Eradication of gastric cancer is now both possible and practical

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Contents lists available at SciVerse ScienceDirect

Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer

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Review

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Eradication of gastric cancer is now both possible and practical

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Akiko Shiotani a , Putao Cen b , David Y. Graham c,∗ a

Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan Medical Oncology University of Texas Health Science Center in Houston, Houston, TX, USA c Department of Medicine, Michael E. DeBakey VAMC and Baylor College of Medicine, Houston, TX, USA b

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Keywords: Prevention Pepsinogen Atrophic gastritis Gastric cancer Helicobacter pylori Risk Surveillance Primary prevention Secondary prevention Natural history Cancer screening

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1. Introduction

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In 1994, Helicobacter pylori was declared a human carcinogen. Evidence has now accumulated to show that at least 95% of gastric cancers are etiologically related to H. pylori. An extensive literature regarding atrophic gastritis and its effects on acid secretion, gastric microflora, and its tight association with gastric cancer has been rediscovered, confirmed, and expanded. Methods to stratify cancer risk based on endoscopic and histologic findings or serologic testing of pepsinogen levels and H. pylori testing have been developed producing practical primary and secondary gastric cancer prevention strategies. H. pylori eradication halts progressive mucosal damage. Cure of the infection in those with non-atrophic gastritis will essentially prevent subsequent development of gastric cancer. For all, the age-related progression in cancer risk is halted and likely reduced as eradication reduces or eliminates mucosal inflammation and reverses or reduces H. pylori-associated molecular events such aberrant activation-induced cytidine deaminase expression, double strand DNA breaks, impaired DNA mismatch repair and aberrant DNA methylation. Those who have developed atrophic gastritis/gastric atrophy however retain some residual risk for gastric cancer which is proportional to the extent and severity of atrophic gastritis. Primary and secondary cancer prevention starts with H. pylori eradication and cancer risk stratification to identify those at higher risk who should also be considered for secondary cancer prevention programs. Japan has embarked on population-wide H. pylori eradication coupled with surveillance targeted to those with significant remaining risk. We anticipate that countries with high gastric cancer burdens will follow their lead. We provide specific recommendations on instituting practical primary and secondary gastric cancer prevention programs as well identifying research needed to make elimination of gastric cancer both efficient and cost effective. © 2013 Published by Elsevier Ltd.

Gastric cancer is the fourth most common cancer and second leading cause of cancer deaths worldwide with more than 700,000 deaths annually [1]. Currently the highest incidence rates are in Japan, Korea, China, Eastern Europe and parts of Central and South America [2]. This is a marked change from the early 20th century when gastric cancer was the most common cancer in many

Abbreviations: AID, activation-induced cytidine deaminase; H. pylori, Helicobacter pylori; IARC, International Agency for Research on Cancer; GI, gastrointestinal; CI, confidence interval; KLF5, Krüppel-like factor 5; VCP, valosin-containing protein; OLGA, Operative Link on Gastritis Assessment; hMLH1, human mutL homolog 1; BRCA1, breast cancer susceptibility gene 1; MGMT, methylated-DNA–proteincysteine methyltransferase; CDKN2A, cyclin-dependent kinase inhibitor 2A; CDH1, cadherin-1; MLH1, mutL homolog 1; RUNX3, runt-related transcription factor 3; CpG, cytosine-phosphate-guanine are regions of DNA. ∗ Corresponding author at: Michael E. DeBakey Veterans Affairs Medical Center, RM 3A-318B (111D), 2002 Holcombe Boulevard, Houston, TX 77030, USA. Tel.: +1 713 795 0232; fax: +1 713 790 1040. E-mail address: [email protected] (D.Y. Graham).

Western countries including the United States [3]. It is now recognized that the vast majority of gastric cancers are etiologically related to infection with the bacterium Helicobacter pylori (H. pylori) [4]. The different clinical outcomes of H. pylori infections (e.g., duodenal ulcer, gastric ulcer, gastric cancer) relate to the different pattern of gastritis that occur (e.g., antral predominant gastritis is associated with duodenal ulcer disease whereas atrophic pangastritis is associated with gastric ulcer and gastric cancer). The predominant pattern of gastritis depends on interactions between the predominant H. pylori strain (and its virulence), host factors (especially those related to genes that enhance or reduce the inflammatory response to the infection), and environmental factors (of which diet appears to be the most important). The prevalence of H. pylori and pattern of gastritis can change rapidly within a population [5,6]. The incidence of gastric cancer can also change rapidly. For example, between 1965 and 1995 the Q2 incidence of gastric cancer in Japan fell approximately 60% in the age groups between 40 and 69 (Fig. 1) [7]. During this short period there was no change in host genes, the prevalence of H. pylori within these age groups, or the predominant H. pylori strain, emphasizing the key role of environmental factors such as methods of food

