Eradication of gastric cancer and more efficient gastric cancer surveillance in Japan: two peas in a pod
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- Graham, D.Y. & Asaka, M. J Gastroenterol (2010) 45: 1. doi:10.1007/s00535-009-0117-8
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We provide a historical review and update on current thinking regarding the possibility of elimination of gastric cancer from Japan. Because Helicobacter pylori infection is the cause gastric cancer, its elimination forms the cornerstone of eradication of gastric cancer. However, simply eradicating H. pylori from the entire population will not immediately solve the problem because many patients with H. pylori infections have already developed the precursor lesion, atrophic gastritis. Cure of H. pylori in these high risk patients will only reduce the risk of subsequent cancer. In contrast, treatment of low risk patients will prevent cancer. Thus, to eliminate gastric cancer it is necessary to identify and treat all infected individuals. In addition, those at increased risk for gastric cancer (i.e., atrophic gastritis irrespective of age) should be considered for endoscopic surveillance to identify those cancers that develop at an early stage. We propose that severity and extent of atrophy be used to separate those expected to benefit from endoscopy and annual surveillance from those with little or no potential benefit. We suggest an algorithm for eradicating gastric cancer that incorporates H. pylori and atrophic gastritis testing, H. pylori therapy, and surveillance to institute a program of surveillance restricted to those who could benefit most (i.e., those with moderate or severe atrophy). This will also allow a much closer matching of surveillance capacity and surveillance need making surveillance more clinically- and cost-effective.
KeywordsGastric cancerSurveillancePepsinogenHelicobacter pyloriNatural history
Although Helicobacter pylori is recognized as the primary cause of gastric cancer, it is a “necessary but insufficient cause,” meaning that while the infection is the primary cause, additional factors must be present to produce gastric cancer. The underlying abnormality appears to be long-standing acute and chronic inflammation that results in marked changes in gastric structure and function. The incidence of gastric cancer varies both between and among populations . The risk of developing gastric cancer correlates best with the severity and extent of atrophic gastritis and gastric atrophy.
Despite the requirement for H. pylori in the pathogenesis of gastric cancer, if H. pylori were to instantly disappear from the world, the incidence of gastric cancer would not perceptibly change, at least for several years. Ultimately, however, eradication of H. pylori would result in elimination of gastric cancer as an important clinical problem. Eradication of the infection reliably results in healing of gastritis and elimination of the progression of mucosal damage. However, its effect on subsequent risk of developing gastric cancer depends on the level of risk at the time of eradication (i.e., the severity and extent of atrophic gastritis or gastric atrophy). Japan is a country with a high incidence of gastric cancer and is thus one in which there is a high prevalence of atrophic gastritis. This paper discusses an approach to the eradication of gastric cancer in Japan, including ways in which current resources and surveillance programs might be utilized more efficiently in cancer prevention.
History of gastric cancer in relation to gastric atrophy/atrophic gastritis
Before 1900, the study of gastric histology was largely restricted of the use of autopsy specimens and the results were plagued by artifacts produced by rapid post mortem autolysis of the delicate mucosal surfaces. In the late 1800s and early 1900s Faber, following up on the observation of Damaschino, Chauffard, and Hayem , solved the autolysis problem by instilling formalin directly into the abdominal cavity and into the stomach immediately after death . Over a period of approximately three decades he used this approach to describe as well as to define normal vs. abnormal histology and the relationship of gastritis/atrophy to disease. He clearly recognized the association of different patterns of gastritis with different clinical diseases .
Possible causes of loss of acid secretory activity in gastric cancer
1. Developmental (congenital)
2. Degenerative process attacking the acid cells
3. Destruction of acid cells by atrophic gastritis
4. Inhibitory substance capable of depressing gastric secretion
5. Secondary to the presence of the cancer
The next 30 years saw the development of fiberoptic endoscopy, advances in understanding of gastric secretion, and development of increasingly powerful drugs to suppress acid secretion. There were also many epidemiological studies of gastritis, largely prompted by attempts to define the relation between gastric diseases and gastritis (e.g., ). In 1975, the entire process, starting with the first year of life, was combined into what is now known as the Correa hypothesis .
