Gastric cancer: epidemiology, prevention, and therapy

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1 DOI: /hel REVIEW ARTICLE Gastric cancer: epidemiology, prevention, and therapy Marino Venerito 1 Riccardo Vasapolli 1 Theodoros Rokkas 2 Peter Malfertheiner 1 1 Department of Gastroenterology, Hepatology and Infectious Diseases, Ottovon-Guericke University Hospital, Magdeburg, Germany 2 Gastroenterology Clinic, Henry Dunant Hospital, Athens, Greece Correspondence Marino Venerito, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany. m.venerito@med.ovgu.de Abstract Gastric cancer (GC) is still the third leading cause of cancer death in both sexes worldwide. Helicobacter pylori infection is the most important risk factor for GC and, in spite of the consistent trend of a decreasing incidence, in 2015 approximately 4.4 billion individuals more than half the world s population were infected with H. pylori. The birth cohort pattern of decreased H. pylori infection reported in a systematic review contributes to explain the declining GC mortality in Japan. Current trends in estimated annual percentage change of GC incidence foreshadow expected reversals in both falling incidence and male predominance among US non- Hispanic whites. Combining serum pepsinogen 1 and H. pylori serology was shown to be useful for GC risk stratification in a Finnish population. Gastritis staging by operative link on gastritis assessment was confirmed to be reliable in predicting GC risk in a large prospective study. In a randomized trial from South Korea, H. pylori eradication therapy significantly reduced the rates of metachronous GC in patients who received curative endoscopic resection for early GC. A study based on a territory- wide health care database of the Hong Kong Hospital Authority showed that aspirin use is associated with a reduced GC risk. Another study based on the same database showed that proton pump inhibitors increase GC risk, but methodological biases have most likely acted as confounders. Confirmatory data on the role of endoscopic submucosal dissection in patients with early GC have been published. The phase III FLOT4 trial has shown that the FLOT triplet regimen (docetaxel, oxaliplatin, leucovorin, and 5- fluorouracil) improves the outcome of patients with GC and locoregional disease as compared to the ECF triplet (epirubicin, cisplatin, and 5- fluorouracil). In the phase III ATTRACTION- 2 trial, nivolumab was shown to be an effective treatment option with a relative safe profile for heavily pretreated patients with advanced GC. 1 INTRODUCTION Helicobacter pylori infection is the principal risk factor for gastric cancer (GC). During the past year, new important epidemiological data indicated that the prevalence of GC is changing. Serological and histomorphological biomarkers, confirming their value for stratifying the risk of GC, were presented. An additional benefit of aspirin use for GC prevention in patients following H. pylori eradication was demonstrated whereas the continued use of proton pump inhibitors (PPI) following eradication poses an increased risk for GC development. The positive effect of H. pylori eradication therapy for secondary prevention of GC in patients who underwent endoscopic resection of early GC was reported in a randomized placebo controlled trial. Finally, advances have been made in the therapy of GC patients with either locally advanced or non- resectable disease. This review summarizes recent epidemiological aspects and clinical advances in the field of GC prevention and therapy published between April 2017 and March Helicobacter. 2018;23(Suppl. 1):e wileyonlinelibrary.com/journal/hel 2018 John Wiley & Sons Ltd 1 of 6

2 2 of 6 2 GASTRIC CANCER: EPIDEMIOLOGICAL ASPECTS To evaluate changes in the global prevalence of H. pylori infection, Hooi et al 1 performed a systematic review and meta- analysis of 184 full- text articles on the prevalence of H. pylori infection published from 1970 through Data were analyzed based on United Nations geoscheme regions and individual countries. Based on regional prevalence estimates, approximately 4.4 billion individuals more than half the world s population were infected with H. pylori worldwide in 2015, although with large amounts of variation among regions. The highest and lowest pooled prevalence of H. pylori infection were observed in Africa (roughly 70%) and Oceania (roughly 24%), respectively. Switzerland (18.9%) and Nigeria (87.7%) were the countries with the lowest and highest prevalence of H. pylori infection. Two time periods ( and ) were used to analyze the H. pylori