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preservation and diet in defining the risk of different outcomes [7]. A causal role for H. pylori in gastric cancer was first accepted by the International Agency for Research on Cancer (IARC) in 1994 when they labeled H. pylori a class I carcinogen [8]. However, this did not immediately result in the worldwide H. pylori eradication programs or even eradication programs in regions where gastric cancer was especially common. One problem with moving forward might have been that the actual risk of gastric cancer attributable to H. pylori was greatly underestimated. This occurred, in part, because those studying H. pylori seemed unaware of (or chose to ignore) the tremendous body of prior research linking atrophic gastritis with gastric cancer [9]. Early H. pylori investigators used serology to assess its prevalence of H. pylori which systematically underestimated its prevalence, and thus the role of H. pylori in gastric cancer. The problem with serology was that the results were frequently falsely negative which occurred because the majority with cancer also had severe atrophic gastritis/gastric atrophy with extensive intestinal metaplasia which produced a gastric environment unsuitable for persistence of H. pylori. Thus, despite the fact that H. pylori had caused the precancerous changes and the serology had once been positive, it had become negative [10]. This bias coupled with a failure to correlate gastric histology to serologic results or to reconcile these new findings with the extensive older literature showing a tight association between atrophic gastritis and gastric cancer likely set back H. pylori eradication programs by many decades, a time during which many millions died of their gastric cancers. This bias was only corrected recently by the addition of CagA serology which generally remains positive despite loss of the active infection as well as a renewed attention to previously extensively studied atrophic gastritis-cancer link [9,11,12]. 2. Pre-H. pylori studies of gastritis and gastric cancer (late 1800s to 1950 the atrophy–achlorhydria period) In 1879, [i.e., before endoscopy, gastrointestinal (GI) surgery, or radiology were available], von den Velden reported that gastric cancer was linked to achlorhydria which for the first time provided a diagnostic test for the presence of gastric cancer [9,13]. The era around the beginning of the 20th century saw a virtual explosion in GI research and was recognized that prior conclusions based on histological examination of post mortem stomachs often provided misleading information because the findings described largely were due to autolysis [14]. The period between 1880 and

1920 saw marked advances in histology, chemistry, GI physiology, as well as the development of safe gastric surgery and contrast radiology. This was a time when many of the heroic figures in gastroenterology were active including Faber, Pavlov, Einhorn, Ewald, Cannon, Moynihan, Sippy, and Mayo. It was also a time when the pattern of gastritis had changed sufficiently such that atrophic gastritis was becoming less common and antral predominant gastritis with duodenal ulcer was becoming a common clinical problem. At mid-20th century, Comfort summarized the research relating acid secretion, gastritis, and gastric cancer from first half of the 20th century [13]. The data showed that (1) gastric cancer was associated with loss of secretory activity, (2) the reduction in gastric secretion was progressive, (3) that gastric secretory activity was subnormal before cancer developed, (4) that acid secretion was subnormal in each decade of life among patients destined to develop gastric cancer, and (5) these observations were true no matter how many years gastric secretion was tested before the cancer developed [13]. Comfort concluded that atrophy of the acid secreting cells was the most likely cause of abnormal gastric acidity in the precancerous stomach and that it (atrophic gastritis) was the soil in which a majority of gastric cancers appeared [13]. These critical insights seem to have been largely unknown to most investigators embarking on the study of H. pylori-related gastritis and its sequalae. 3. Research in the second half of the 20th century Two Finnish pathologists, Jarvi and Lauren, classified gastric cancer as intestinal type, diffuse type, and mixed type and proposed that gastric cancer might originate from islands of intestinal epithelium within the gastric mucosa [15,16]. They also suggested that islands of intestinal metaplasia arose in a background of chronic gastritis and noted that intestinal-type cancer was surrounded by metaplastic mucosa more frequently than diffuse carcinomas. Finally, they recommended that “prophylaxis should obviously be directed against gastritis”. Correa in 1975 described a series of sequential steps that culminated in intestinal-type of adenocarcinoma consisting of chronic active nonatrophic gastritis, atrophic gastritis, intestinal metaplasia and finally intraepithelial neoplasia (then called dysplasia) [2,17–20]. Correa also hypothesized that the initial stages of inflammation and atrophy might create a microenvironment favoring engraftment of cancer stem cells [2]. However, the origin of the cancer stem cell remains unsettled with data supporting stem cells being locally derived and other data suggesting they are bone marrow-derived [21,22]. It is now thought unlikely that cancer evolves directly from intestinal metaplasia and most agree that the presence, extent, and possibly the type of intestinal metaplasia should best be considered an easily recognized biomarker associated with increasing degrees of risk for gastric cancer [23–28]. By the late 1930s it was recognized that if one could find the cause of gastritis one should be able to prevent peptic ulcer and gastric cancer and in the period between 1960 through period of the discovery of H. pylori there were many experimental and epidemiologic studies. Many different associations with gastritis were reported from different areas of the world [29] and overall they failed to find a common denominator. The discovery of H. pylori, the proof it caused gastritis, and that H. pylori eradication led to healing of gastritis in the 1980s provided the key to breaking the chain of events leading to gastric cancer. 4. The natural history of gastritis within the stomach – the advancing atrophic front H. pylori gastritis is characterized by infiltration of the gastric mucosa with both chronic inflammatory cells (lymphocytes,