The H. pylori era
Identification of the extent and severity of gastric atrophy
Location of gastric border
Targeted biopsy protocols (e.g., OLGA staging)
Nonetheless, the critical experiments proving that H. pylori was the major cause of gastritis, peptic ulcer, and gastric cancer were completed, and they confirmed Warren and Marshall’s suggestion that H. pylori is a bacterial pathogen that caused gastroduodenal inflammation and resulted in alterations in gastroduodenal structure and function resulting in duodenal ulcer disease, gastric ulcer disease, and atrophic gastritis . H. pylori-induced atrophic gastritis in turn could result in iron and/or vitamin B12 deficiency, gastric adenocarcinoma and/or primary B-cell gastric lymphoma [18–21]. Although the road was possibly longer than necessary, H. pylori is now generally accepted as the cause of gastric cancer.
Eradication of gastric cancer
H. pylori is typically acquired in childhood. Transmission of the infection is enhanced by poor sanitation, poor household hygiene, and poor standards of living. Improvements in the standards of living, sanitation and clean water supplies in regions where the infection was common has resulted in disruption of the chain of transmission such that the disease has begun to disappear. Naturally, this process requires many generations. The prevalence of the infection at about age 20 for any birth cohort is the prevalence for that birth cohort throughout life. The fall in prevalence in any population is therefore dependent on a succession of birth cohorts of increasingly lower prevalence replacing those born in eras when the acquisition of the infection was more common. This happened long ago in Europe and the United States and is currently in progress in Japan and some other Asian countries .
The prevalence of different clinical outcomes varies both within and between populations . However, the likelihood of a particular clinical outcome of an infection can be predicted based on the pattern of and severity of gastritis (atrophic vs. non-atrophic and antral predominant vs. pangastritis or corpus predominant) with duodenal ulcer disease being associated with antral predominant (corpus sparing) gastritis and gastric cancer with atrophic gastritis. The predominant pattern of gastritis depends upon interactions between the host, the bacteria, and the environment. Environmental factors appear to be the dominant factors as evidenced by the rapid change in outcome experienced by migrants (i.e., Japanese to Hawaii) or associated with changes in food preservation (e.g., use of refrigeration instead of salt) and year around availability of fresh fruits and vegetables instead of seasonal diets entailing long periods without fresh fruits and vegetables [1, 23].
Within any population there are subpopulations at increased risk of developing atrophic gastritis and gastric cancer . Host factors are known to increase this risk . The best-studied host factors relate to those associated with an enhanced inflammatory response to the infection (i.e., polymorphisms in genes controlling the inflammatory response) . However, such polymorphisms are actually uncommon and despite their importance in enhancing our understanding of disease pathogenesis, they have little or no effect on the overall risk to the population. Similarly, some H. pylori strains are associated with enhanced inflammation (e.g., cag pathogenicity island-containing H. pylori) and also increase the risk of disease. However, strains lacking these putative virulence factors also cause gastric inflammation, peptic ulcer and gastric cancer, leading one to conclude that when one considers elimination of H. pylori-related diseases from a population, there is scant evidence to support a strategy of targeting “high risk groups” in preference to targeting the entire population for H. pylori eradication.
Risk stratification as part of population wide H. pylori eradication
Population-wide H. pylori eradication will eliminate H. pylori-induced disease [26, 27]. Eradication of H. pylori results in healing of the gastritis, prevention of gastritis progression, elimination of the ongoing inflammatory response, recovery of the normal feedback loops controlling acid secretion, and removal of cytokine-associated suppression of parietal cells. However, there are few data supporting recovery of lost cellular components or reversal of metaplastic epithelia to normal . The greatest yield comes from H. pylori eradication of those with non-atrophic gastritis, as their risk of subsequent development of gastric cancer is so minimal that no follow-up is needed or, indeed, indicated. In contrast, those with atrophic gastritis have an elevated risk and while one can expect their risk to no longer increase, it will be unlikely to completely disappear, at least over the near future. Risk stratification is therefore a necessary part of any population-based eradication program .