prevalence trend over time. H. pylori prevalence after 2000 was lower than before in Europe (from 48.8% to 39.8%), Northern America (42.7% to 26.6%), and Oceania (26.6% to 18.7%). In contrast, the prevalence of H. pylori positivity did not change in Asia (53.6% before 2000 vs 54.3% after 2000), and Latin America and the Caribbean (62.8% before 2000 vs 60.2% after 2000). The changing prevalence of H. pylori infection in the general population over time is considered as the main cause for the declining GC mortality in Japan. In a systematic review with meta- regression analysis, Wang et al 2 reported the prevalence of H. pylori infection among Japanese individuals. The predicted prevalence of H. pylori infection was 60.9% (95% CI ), 64.1% (95% CI ), 34.9% (95% CI ), and 6.6% (95% CI ) among those who were born in the year 1910, 1940, 1970, and 2000, respectively. The birth cohort pattern of H. pylori infection observed fits with the declining GC mortality in Japan. Both H. pylori infection and autoimmune gastritis cause atrophic gastritis, the initial step for non- cardia gastric carcinogenesis. In an epidemiological study, GC incidence trends for U.S. race/ethnic groups in the period was assessed from 45 North American Association of Central Cancer Tumor Registries. 3 There were non- cardia GC in 4.4 billion person- years of observation. Among non- Hispanic whites, the age- standardized rate was 2.2 per person- years, with an estimated annual percentage change (EAPC) of 2.3% (95% CI = 2.0to 2.6). Notwithstanding this overall decline, EAPCs rose 1.3% (95% CI = ) for persons younger than 50 years and fell 2.6% (95% CI = 2.4 to 2.9) for older individuals. These converging trends exhibited a birth cohort effect more pronounced among women than men, with incidence among women born in 1983 twofold (95% CI = 1.1- to 3.6- fold) greater than those born in Age interaction was also statistically significant among Hispanic whites, with slightly increasing vs. decreasing EAPCs for younger and older individuals, respectively. Incidence declined regardless of age for other races. Current trends foreshadow expected reversals in both falling incidence and male predominance among non- Hispanic whites. Possible explanations for the observed trends are the decline in H. pylori prevalence, an increase in smoking for young women and a hypothesized increase in the prevalence of autoimmune gastritis, which is more prevalent among women. These epidemiological observations clearly call for analytical studies to identify potential causal mechanisms and improve prevention strategies. The investigation of non- H. pylori gastric microbiota composition will be of crucial importance in this context. Whether in low prevalence areas for GC patients with gastric intestinal metaplasia (IM), a premalignant condition in gastric carcinogenesis should receive follow- up endoscopy for prevention purposes is still a matter of debate. In a retrospective cohort study, patients with gastric IM diagnosed between 2004 and 2014 (N = 91) received esophagogastroduodenoscopy surveillance every 6-12 months until a diagnosis of GC or completion of the planned 5- year follow- up duration was reached. 4 Possible risk factors for GC were assessed. At baseline, 81 of the 91 patients (89%) had complete IM, whereas the remaining 11% had incomplete IM. None of the patients with complete IM developed GC, whereas five of the 10 patients with incomplete IM (50%) developed high- grade dysplasia (N = 2) or GC (N = 3). Male patients (P = 0.027) and those with incomplete IM (P = 0.001) were at greatest risk of developing dysplasia or early GC. There was also a trend toward an association with smoking (P = 0.08). The authors concluded that further studies are required for determining optimal surveillance intervals to reduce GC incidence and mortality. To evaluate the prevalence and the long- term course of gastric precancerous lesions in patients with gastric MALT- lymphoma (GML), records of patients with GML (N = 179), gastric diffuse large B- cell lymphoma (N = 70), and H. pylori gastritis (N = 152), from a single- center from January 1995 to January 2014 were retrospectively evaluated. 5 At baseline, gastric atrophy was more frequent in the GML group. Furthermore, in patients with GML, gastric atrophy, IM, and gastric dysplasia were more frequent in the GML area than in other part of the stomach. During follow- up, the prevalence of gastric atrophy remained stable whereas IM and dysplasia tended to increase over time. In the multivariate analysis, the development of dysplasia or GC was associated with the presence of IM at baseline and male gender. Thus, after achieving complete remission, GML patients with gastric precancerous lesions may benefit from endoscopic surveillance. 3 GASTRIC CANCER: PREVENTION STRATEGIES/SCREENING FOR PRENEOPLASTIC CONDITIONS Serum pepsinogen 1 (PG1) and H. pylori serology are useful tools for GC risk stratification in Asia. Testing the sera of Finnish male smokers from the Alpha- Tocopherol, Beta- Carotene Cancer Prevention Study, Song et al 6 were also able to show the usefulness of these markers in the Finnish population. PG1 measurements were available for study participants. In a subset (N = 3555) with H. pylori