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plasma cells, and macrophages) and acute inflammatory cells (polymorphonuclear leukocytes) this is often referred to as acuteon-chronic inflammation. H. pylori infections initially are localized predominantly to the antrum a site where parietal (acid producing) cells are absent and thus acid secretion is not directly affected. The ability to maintain an acid secretory capacity of at least 12 mmol/h is needed to sustain duodenal ulcer and antral predominant or the antral restricted or corpus sparing pattern of gastritis is thus characteristically associated with duodenal ulcer disease. Over time the zone of inflammation, which is also associated with focal loss of glands (atrophy), progresses from the antrum–corpus junction and extends proximally into the corpus. This front advances rapidly along the lesser curvature of the gastric corpus and more slowly along the greater curvature of the corpus leaving behind a sheet of atrophic mucosa characterized by loss of parietal cells (i.e., pseudopyloric atrophy) [14,30,31]. The finding of atrophy on the greater curvature of the corpus signifies the presence of more extensive atrophy; the more proximal the atrophy the greater the extent of atrophy. The loss of parietal and chief cells results in a mucosa that histologically resembles antral mucosa called pyloric metaplasia or pseudopyloric metaplasia which can be identified histologically by the presence of pepsinogen-I containing glands which are normally only found in the corpus. Islands of intestinal metaplasia may develop within this lawn of pyloric metaplasia and eventually metaplastic mucosa may encompass the majority of the gastric mucosal surface [32,33]. 5. Effect of H. pylori eradication on gastric structure and function H. pylori eradication is associated with rapid resolution of the acute inflammation followed by more gradual reversal of the chronic inflammatory response which may continue over some years [34] and is thought to halt the gastric oncogenic cascades. Elimination of the inflammatory infiltrate results in removal of inflammation-associated inhibitors of acid secretion such as IL1␤ allowing any remaining parietal cells to secrete acid normally [35,36]. It is thought unlikely that H. pylori eradication will significantly reverse the remodeling that has occurred in gastric mucosa replaced by either pseudopyloric or intestinal metaplasia [26,37,38]. Despite halting the progression of H. pylori-associated mucosal damage and prevention of development of new precancerous lesions, it remains unclear whether H. pylori eradication is able to reverse or simply delay the progression of existing precancerous lesions such as intraepithelial neoplastic lesions (gastric adenoma or dysplasia) to more advanced forms of malignancy. 6. Effect of H. pylori eradication on cancer incidence The effect of H. pylori eradication on reducing gastric cancer incidence is related to the risk existing at the time of eradication therapy. The major benefits for treatment of those at little or no cancer risk at the time of eradication include removal from the reservoir of infection responsible for spread within society, prevention of development of diseases caused by H. pylori such as peptic ulcer disease and prevention of progression of gastritis with its associated risk of gastric cancer. Early studies of H. pylori eradication in gastric cancer used mixed populations with varying degrees of cancer risk and were of relatively short duration. The failure to risk stratify made it difficult or impossible to see a benefit even if a large one was present [26]. An idea trial would have stratified subjects based on established criteria for risk such as the degree and extent of atrophic changes and then to follow those subjects for a sufficient period to see if there was a reduction in risk, whether

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the risk continued to increase with age, remained at the level it was at the time of H. pylori eradication or decreased (Fig. 2) [26]. No such study was done. However, it became clear that eradication of H. pylori after the development of atrophic gastritis did not completely return to zero [37,38]. Subsequently studies were done in subjects at very high risk of developing gastric cancer and, because cancer risk/year of follow up was high, only small number of patients was needed and the follow-up could be relatively short [39]. In 2008, such a multicenter clinical study was begun in Japan to examine the incidence of new gastric cancers occurring after endoscopic mucosal resection (EMR) of an early gastric cancer [39]. Subjects were randomized to eradication of H. pylori or no eradication. The results showed that the incidence of new gastric cancers was reduced by one-third among those with H. pylori eradication compared to no eradication therapy. The study also confirmed that H. pylori eradication did not completely prevent development of gastric cancer and showed there was a definite role for secondary prevention (i.e., surveillance programs for patients whose risk remained high despite H. pylori eradication). It remains unclear whether H. pylori eradication among those at lower risk (e.g., atrophic changes that are neither severe nor extensive) is similarly reduced either immediately, or over time, or whether it remains at the level it was pretreatment. That question can only be answered by properly powered studies in which the participants are precisely matched in terms of risk. For example, one could compare the subsequent cancer risk among subjects with different extents and severity of atrophic gastritis over time to identify the time course of change and whether the trajectory of risk over time was up, down or remained stable [26]. A large-scale cohort study from Taiwan followed 80,000 patients with peptic ulcer for 10 years after H. pylori eradication therapy [40]. The patients were assigned to an early eradication group (patients underwent H. pylori eradication therapy at the time of diagnosis) or a late eradication group (patients underwent H. pylori eradication therapy 1 year after diagnosis). The incidence of gastric cancer was markedly lower in the early eradication group than in the late eradication group suggesting that, while the effect of H. pylori eradication therapy in reducing the incidence of gastric cancer is obvious, the earlier the eradication the better. Mass eradication of H. pylori was started in Taiwan in 2004 and initially included 4121 subjects. Compared to the 5 year period before H. pylori therapy, the effectiveness of H. pylori eradication therapy in reducing the incidence of gastric cancer was estimated to be 25%

