cancer, which forms part of the World Health Organization, clas- si fied acetaldehyde included in, and generated endogenously from, alcoholic beverages as a group I human carcinogen. This compound is found in alcoholic beverages and is also generated endogenously from them. Acetaldehyde which is also related to H pylori is a rele- vant carcinogen especially in patients with atrophic gastritis. 218 Regular NSAID intake may be bene ficial in preventing gastric cancer. There is some evidence for this in patients with gastric ulcer, particularly in those infected by H pylori. A recent meta-analysis concluded that the regular use of aspirin was associated with a reduced risk of non-cardiac gastric cancer, especially among Caucasians. 219 Statement 6: Histopathological changes at the morphological level indicate that: 1. gastric cancer is rare in the absence of chronic active gastritis; 2. the extent and severity of the gastritis together with atrophy and IM is positively associated with cancer. Evidence level: 2b Grade of recommendation: A Gastric cancer is a multistep and multifactorial disease. H pylori infection is the most important factor in the pathogenesis of chronic gastritis 42 43 220 and is an essential factor in 71e95% of all gastric cancers. 84 H pylori induces chronic active gastritis in all those infected. 221
Patients with corpus-dominant H pylori gastritis are at a substantially increased risk for gastric cancer. 222 Prospec-
tive data indicate that H pylori-infected subjects with atrophy and IM (5e6 3 risk), pan-gastritis (15 3 risk) and corpus-dominant gastritis (34 3 risk) have a significantly increased risk developing gastric cancer. 223
IM and atrophy are indicators of an increased risk of malignant transformation and serve as precancerous markers. 224 IM, which occurs as a result of H pylori infection and after the development of atrophic gastritis, 225
is common in the human stomach and is associated with an increased risk of gastric cancer. 226 227
Intestinal-type adenocarcinoma is often preceded or accompanied by metaplastic changes, whereas diffuse-type adenocarcinoma can arise in non-metaplastic gastric mucosa. However, some cases of intestinal-type adenocarcinoma do arise from the gastric mucosa without IM. 228
Less than 1% of gastric carcinomas can be attributed to hereditary diffuse gastric cancer. This is an autosomal dominant condition and is not related to H pylori infection or gastritis. The lifetime risk for gastric carcinoma for individuals with mutation of the CDH-1 gene is 40e70% for men and 60e80% for women.
229e232 Statement 7: Mechanisms at the functional level indicate: 1. atrophic corpus gastritis causes hypochlorhydria; 2. hypochlorhydria allows the overgrowth of non-H pylori organisms that are capable of producing metabolites with a carcinogenic potential. Evidence level: 2c Grade of recommendation: A There is direct and indirect evidence of atrophic corpus gastritis leading to hypochlorhydria. 233
Patients with a hypo- chlorhydria have an overgrowth of salivary and faecal-type organisms in the gastric lumen. Studies that have compared individuals receiving acid suppression or after truncal vagotomy with controls con firm that hypochlorhydria also leads to bacte- rial overgrowth. Some of these organisms can reduce nitrate to nitrite, causing a rise in intraluminal nitrite. Nitrosating bacteria present in the lumen are capable of generating potentially carcinogenic N-nitrosamines and reactive oxygen species. 234e240 Overgrowth in several bacterial species cohabiting with H pylori has been shown in conditions of hypochlorhydria and pharmacological acid suppression. 241 242 The hypochlorhydric stomach contains reduced or absent concentrations of the free oxygen scavenger ascorbic acid. Ascorbic acid is an antioxidant that scavenges carcinogenic N-nitrosamines and reactive oxygen species. It is concentrated in the gastric mucosa, and in the healthy stomach luminal concentrations are higher than in plasma. Infection with H pylori causes the luminal concentration to fall. In the achlorhydric stomach it disappears almost completely. 243e249
Statement 8: H pylori eradication abolishes the inflammatory response and slows or may arrest the progression of atrophy. In some cases it may reverse atrophy. Evidence level: 1a Grade of recommendation: A In the absence of preneoplastic conditions successful H pylori eradication restores the in flamed gastric mucosa to normal. The active in flammatory process characterised by infiltration with polymorphonuclear cells is usually abolished within 4 weeks but chronic in flammation with lymphocytic infiltration often persists for up to 1 year. 250
The changes associated with atrophy do regress to a certain extent, but reports are con flicting. 46 251 252 Data are limited because usually only a small number of biopsy specimens have been taken and this may lead to observer bias in its assessment. A recent meta-analysis indicated that gastric atrophy may be reversible only in the corpus, but not in the antrum. There is uniform agreement that IM is irreversible. 46 250 251 253e266 Statement 9: There is strong evidence that H pylori eradication reduces the risk of gastric cancer development. Evidence level: 1c Grade of recommendation: A The plausibility of H pylori eradication in the prevention of gastric cancer was initially suggested based on the evidence obtained from epidemiological and interventional studies in animals and from observational studies in humans. 42 Rando- mised controlled trials have further proved the bene ficial effect of H pylori eradication on preneoplastic conditions 43 44 180 and in primary and secondary gastric cancer prevention. 45 267 Moreover, several important cohort studies have all con firmed the positive effect of H pylori eradication in the prevention of gastric cancer,
182 184 223 268e272 and related aspects have been critically evaluated in meta-analyses 183 251
and reviews. 252 273
Statement 10: The risk of gastric cancer can be reduced more effectively by employing eradication treatment before the development of preneoplastic conditions. Evidence level: 1a Grade of recommendation: A A number of cohort studies have shown a decreased risk of gastric cancer development after H pylori eradication. A recent meta-analysis demonstrated that H pylori eradication leads to the reduction of gastric cancer risk. 183 In one study a signi ficant 656
Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084 Guidelines reduction of gastric cancer after treatment was shown only in the group without preneoplastic conditions (lesions). 45 Early
eradication of H pylori was shown to prevent gastric cancer in patients with peptic ulcer disease. 182 272 The more advanced the preneoplastic condition is the more likely it is that the devel- opment of gastric cancer cannot be halted. 172 274 The exact point of no return has not been identi fied.