3 3 of 6 positive serology, both markers jointly defined four groups: the normal PG1 groups A (H. pylori- negative) and B (H. pylori-positive) and the low PG1 groups C (H. pylori- positive) and D (H. pylori- negative). Overall, 329 GCs were diagnosed with an average of 13.9 years after baseline. Low PG1 at baseline was associated with a roughly threefold GC risk (HR 2.68, 95% CI ). Among study participants with both PG1 and H. pylori serology, the GC risk in groups B, C, and D was roughly twofold, fourfold, and sixfold, respectively. Within group B, CagA seropositivity was also associated with an increased GC risk. For groups B and C, repeat measurements of PG1 at 3 years did not add any information in terms of further GC risk stratification. Operative link on gastritis assessment (OLGA) staging estimates the risk for GC in progressive stages (0- IV). In a prospective study performed on a cohort of 1755 consecutive dyspeptic patients with a median follow- up of 55 months, Rugge et al 7 confirmed that OLGA gastritis staging is reliable in predicting the risk for gastric epithelial neoplasia development. After initial endoscopy with mapped gastric biopsies, OLGA staging, and assessment of H. pylori infection, patients with stages II III and IV underwent a second endoscopy with restaging, whereas those with stages 0 and I were followed clinically. At baseline, the majority of patients had stage 0 (77.6%), whereas 14.4%, 5.1%, 2.1%, and 0.85% have stage I, II, III, and IV, respectively. Of the 603 patients with initially detected H. pylori infection, 602 were successfully eradicated. A further 220 patients had a documented history of H. pylori eradication whereas 932 were H. pylori naive- negative. Only patients with stages III- IV developed incident neoplastic lesions (prevalence = 0.4%; low- grade intraepithelial neoplasia = 4; high- grade intraepithelial neoplasia = 1; GC = 2). The risk for epithelial neoplasia was non- existent in patients at stages 0, I, and II, 36.5 per 1000 person- years in patients at stage III (95% CI ) and 63.1 per 1000 person- years in patients at stage IV (95% CI ). In subjects with advanced stages (III- IV), H. pylori eradication did not abolish the risk for neoplastic progression. Patients with early GCs limited to gastric mucosa or submucosa usually have an advanced gastric atrophy and are at high risk for subsequent (metachronous) development of new GC. In a prospective, double- blind, placebo- controlled, randomized trial, 470 patients from South Korea who had undergone endoscopic resection of early GC or high grade adenoma were assigned to receive either H. pylori eradication therapy with antibiotics (amoxicillin 1000 mg and clarithromycin 500 mg twice daily for 7 days) or placebo. 8 Furthermore, the PPI rabeprazole (10 mg twice daily) was given and maintained in both groups for an additional 4 weeks to promote ulcer healing. Two primary outcomes were the incidence of metachronous GC detected on endoscopy performed at the 1- year follow- up or later and improvement from baseline in the grade of gastric atrophy in the gastric corpus lesser curvature at the 3- year follow- up. Overall, 396 patients (194 in the treatment group and 202 in placebo group) were included in the modified intention- to- treat analysis population. During a median follow- up of 5.9 years, lower rates of metachronous GC were observed in the treatment group compared to the placebo group (7.2% vs 13.4%, respectively; HR 0.50; 95% CI ; P = 0.03). Improvement from baseline in the atrophy grade at the gastric corpus lesser curvature was observed in 48.4% and 15.0% of the patients in the treatment and placebo group, respectively (P < 0.001). Thus, in patients undergoing curative endoscopic resection for early GC, H. pylori eradication therapy should be considered mandatory. This study underlines that cure of H. pylori infection should be attempted at all times and rejects the traditional concept of the point of no return. It suggests a strategy of combined colorectal cancer and gastric preneoplasia screening at the age >50 years still in time for an effective GC prevention strategy. 