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Fig. 3. Molecular mechanisms possibly involved in carcinogenesis directly related to the presence of H. pylori. Aberrant activation-induced cytidine deaminase (AID) expression, double strand DNA breaks, impaired DNA mismatch repair and aberrant DNA methylation have all been demonstrated to occur in H. pylori infected cells and/or gastric mucosa and to improve following removal of the organism/H. pylori eradication consistent with the observation that halting of the progression and/or reduction in the risk of developing gastric cancer.

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(rate ratio 0.753, 95% confidence interval (CI) 0.372–1.525) and the reduction in peptic ulcer disease 67.4% (95% CI 52.2–77.8) [41]. Because clinical trials have tended to avoid the elderly and do not risk stratify, many if not most subjects will have been at low risk. Any differences in development of cancer will depend on the fact that the risk among the untreated continues to increase exponentially and thus the two groups (treated and untreated) will continue to separate over time. Any differences may only become significant if the follow-up is sufficiently long to exaggerate the difference (Fig. 2) [42]. For example, the Shangdong intervention trial failed to find a difference in gastric cancer incidence after 7.3 years but after 14.7 years the incidence of gastric cancer was significantly reduced among those who had received H. pylori eradication therapy [43].

7. How eradication reduces subsequent cancer risk? Even though fundamentally, H. pylori causes the inflammation that ultimately results in gastric cancer, the timing of the eradication of the infection is important in that irreversible changes occur that cannot be expected to be completely reversed. Because the course of mucosal damage varies between individuals, any cohort of adults from regions where gastric cancer is common will contain individual with a wide variety of H. pylori-associated histologic findings varying from nonatrophic gastritis to advanced atrophic gastritis. Thus, within an age group the risk for development of gastric cancer following successful H. pylori eradication will also vary in that the despite healing, the gastric has mucosa already suffered “field defects” and precancerous lesions are already present [44,45]. Cancer is a genetic disease and genome-wide analyses of cancer cells have shown that a single cancer cell often possesses 100 or more mutations in coding regions along with somatic gene rearrangements and epigenetic changes especially methylation [46–48]. Aberrant DNA methylation also often extends beyond the actual tumor such that field cancerization may be extensive [45,49,50] (Fig. 3). The gastric mucosa in patients with gastric adenocarcinoma typically shows severe injury with intestinal metaplasia and areas with dysplasia [32]; intestinal metaplasia, dysplasia, and adenocarcinoma are thought to often arise coincidentally [51] and detailed examination of stomachs resected for gastric cancer reveals actual microcarcinomas in up to 10% of cases [51,52]. Nonetheless, H. pylori eradication following endoscopic resection of early cancer resulted in a marked reduction in risk for development of a metachronous cancer [39] suggesting that, irrespective the stage of the risk, removal of the infection and reduction

in H. pylori-induced inflammation can results in a change in the local intragastric environment affecting cancer promotion and possibly initiation [44,53]. As described above, in the Japan GAST study, the reduction in cancer incidence was reduced from one third to one half [39]. This was a very high risk group and it remains unclear whether the effects seen represent slower grown thus requiring a longer time before the second cancer was discovered, prevention of progression of precancerous lesions to actual cancer, regression of foci of high grade dysplasia, or some other combination. A bystander effect is related to the fact that elimination of H. pylori eliminates or reduces cytokine-induced suppression of the parietal cells such that if parietal cell remain, recover, or regenerate, one can expect improvement in gastric acidity [36,54]. An increase in gastric acidity will have an additional benefit of reducing or eliminating overgrowth of non-H. pylori bacteria that colonize the hypochlorhydric stomach and are thought to be in part responsible for production of carcinogens from natural and dietary components [36,55,56]. H. pylori itself may have direct effects due to exposure of H. pylori to gastric epithelial cells. For example, in vitro studies using tissue culture have shown that H. pylori can trigger DNA double-strand breaks [57] as well as impair DNA mismatch repair [58] (Fig. 3). Toller et al. suggested that prolonged active infection might itself lead to saturation of cellular repair capabilities and contributes to the genetic instability and frequent chromosomal aberrations found in infected stomachs [57]. Recent studies have shown that H. pylori infection affects activation-induced cytidine deaminase (AID), which is one of several human enzymes inducing nucleotide alterations involved in DNA mutations [59] (Fig. 3). Aberrant AID expression is widely detectable not only in inflammation-induced cancer tissues but also in a various inflammatory epithelial tissues with tumorigenic high risk including H pylori chronic gastritis [53,60]. H. pylori infection has also been shown to induce aberrant methylation in a number of gene promoters in the gastric mucosa, including cell growth-related genes p16(INK4a) and APC; DNArepair genes, hMLH1, BRCA1 and MGMT; tumor-suppressor genes such as CDKN2A, CDH1, MLH1, and RUNX3; the cell adherence gene E-cadherin; and CpG islands of certain microRNA genes [45,61,62]. There are a large number of factors that are upregulated and possibly involved in H. pylori-induced gastric carcinogenesis such as Krüppel-like factor 5 (KLF5) and valosin-containing protein (VCP) [63,64]. The post endoscopic resection of early gastric cancer provides and excellent model as it allows one to compare changes in gene expression between individuals with different rates of