Gastric cancer surveillance programs: today and tomorrow
Current surveillance programs were designed to identify gastric cancers at an early stage where they were still curable (i.e., to discover incident cancer). When these programs were introduced they were state-of-the-art and have provided an important service. However, now that we have evidence that we can both identify and modify an individual’s risk of developing gastric cancer and also can prevent progression to cancer, there is a need to rethink how surveillance can best be used. The weaknesses of the current surveillance programs include: (1) they can examine only a small proportion of the at-risk population (e.g., 20%), (2) they include those that benefit as well as those who cannot benefit, (3) they do not prevent progression of risk, and (4) they have limited or no “preventive” role .
The natural history of gastritis is to progress toward increasing atrophy [35–38]. This tendency is reflected in the well-described age-related increase in the incidence of atrophy and of gastric cancer. Annual surveillance does not affect the “natural history” of the disease, in that cancer risk steadily increases each year irrespective of whether the patient is or is not participating in a surveillance program. The advantage of participation is that if cancer develops, it would likely be detected at an early stage. However, any population-based program will include those with and without H. pylori infection (i.e., include those with some risk as well as those with no risk). Among those with gastritis, it will include those at very low risk (non-atrophic gastritis, duodenal ulcer, etc.) and those at high risk (severe atrophic gastritis/atrophy). The surveillance capacity (number that can be examined in a year) has always been limited and non-selectivity has resulted in most of the at-risk population being excluded, because of their number greatly exceeds the capacity of any program. The new knowledge regarding the ability to prevent progression of low risk patients becoming high risk patients and the ability to focus on those at significant cancer risk (risk stratification) allows the possibility that, by excluding those who have little or no benefit, surveillance capacity can be brought into line with need.
The relatively large group with H. pylori and pepsinogen levels below the range of normal but above the cut-off for severe atrophic gastritis (i.e., atrophic gastritis but not severe atrophic gastritis) contains patients with varying degrees of cancer risk. It would be desirable to further stratify those patients into those who would benefit from surveillance and those for whom surveillance would be optional. Because pepsinogen testing has only a modest sensitivity and specificity, other markers for risk will probably be required. Since the group is manageable in terms of size, we suggest research using targeted gastric biopsy and a validated histology staging system. This should allow better stratification and improved identification of the population likely to obtain the greatest benefit from surveillance. For example, those with OLGA stage IV might need annual surveillance, OLGA III every 2 years, OLGA II every 5 years, and OLGA I, no surveillance. Clearly, further work is needed to refine risk markers, surveillance methods, surveillance intervals and duration. Other areas of study for further risk reduction include the role of adjuvants such as anti-inflammatory agents or gastroprotectives.
Risk reduction and surveillance prevention programs
Cancer risk groups
1. No risk (never infected, OLGA 0)
2. Minimal risk (non-atrophic gastritis, OLGA 1)
3. Modest risk (mild atrophic gastritis (OLGA 2)
4. Increased risk (moderate or severe atrophic gastritis, OLGA 3 and 4)
The natural history of H. pylori infection in Japan has been to fall, such that at any age, the proportion not requiring surveillance will steadily decline, although without an H. pylori eradication program it will require approximately 70 more years before gastric cancer becomes a rare disease . Because H. pylori infection is the cause of gastric cancer, its elimination forms the cornerstone of eradication of gastric cancer. However, simply eradicating H. pylori from the entire population will not immediately solve the problem because many patients with H. pylori infections have already developed the precursor lesion, atrophic gastritis. Cure of H. pylori in these high risk patients will only reduce the risk of subsequent cancer. In contrast, treatment of low risk patients will prevent cancer. Thus, to eliminate gastric cancer it is necessary to identify and treat all infected individuals. In addition, those at increased risk for gastric cancer (i.e., atrophic gastritis irrespective of age) should be considered for endoscopic surveillance to identify those cancers that develop at an early stage. We propose that severity and extent of atrophy be used to separate those expected to benefit from endoscopy and annual surveillance from those with little or no potential benefit to institute a program of surveillance restricted to those who could benefit most (i.e., those with moderate or severe atrophy). This will also allow a much closer matching of surveillance capacity and surveillance need making surveillance more clinically- and cost-effective. We look forward to the day when Japan declares a population-wide program to eradicate H. pylori while restricting cancer surveillance to those who will benefit most (Fig. 2).
This material is based upon work supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs and by Public Health Service grant DK56338 which funds the Texas Gulf Coast Digestive Diseases Center.