9 The role of aspirin for GC prevention is still uncertain. Based on data from the electronic database of the Clinical Data Analysis and Reporting System of the Hong Kong Hospital Authority, Cheung et al 10 identified subjects who had received a prescription of clarithromycin- based triple therapy for H. pylori between 2003 and The observation period started from prescription dates of H. pylori eradication therapy, and the follow- up was censored at the end of the study (December 2015), death, or GC diagnosis. The frequency (once or more often weekly), dose, and duration of aspirin intake were analyzed. Subjects who failed H. pylori eradication or were diagnosed with GC within 12 months of H. pylori therapy were excluded from the analysis. During a median follow- up of 7.6 years, 169 (0.27%) of patients developed GC. The incidence rate of GC was 3.5 per person- years. Aspirin use was associated with a reduced GC risk (HR 0.30, 95% CI ). The risk of GC significantly decreased with increasing frequency, duration, and dose of aspirin. Overall, the adjusted absolute risk difference between aspirin and non- aspirin use was modest to low (2.52 fewer GCs per person- years). As aspirin is also a major cause of gastrointestinal bleeding, the risk- benefit profile of aspirin use on GC prevention has yet to be defined. The benefit of aspirin use on GC prevention may be highest among patients with advanced preneoplastic conditions (ie, gastric atrophy, IM) whereas in the absence of preneoplastic changes of the gastric mucosa, no further benefit is expected after H. pylori eradication. PPI use is associated with worsening of gastric atrophy, particularly in H. pylori-infected subjects. 11 Using the territory- wide health database of Hong Kong, Cheung et al aimed to determine the association between PPI use and GC among H. pylori-infected subjects who had received H. pylori eradication therapy. 12 Adults who had received an outpatient prescription of clarithromycin- based triple therapy between year 2003 and 2012 were identified. Patients requiring subsequent prescriptions of H. pylori eradication therapies were considered to have failed this regimen and were excluded. Patients diagnosed to have GC within 12 months after H. pylori therapy or gastric ulcer after therapy were also excluded. Finally, prescriptions of PPIs or histamine- 2 receptor antagonists (H2RA) started within 6 months before diagnosis of GC were also exclusion criteria. H2RA was used as a negative control exposure. Among the eligible subjects, 153 (0.24%) developed GC during a median follow- up of 7.6 years. PPI use was associated with an increased GC risk (HR 2.44, 95% CI ), while H2RA was not (HR 0.72, 95% CI ). The risk increased with duration of

4 4 of 6 PPI use (HR 5.04, 95% CI for 1 year; 6.65, 95% CI for 2 years and 8.34, 95% CI , for 3 years). The adjusted absolute risk difference for PPI vs non- PPIs- use was 4.29 excess GC (95% CI ) per person- years. Long- term use of PPIs was still associated with an increased GC risk in subjects even after H. pylori eradication therapy. This study has been criticized for several aspects. First of all, successful eradication therapy was not documented but presumed on the basis of a missing further prescription for H. pylori eradication. Thus, patients developing GC may have had H. pylori eradication failure. 13 Furthermore, the indication for PPI intake after H. pylori eradication was not declared in the study. 4 GASTRIC CANCER: TREATMENT Confirmatory data on the role of endoscopic submucosal dissection (ESD) in patients with early GC were published in the last year. In a Korean prospective multicenter study by Kim et al, patients with early GC who met the absolute and extended criteria and underwent ESD were followed for 5 years. Only selected centers performing a minimum of 20 ESD per year took part to this study. The rate of enbloc resection was 99.1%, whereas complete resections (resection of tumor confined to mucosa with tumor- free margins and without lymphovascular invasion determined by histology) and curative resections (en-bloc resection with tumor- free margins within expanded criteria) were achieved in 81.3% and 86.1%, respectively. The 5- year diseasespecific free survival rate was 90.6%, the 5- year overall survival (OS) rate was 96.6% while the 5- year disease- specific survival rate was 99.8%. Patients developing local recurrence (0.9%) or metachronous lesions (7.8%) were