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they age and although it will probably decrease somewhat, some risk remains. Recommendations for the future should therefore be based on an estimate of that risk [65].

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The vast majority of gastric cancer in the world is caused by H. pylori and eradication of H. pylori will result in gastric cancer becoming a rare disease with the few remaining cases primarily related to congenital genetic abnormalities and rare non-H. pylori causes of chronic gastric inflammation. Essentially, the statement no H. pylori, no gastric cancer is true and eradication of H. pylori is the most effective method of primary prevention. Although approximately one-half of the world’s population has active H. pylori infections, the incidence of cancer varies widely within and between populations and the risk typically increases over the life of any one infected individual. For many individuals H. pylori eradication equates with cancer prevention whereas for others it only produces a reduction in risk. This difference in outcome depends on the level of risk when the eradication is performed. For those at high risk of gastric cancer, H. pylori eradication followed by surveillance for gastric cancer may often be indicated (i.e., a combination of primary and secondary prevention), because for many an increased risk of gastric cancer remains even after H. pylori eradication [9,65,66]. Until recently, gastric cancer surveillance programs were aimed entirely at secondary prevention with the primary objective of identifying cancers at an early stage when curative therapy could still be employed [9]. The history of these programs has been one of progressive involvement of new technologies starting with radiographic screening using contrast barium meals, screening using gastro-cameras, and more recently with fiberoptic and video endoscopy [67]. These programs have resulted in increased identification of early gastric cancers which currently are often treated with endoscopically applied mucosal resection or dissection. While, these programs have been successful in finding many curable cancers, the proportion of the population served has remained small and screening programs are not responsible for the majority of the decline in gastric cancer deaths in Japan (i.e., the decline has been a general phenomenon and encompasses both the screened and unscreened populations) [68]. H. pylori gastritis is progressive such that over time both the extent and severity of atrophy increase which is reflected in the age-related increase in the incidence of gastric cancer [69]. Secondary prevention is not designed to alter the natural of the disease, and although an individual may participate as they age, their cancer risk continues to increase exponentially (Fig. 4A). On the other hand primary prevention is designed to change the natural history and prevent cancer, or at a minimum, to eliminate any further increases in risk (Fig. 4B). Primary prevention of gastric cancer has only recently become practical and has recently been begun in Japan as a combination of primary and targeted secondary prevention [67]. 9. Rationale for combined primary and secondary prevention programs If H. pylori eradication alone would eliminate the risk of gastric cancer, secondary prevention programs could be eliminated [65]. However, as noted above, the link between H. pylori and cancer runs through atrophic gastritis. Eradication of the infection stops the inflammatory process, allows healing of gastritis and resolution of inflammation. Nonetheless, eradication alone cannot undo the atrophic damage that has already occurred. H. pylori eradication will thus produce two populations: those with minimal to no risk and those with some residual risks for cancer. Those with residual risk can likely be assured that their risk will not increase as