Statement 11: H pylori eradication for gastric cancer prevention is cost-effective in certain communities with a high risk for gastric cancer. Evidence level: 3 Grade of recommendation: B The incidence of gastric cancer differs widely between popu- lations and there is a wide range in the prevalence of H pylori infection between children and adults. 275
When considering a H pylori eradication strategy, differences in H pylori virulence factors must be taken into account together with the effects of global population migration patterns and the available healthcare resources. Screening young adults for H pylori could prevent one in every four to six gastric cancers in China and would represent a cost- effective strategy. 276 In selected populations at very high risk of developing gastric cancer (eg, resected early gastric cancer), H pylori eradication should be reimbursed to prevent subsequent cancer and in order to reduce healthcare costs. 277
Early once-in-a- lifetime H pylori eradication is more cost-effective than a surveillance strategy. However, this approach is still subject to the risk of reinfection, the ability to detect early gastric cancer and the timing of intervention. 278
H pylori eradication for gastric cancer prevention is cost-effective in certain communities at high risk for gastric cancer. Statement 12: H pylori eradication offers additional clinical and financial benefits in addition to gastric cancer prevention. Evidence level: varies with disease (1a to 4) Grade of recommendation: A H pylori eradication treatment offers additional clinical and financial benefits besides gastric cancer prevention, as outlined in the section on indications. Eradication prevents future H pylori-induced peptic ulcera- tion of the stomach and/or duodenum. 279
Patients with GI risk factors taking ASS are often not provided with concom- itant gastroprotective drugs and thus at increased risk for mucosal lesions in the presence of H. pylori. 280 Furthermore, because prophylactic eradication reduces the risk of ASS, ulcer eradication indirectly prevents possible interaction between PPIs and dual antiplatelet treatment. 281
Eradication treatment reduces the risk of FD and prevents gastric MALT lymphoma. Iron-de ficiency anaemia, ITP, lymphocytic gastritis and Morbus Menetrier may be prevented by eradication treatment as well. Finally, H pylori eradication heals gastritis (ICD-10) and may prevent the spread of the infection and reduces future costs arising from treatment of later H pylori associated disease. One prospective study has shown that a community test-and-treat policy in a developed country would pay for itself over 10 years. 282e284
Statement 13: A screen-and-treat strategy of H pylori should be explored in communities with a significant burden of gastric cancer Evidence level: 2c Grade of recommendation: A Population-based screening is probably the best option for the primary prevention of gastric cancer. However, there are large differences in incidence between populations and this is mainly attributable to differences in H pylori virulence and dietary factors. 199 217 285 The Asian-Paci fic consensus 172 has already recommended a policy of H pylori eradication in populations at high risk of gastric cancer. This approach should be considered in other high-risk areas around the world, including Europe. Statement 14: Validated serological tests for H pylori and markers of atrophy (ie, pepsinogens) are the best available non-invasive tests to identify subjects at high risk of gastric cancer. Evidence level: 1a Grade of recommendation: B Measurement of serum pepsinogen I detects severe preneo- plastic conditions (ie, severe atrophy) and has gained attention as a candidate screening test for gastric cancer. 286
Most cases detected by the pepsinogen method in Japan are asymptomatic early gastric cancers limited to the mucosa and these are particularly well suited for endoscopic treatment. 287 288 Serological screening is suitable for clinical use in countries with a relatively low incidence of gastric cancer because it enables endoscopic follow-up of cases with an abnormal sero- logical pro file suggestive of atrophic gastritis. 289 Regionally validated serological testing for H pylori and markers of atrophy (ie, pepsinogens) together are therefore the best non-invasive Table 4 Helicobacter pylori and gastric cancerdkey statements relevant for prevention strategies Statement Level of
evidence Grade of
recommendation Helicobacter pylori infection is the most consistent risk factor for gastric cancer. Its elimination is therefore the most promising strategy to reduce the incidence of gastric cancer 1a A The influence of environmental factors is subordinate to the effect of H pylori infection 1a A H pylori eradication abolishes the inflammatory response and slows or may arrest the progression of atrophy. In some cases it may reserve atrophy 1a A
1c A The risk of gastric cancer can be reduced more effectively by employing eradication treatment before the development of preneoplastic conditions 1a A H pylori eradication for gastric cancer prevention is cost-effective in certain communities with a high risk for gastric cancer 3 B H pylori eradication offers additional clinical and financial benefits in addition to gastric cancer prevention varies with disease (1a to 4) A A screen-and-treat strategy of H pylori should be explored in communities with a significant burden of gastric cancer 2c A Validated serological tests for H pylori and markers of atrophy (ie, pepsinogens) are the best available non-invasive tests to identify subjects at high risk of gastric cancer Yüklə 0,54 Mb. Dostları ilə paylaş:
|