treated by endoscopic or surgical treatment with an excellent long- term survival. Distant metastases were detected in a very low proportion of cases (0.5%) during follow- up. Thus, based on these results, ESD provides a valid curative treatment with an excellent clinical outcome comparable to surgery, at least for Korean patients with early GC presenting themselves in a high volume centre. In a meta- analysis, Hu et al 15 analyzed 13 studies (2106 patients) comparing ESD and surgery for the treatment of early GC. ESD treatment was clearly preferable to surgery in terms of reduced hospitalization time, cost effectiveness, quality of life, and occurrence of adverse events. ESD- treated patients showed a roughly sevenfold higher prevalence of metachronous lesions and recurrence rates compared to the surgically treated patients. This is conceivable, as ESD- treated patients maintained both their stomach and possibly atrophic changes of the gastric mucosa, increasing the risk of metachronous lesions. Also complete resection rates were higher in the surgical group compared to the ESD group (82.7% vs 56.3%, OR = 0.32, 95% CI ). As most of the studies included were retrospective, conducted mostly in one single country (Korea), and lacking relevant information such as survival outcomes and shortterm endoscopic surveillance, data from this analysis should be interpreted cautiously and, at least for the time being, not generalized to the Western population. Due to the lower prevalence of GC, in Western countries, the experience with ESD for patients with early GC is limited to high volume centers. In a monocentric retrospective study, Petruzziello et al 16 reviewed their experience in a series of 70 patients with early GC recruited between November 2007 and May 2015 at the University Hospital Gemelli in Rome, Italy. The majority of ESD procedures (53/70) were performed according to the extended criteria. En-bloc resection was achieved in 68 of 70 (97%) procedures. Histopathologically proven curative R0 resection was reported in 65.6% of cases whereas 22% and 12.4% of patients had a R1 and Rx resection, respectively. Major peri- and postinterventional complications, such as bleeding, occurred in 2.8% of cases. No significant difference in terms of complete resection, complications, and local recurrence rates was observed between patients with standard and extended indications. Although these results are in line with data from series published in the Far East, larger studies are needed to clearly define the role and the outcomes of GC patients treated by ESD in Western countries with low GC incidence. Compared to surgery alone, neoadjuvant and adjuvant strategies improve the outcome of patients with locally advanced GC and adenocarcinoma of the esophagogastric junction (AEG) who receive curative- intent surgery, both in younger and elderly patients. 17 The OE05 multicenter phase III clinical trial conducted in the United Kingdom assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. Patients were recruited between January 2005 and October Overall, 897 patients with surgically resectable AEG Siewert types 1 and 2 were randomized to receive four cycle neoadjuvant chemotherapy with epirubicin, cisplatin, and capecitabine (ECX, N = 451) or the standard 2- cycle neoadjuvant therapy with cisplatin and 5- fluorouracil (CF, N = 446). The median follow- up of the surviving patients was 6.4 years (IQR ), and 93% of the patients had at least 3 years of follow- up assessments. Median OS was 23.4 months (95% CI ) in the CF group and 26.1 months ( ) in the ECX group, with a hazard ratio (HR) of 0.90 (95% CI , P = 0.19), indicating no survival advantages in patients treated with the more intensive ECX- regime. In a multicentric study on adjuvant chemoradiation after resection of GC, Fuchs et al 18 investigated whether the replacement of 5- fluorouracil and leucovorin (5- FU/LV) with the potentially more active ECF regimen (epirubicin, cisplatin, and 5- fluorouracil) leads to an improvement of the patients outcome. In this trial, 546 patients with GC or AEG who underwent surgery were randomized between April 2002 and May 2009 to receive postoperative 5- FU plus LV or ECF, both before and after radiotherapy with 5- FU. No significant differences in the 5- year OS and in the 5- year disease- free survival (DFS) rates were observed between the two study arms (OS 44% in both arms; DFS 39% in the 5- FU/LV arm and 37% in the ECF arm). The addition of docetaxel to a platinum/fluoropyrimidine has been under scrutiny in the German multicenter, open- label, randomized phase III FLOT4 trial presented at the ASCO 2017 meeting. 19 The FLOT regimen consists of docetaxel, oxaliplatin, leucovorin,