There are many approaches to stratify risk for gastric cancer. The initial approach was to stratify according to age. The weakness of that approach is that age provides an average for that subgroup such that any birth cohort group will include individuals ranging from those with no risk to those with a very high risk. Generally, the age to start screening has been chosen based on the age where the risk increased exponentially. This was reasonable when the goal was secondary prevention (i.e., to identify early cancers) but is less attractive when the goal is to prevent cancer. The level of risk can be more precisely identified using invasive methods such as assessment of gastric secretory ability, endoscopic identification of the location of the atrophic border, or histologic assessment of degree and extent of gastric damage. While effective, these methods may not be cost-effective for screening most populations especially when a cadre of endoscopists trained in screening for gastric atrophy is not already present. Duodenal ulcer has long been known to “protect against” gastric cancer although both duodenal ulcer and gastric cancer are caused by H. pylori infections. This seeming paradox is a reflection of the fact that active duodenal ulcers require the presence of a non-atrophic gastric mucosa which can maintain the high levels of acid secretion needed to stain the ulcer. However, as the advancing front damages the corpus mucosa, acid secretion falls causing the ulcer disease to “burn out” [70]. This is reflected in the fact scars from prior duodenal ulcers may be found in patients presenting with atrophic gastritis and gastric cancer. These scars result from duodenal ulcers that occurred decades previously and have burned out [71]. Age is a surrogate for the age-related increase in risk which is a manifestation of the size of the proportion of that cohort with advanced degrees of atrophy (Fig. 5). Because any birth cohort of infected individuals may contain individuals currently at high risk for development of gastric cancer, and because the effect of H. pylori eradication on subsequent risk depends on the risk when eradication is accomplished, most cancer prevention programs must consist of a combination of primary and secondary prevention. A comprehensive program would thus include H. pylori eradication (i.e., primary prevention) along with risk stratification to identify those still at significant risk of development of gastric cancer. Those with significant risk would then be invited to participate in a secondary prevention program. H. pylori is a necessary but not sufficient cause of gastric cancer and eradication of H. pylori will ultimately make gastric cancer a rare disease. The incidence of gastric cancer is related to the frequency and severity of atrophic gastritis (i.e., those with no H. pylori and no atrophy have essentially no risk and those with non-atrophic gastritis have very low risk, as long as the gastritis remains nonatrophic. Risk increases in proportion to the extent and severity of gastric mucosal damage and is highest among those with gastric atrophy. As noted above, the age related increase in incidence of gastric cancer is a reflection of the progressive nature of H. pylori gastritis. 11. Assessment of cancer risk: non-invasive serum pepsinogen and H. pylori testing Non-invasive testing for the presence and extent of atrophic gastritis currently relies primarily on measurement of serum pepsinogen levels [33]. Pepsinogens are proteolytic enzymes produced in the stomach. Pepsinogen I is found only in the gastric

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Fig. 4. (A) Illustration of the natural history of subjects entering a secondary prevention program after H. pylori eradication at age 50. At age 50 the average risk of gastric cancer is 150/100,000 per year and increases to 800/100,000 per year at age 80. Thus, despite annual surveillance the gastric cancer risk would increase 533%. (B) The postulated effect if H. pylori eradication were done at age 60. After that point their risk stop increasing and would likely remain stable or decrease as healing occurred. Importantly, the risk does not return to zero.

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corpus whereas pepsinogen II is present in both the antrum and corpus. Atrophic damage of the gastric corpus results in a progressive decline in pepsinogen I levels such that both pepsinogen I levels and the ratio of pepsinogen I to pepsinogen II (pepsinogen I/II) can be used as biomarkers for the extent and severity of atrophic gastritis/gastric atrophy. Pepsinogen testing has a long history and was in use long before the discovery of H. pylori [72]. Pepsinogen testing has been standardized in Japan and in Europe [73,74]. In Japan a serum pepsinogen I concentration of less than 70 ng/mL and a pepsinogen I/II of less than 3.0 is indicative of severe atrophic gastritis and it has been successfully used to identify those at high risk of gastric cancer [73]. The use of biomarkers for the detection of atrophic gastritis was studied in 22,000 individuals in Finland and the sensitivity and specificity were high (e.g., 83% and 93% respectively) [75]. Using serum/plasma pepsinogen I of <30 ␮g/L and/or pepsinogen I/II of <3, the accuracy to diagnose atrophic gastritis (40–100%

800 700 Age-specific Incidence Rate/100,000

466

600

Degree of gastritis

500

None/nonatrophic Moderate damage Atrophic/atrophy

400 300 200 100

loss of normal oxyntic glands with the appearance of intestinal metaplasia and chronic inflammation) was 87%, the sensitivity was 40% and the specificity 94% [74]. The results clearly depend on the cut-off of serum pepsinogen levels as well as the definition used to identify atrophy. There are also a number of validated non-invasive methods to detect H. pylori infection including IgG anti-H. pylori antibody, urea breath tests, and H. pylori stool antigen tests. Because of the simplicity and cost, most envision preliminary screening will consist of H. pylori serology and pepsinogen testing. As neither H. pylori IgG serology nor serum pepsinogen testing are 100% sensitive and specific, an actual screening program would need to consider the costs and benefits of staged testing as well as the role and nature of confirmatory testing [76]. For example, H. pylori antibodies can remain positive for many years after successful H. pylori eradication and the question about when, how, and whether to confirm active infection before recommending antibiotic therapy will need be addressed when planning for a population wide eradication program. For those with H. pylori infection and non-atrophic gastritis, H. pylori eradication alone suffices to eliminate gastric cancer risk. For those with atrophic damage the risk may vary from low to very high and it is likely prudent to confirm the actual level of risk to properly assess the need to commit the individual to long term surveillance. For population wide-screening programs, in general children need not be tested as H. pylori infection among children has become increasingly rare in developed countries. However, H. pylori is transmitted within families, making it prudent to consider testing children of couples in which one or both parents is found to be infected. Because failure to test all children initially would leave a small pool of infected individuals, it would be useful to consider testing couples applying for a marriage license in order find missed infections and to prevent transmission to their children. Similar programs were common when syphilis was still prevalent.