5 5 of 6 and 5- fluorouracil. Overall, in the FLOT4 trial, 714 patients with resectable GC or AEG were randomly assigned to receive either thee preoperative and three postoperative cycles of ECF/ECX or four preoperative and four postoperative cycles of FLOT. The wide majority of included patients had an ECOG of 0-1, whereas about 75% were younger than 70 years old. In this population, FLOT significantly increased rates of curative surgery and prolonged median progression- free- survival (18 vs 30 months) and median OS (35 vs 50 months) as compared to ECF/ECX. Toxicity was drug- specific but overall similar between both regimens. Moreover, no differences were observed with respect to serious adverse events or toxic deaths. Accordingly, FLOT can be considered the new standard of care in the perioperative treatment of patients with resectable GC or AEG with a good performance status. In particular, as both FLOT and ECF are platinum/fluoropyrimidine- based triplets and taking into account the data from the OE 05 trial, the advantage of FLOT over ECF/ECX appears to be mainly based on the higher effectiveness of docetaxel compared to epirubicin. 20 Patients with inoperable advanced or metastatic GC undergo palliative chemotherapy usually consisting of a combination of platinum and fluoropyrimidines in the first- line. Second- line treatments generally include a taxane (docetaxel, paclitaxel), or irinotecan, or ramucirumab as a single agent or in combination with paclitaxel. 21 Recent preliminary studies have supported a beneficial effect of therapies with immune checkpoint inhibitors in patients with chemotherapy- refractory advanced disease. In a multicenter randomized, double- blind, placebo- controlled, phase 3 trial, Kang et al 22 assessed the efficacy and the safety of nivolumab, a fully human monoclonal PD- 1 inhibitor antibody, in patients with advanced GC or AEG previously treated with two or more regimens of chemotherapy but naive for any other immunotherapy. Between November 2014 and February 2016, patients from Japan, South Korea, and Taiwan (N = 493) were randomized 2:1 to receive either nivolumab (n = 330) or placebo (n = 163). The median OS was higher in patients treated with nivolumab compared to patients treated with placebo (median OS = 5.26 months, 95% CI and 4.14 months, 95% CI for nivolumab and placebo, respectively, HR 0.63, 95% CI ; P < ). Also the 12- month OS rate was higher in patients treated with nivolumab (12- month OS 26.2%, 95% CI vs. 10.9%, 95% CI for nivolumab and placebo, respectively). Thus, nivolumab might be a new treatment option with a relative safe profile for heavily pretreated patients with advanced GC and AEG. 5 CONCLUSIONS The epidemiology of GC is changing. The birth cohort effect observed for H. pylori infection explains, at least in part, the declining GC mortality in Japan whereas the causal mechanisms responsible for the increasing GC incidence among younger women in the United States need to be unraveled. New evidence supports the usefulness of serological (Pepsinogen I) and histomorphological biomarkers (OLGA staging system) for stratifying GC risk. H. pylori eradication therapy reduces but does not abolish the rate of metachronous GC in patients undergoing endoscopic resection for early GC. Whether regular aspirin use may be an alternative to follow- up endoscopy in these high risk patients has still to be determined. More data has been gained on the role of ESD in patients with early GC. The triplet FLOT can be considered the new standard of care in the perioperative treatment of patients with resectable GC or AEG, whereas nivolumab represents a new treatment option with a relative safe profile for heavily pretreated patients with advanced GC and AEG. DISCLOSURE OF INTERESTS M.V. has served as a speaker, a consultant or an advisory board member for Lilly, Bristol-Myers Squibb, Merck Serono, Bayer vital, Amgen, Nordic Pharma, Shire, Ipsen and Celgene. P.M. has served as a speaker for Abbott Laboratories, Allergan, Alfasigma, Bayer, Biocodex, AstraZeneca, Falk Pharma and Takeda. R.V. and T.R. declare no conflict of interest. REFERENCES 1. Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection: systematic review and meta- analysis. Gastroenterology. 2017;153: Wang C, Nishiyama T, Kikuchi S, et al. Changing trends in the prevalence of H. pylori infection in Japan ( ): a systematic review and meta- regression analysis of 170,752 individuals. 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