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Age Fig. 5. Illustration of how age is a surrogate for average risk for a birth cohort and how, because H. pylori gastritis is progressive the proportion with severe damage (i.e., highest risk) increases over time. Importantly, even at ages less than 50 any birth cohort of H. pylori infected individuals will likely contain some proportion of individuals at high risk.

12. Experience with combined pepsinogen – H. pylori testing There are a number of examples, for example, Ohata et al. used pepsinogen testing and H. pylori serology to identify chronic atrophic gastritis among 4655 candidates for Japanese cancer screening [77]. Using these tests 967 (21%) were H. pylori

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Atrophic gastritis H. pylori Pepsinogen Cancer risk

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H. pylori antibody and pepsinogen testing Adults plus children of infected parents

Group A

Group B

Group C

Group D

None Negative Negative None

Mild Positive Negative Low

Moderate Positive Positive High

Severe Negative Positive Highest

negative without chronic atrophic gastritis, 2341 (52%) had H. pylori infections and non-atrophic gastritis, 1316 (28%) had H. pylori and atrophic gastritis; 31 (0.7%) had severe atrophic gastritis. The rates of development of gastric cancer per 100,000/year with a mean follow-up of 7.7 years were: none, 107, 238, and 871, respectively for the 4 groups. The number of endoscopies per year (as cancers/1000 endoscopies) needed to find one cancer by annual surveillance were none, 1/1000, 1/410, and 1/114, respectively for the 4 groups. All underwent annual surveillance although only about 0.8% of the total population was in the very high risk group and if one included those with mild to moderate atrophic gastritis the proportion who would likely to have benefited by participation in annual screening only increased to 29%. This study is typical showing following H. pylori eradication, at least 70% of the population undergoing annual surveillance is unlikely to benefit from participation in annual surveillance. Similar data are available from Watabe et al. who studied 6985 patients (approximately one-third women) average age approximately 50 [78]. Approximately half, 47.6%, were uninfected and an additional 30.5% had non-atrophic H. pylori gastritis such that only approximately 22% were at higher risk and 0nly 6% were in the highest risk group. Even if one restricted surveillance to those ages 70 or above the proportion potentially benefiting from surveillance would likely remain below 50%. 13. Risk stratification using combined pepsinogen – H. pylori antibody testing Recent experience with combined H. pylori antibody/pepsinogen testing in Japan provides insights into the feasibility of this approach. The most recent iteration of risk stratification is called ABC or ABCD stratification (Table 1) [79–81]. To date this approach has primarily been used as part of secondary prevention programs. As noted above, in the Ohata study [77] no gastric cancer developed in the H. pylori antibody negative individuals with normal pepsinogens (i.e., group A). There was a stepwise increase in the risk of developing gastric cancer risk with increasing atrophy: lowest in those H. pylori antibody positive with normal pepsinogens (Group B), moderate in the H. pylori positive with atrophic gastritis pepsinogen values (Group C) and highest those with the most severe atrophy (i.e., H. pylori antibody negative/pepsinogen positive for atrophic gastritis. Group D, by far the smallest group, is enriched in patients with extensive intestinal metaplasia that resulted in spontaneous loss of the H. pylori infection. Both H. pylori eradication and the use of proton pump inhibitors can substantially alter serum pepsinogen concentrations and compromise the predictive value of pepsinogens even among those at high risk for gastric cancer [82,83]. Because low pepsinogen I and pepsinogen I/II levels are not limited to only those with atrophic gastritis, pepsinogen testing is not 100% diagnostic such that the actual risk category should be confirmed before committing a patient to a long term endoscopic surveillance program. The limitations require that patients who are candidates for endoscopic surveillance programs have confirmatory testing done as part of their initial surveillance at which time false positive tests can be identified. Confirmation typically involves endoscopy as well as a validated method for determining the degree and extent of atrophy

Hp neg PG norm

Hp pos PG norm

Hp pos PG inter

Hp pos PG low

Hp neg PG neg

Hp eradication with confirmation of cure

No Follow-up Required

Cured PG norm

Cured PG inter

Endoscopy for Atrophic changes - Atrophy -

Cured PG low

?

None

?

Mild

Moderate/ Severe

?

Surveillance?

Surveillance (

adjuvants)

Fig. 6. Possible scenario of population-wide detection and eradication program to eliminate gastric cancer. The proposal is based on initially identifying those with H. pylori infections and assessing the health of the gastric mucosa. We outline a plan using non-invasive testing with a locally or regionally validated IgG H. pylori serology and serum pepsinogen testing. Those without H. pylori infection or atrophic gastritis would require no further evaluation or follow-up. All those with H. pylori infections would undergo eradication therapy with confirmation of cure, preferably using non-invasive testing with a urea breath or stool antigen testing. After H. pylori eradication, those with non-atrophic gastritis would require no further follow-up. Those with suspected atrophic gastritis (based on pepsinogen testing) would undergo endoscopy for proper risk stratification (e.g., using a validated histologic staging system). Those with cured H. pylori and healed non-atrophic gastritis would require no further follow-up. Those with confirmed atrophic gastritis (e.g., OLGA stage III or IV) would be entered in to a long term endoscopic surveillance program. Because the cancer risk if likely to decline over time, they are also candidates for research regarding surveillance intervals and whether adjuvant therapy such as anti-inflammatory or anti-oxidant therapy would further reduce the risk Current data does not allow firm recommendations for those after H. pylori eradication with mild atrophy (e.g., OLGA I and II) and they are considered candidates for research regarding the best strategy.

such as histologic confirmation using a gastric cancer staging system such as the Operative Link on Gastritis Assessment (OLGA) or OLGA-IM staging systems [84,85], Despite some limitations, serum pepsinogen testing has a high negative predictive value allowing confirmatory endoscopic examination to be limited to only a subset of the population (Fig. 6). 14. What should surveillance programs look like? There is considerable experience with the “one size fits all” approach to gastric cancer surveillance. All the previous attempts have been labor intensive, only a small proportion of those eligible could participate, and a high proportion of those screened was at low or negligible risk. Pepsinogen testing is not perfect as some will have values below normal but still above the cut-off for severe atrophic gastritis (currently called intermediate in Fig. 6). Research is needed to address how to stratify those patients non-invasively into those who would benefit from surveillance from those where surveillance would not be cost-effective. One approach would be to resolve the quandary by endoscopic risk stratification. The natural history of atrophic gastritis after H. pylori eradication has also not been examined critically. Because risk likely declines after H. pylori eradication, it may be possible to reduce the screening interval or possibly stop surveillance altogether over time. While targeted gastric biopsy using a validated histology staging system is currently the best approach for more precise risk stratification, it is important to note that histologic risk stratification is based on data from untreated H. pylori infected individuals. Whether the same surveillance intervals are appropriate for different histologic types and patterns remains to be evaluated (i.e., those with OLGA stage IV

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might require annual surveillance compared to every two or three years for OLGA III etc.). The potential to rationally stratify surveillance based on histologic or other parameters emphasizes the need for further research to refine risk markers as well as surveillance methods, intervals, and duration. Other areas of study include the role of adjuvants that in addition to H. pylori eradication further reduce risk such as co-therapy with anti-inflammatory agents, gastroprotectives, or antioxidants [65,86,87]. 15. Summary The data regarding gastric cancer are now sufficient to support the proposal that all with H. pylori infection should receive H. pylori eradication therapy. In countries, regions, and populations at increased risk of gastric cancer, evaluation for the presence and severity of atrophic gastritis is recommended to identify the subgroup of patients for which continued surveillance (secondary prevention) should be considered. Japan has already embarked on an H. pylori eradication program and because of the widespread availability and expertise in endoscopic surveillance Japan has chosen endoscopy as the screening method for determining the extent and severity of atrophic gastritis [67]. Other countries with fewer resources or lacking the widespread expertise in endoscopic screening will likely prefer noninvasive screening using pepsinogen levels. Because of the limitation in sensitivity and specificity of pepsinogen screening, endoscopic/histologic confirmation can then be targeted to the subpopulation likely to benefit and better stratify patients to ensure that those who would obtain little or no benefits from continued surveillance are triaged out of surveillance programs. The ideal frequency and duration of surveillance following H. pylori eradication remains unknown. For those at very high risk (e.g., extensive atrophy or intramucosal neoplastic lesions, or after endoscopic therapy of early gastric cancer) most would recommend an interval of 1 year although studies are needed to determine when, if, and for what circumstances this interval could be lengthened. Studies are also needed to identify the appropriate frequency and duration of follow-up for those with lesser degrees of damage with recommendation being subject to the outcome of surveillance studies based on risk stratification. Because risk stratified targeted surveillance allows surveillance to be restricted to those who might benefit most and it provides much closer matching of surveillance capacity to surveillance needs thus making surveillance potentially both clinically and cost effective. Japan has been the first country to step up to the plate and seriously begin the process of eradication of gastric cancer by widespread H. pylori eradication. The approach in other countries will differ based on the size of the problem and the resources that can be devoted to it. Nonetheless, making gastric cancer a rare disease is now both possible and practical. Conflict of interest Dr. Graham is a unpaid consultant for Novartis in relation to vaccine development for treatment or prevention of H. pylori infection. Dr. Graham is a also a paid consultant for RedHill Biopharma regarding novel H. pylori therapies and for Otsuka Pharmaceuticals regarding diagnostic testing. Dr. Graham has received royalties from Baylor College of Medicine patents covering materials related to 13 C-urea breath test. Dr. Shiotani and Dr. Cen have no potential conflicts. Acknowledgements Dr. Graham is supported in part by the Office of Research and Development Medical Research Service Department of Veterans

Affairs, Public Health Service grants DK067366, CA116845 and DK56338 which funds the Texas Medical Center Digestive Diseases Center. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the VA or NIH.

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