Helicobacter ISSN 1523-5378 doi: 10.1111/j.1523-5378.2012.00980.

REVIEW ARTICLE

Helicobacter pylori: Gastric Cancer and Extragastric Intestinal Malignancies

Michael Selgrad,*1 Jan Bornschein,*1 Theodore Rokkas and Peter Malfertheiner*
*Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany, Gastroenterology Clinic, Henry Dunant Hospital, Athens, Greece

Keywords gastric cancer, colorectal cancer, pepsinogen EMR, atrophic gastritis.

Reprint requests to: Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-GuerickeUniversity of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. E-mail: peter. malfertheiner@med.ovgu.de
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Abstract The greatest challenge in Helicobacter pylorirelated diseases continues to remain prevention of gastric cancer. New evidence supports the benecial effect of H. pylori eradication not only on prevention of gastric cancer but also on the regression of preneoplastic conditions of the gastric mucosa. Concerning early detection of gastric cancer there are still no adequate means and there is urgent need to dene appropriate markers, for example, by genome-wide research approaches. Currently, the best available method is the serologic biopsy based on pepsinogen I and the pepsinogen I/II ratio for identication of patients with severe gastric atrophy at increased risk for gastric cancer development. The treatment of early gastric cancer by endoscopic techniques can be performed safely and efciently, but patients need meticulous follow-up for detection of metachronous lesions. In case of advanced disease, laparoscopically assisted surgical procedures are safe and favorable compared to open surgery. Two phase III trials support the role of adjuvant systemic treatment with different regimens. Unfortunately, there is still only slow progress in the development of palliative treatment regimens or modication of the existing therapy protocols. There is accumulating evidence for a role of H. pylori infection also in colorectal carcinogenesis. Seropositive individuals are at higher risk for the development of colorectal adenomas and consequently adenocarcinomas of this anatomical region. This phenomenon can partly be attributed to the increase of serum gastrin as response to atrophic changes of the gastric mucosa.

These authors equally contributed to this manuscript.

In 2012, the infection with Helicobacter pylori remains one of the most challenging infectious diseases of the world, causing high morbidity and mortality. The major burden in global health care is still given by H. pylori representing the main risk factor for gastric cancer (GC), the second leading cause of cancer-related death. During the past years, the progress in the clinical management of GC has been modest. Innovations are limited to modications of the existing chemotherapy regimens in either palliative or perioperative settings. Furthermore, new data have been gained concerning the endoscopic treatment of early GC. This review summarizes recent clinical- and researchrelated advances in the eld of H. pylori and GC that have been published between April 2011 and April 2012, including also recent insights concerning the association between H. pylori infection and colorectal neoplasias.

Prevention and Screening of Gastric Cancer

H. pylori infection leads in all infected individuals to a chronic active gastritis, which can proceed, via the so-called Correa cascade, to gastric mucosal atrophy and intestinal metaplasia (IM), and nally to the development of GC. Thus, atrophy and IM are considered as precancerous conditions, and H. pylori eradication therapy is considered as preventive for GC [1]. Several studies have proven that eradication therapy also improves, or at least prevents, progression of gastric atrophy and IM; however, some did not show a benet [25]. A recent study therefore evaluated the gastric mucosa of patients that underwent eradication therapy in a long-term follow-up [6]. A total of 118 patients have been monitored after successful eradication ther-

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apy, for a mean of 8.6 years. After eradication therapy, atrophy scores signicantly decreased both in the antrum and corpus. The score for IM signicantly decreased in the corpus of the stomach, but not in the antrum. In this study, 21 patients with unsuccessful eradication therapy were also monitored for a mean of 7.2 years. In this group, no difference in the scores was observed. The signicant improvements in gastric atrophy and IM that were observed after H. pylori eradication may result in a decreased risk for GC development. Early detection of GC represents the current best option to reduce its morbidity and mortality. The combination of the detection of serum anti-H. pylori antibodies and the measurement of serum pepsinogens has been widely applied in high-risk populations for screening of GC [79]. The crucial question is if serologic testing is adequate to screen for the GC itself or if it gives only information about the prevalence and severity of preneoplastic conditions. In a recent study from Japan, different cut-off levels for both pepsinogen I and the pepsinogen I/II ratio have been applied [10]. This resulted in a sensitivity and specicity to detect the occurence of GC of 71.0% and 69.2% for pepsinogen I  59 ng/mL and the pepsinogen I/II ratio  3.9. Performance of this test was signicantly improved when analysis of H. pylori antibodies has been included [10]. Similar cut-offs, although higher for the pepsinogen I/II ratio (  5.0), have been identied by an Iranian group for the detection of atrophy [11]. The data also support the role of pepsinogen II being an adequate marker for non-atrophic pangastritis, which is also considered as a risk condition for GC development. However, serum pepsinogen testing serves as high-risk indicator for GC development but not as a screening tool for the cancer itself [12]. A large cohort study in a population from Portugal followed up a total of 13,118 individuals for 5 years [13]. Endoscopy was performed in 274 individuals of the 446 with a positive pepsinogen test in the whole population (3.4%). Six GC have been detected resulting in one per 2200 tests or one case per 74 positive tests. Three GC have been detected in the 96.6% with negative test results [13]. In contrast, a recent study from Japan evaluated the value of this screening method in a rural population with a high incidence of GC [14]. Concluding from their data, the authors stated that in an aging population with high incidence of GC there is also a high prevalence of gastric mucosal atrophy and H. pylori infection. Therefore, the number of subjects identied for further endoscopic examinations might be too high in such populations [14]. We assessed the inuence of specic biologic characteristics of gastric adenocarcinomas on the outcome of

tests for serum pepsinogens [15]. The aim was the identication of modiers that can be used to improve the diagnostic value of this method for GC screening. n type nor tumor localization or tumor Neither Laure stage had an inuence on the serum values for pepsinogen I, II, and the pepsinogen I/II ratio. Only the degree of atrophy as well as the positive CagA status were independent factors inuencing the outcome. This limitation of the pepsinogen method needs to be considered, but its role as a reliable screening method for preneoplastic conditions of the stomach in other populations is well established [16]. Thus, recent European guidelines and consensus recommend serologic screening for preneoplastic conditions like severe gastric atrophy and IM of the stomach [1,17]. Although not yet generally accepted, a regular endoscopic followup for patients who present with atrophic gastritis is suggested at 3-year intervals [17]. Another interesting approach for GC screening is the determination of GC risk markers that reect epigenetic changes induced by H. pylori infection. By microarray analysis, a group from Japan identied seven epigenetic GC risk markers that are highly informative in individuals with past H. pylori infection [18]. This novel approach by applying genome-wide analysis may be useful in the near future to estimate GC risk.

Treatment of Gastric Cancer

There is ongoing debate about the risk pattern and predictive factors concerning high risk of metachronous malignancies after endoscopic resection of early GC. In a retrospective cross-sectional study from Japan, 149 patients have been included for a 10-year follow-up period after either endoscopic en bloc or piecemeal snare resection (endoscopic mucosal resection: EMR) of early GC [19]. There was no case with recurrent or metachronous disease in the group that received en bloc resection, whereas the local recurrence rate in patients with piecemeal resection was 30% at 5 and 10 years. Piecemeal resection was associated with a higher rate of unclear horizontal tumor margins, resulting in a hazard ratio (HR) of 1.63 [95% CI: 1.122.36] for recurrent disease. A group from Korea reported an annual incidence of 3.3% for metachronous GC after endoscopic submucosal dissection (ESD) in their patients with a median interval till the lesion occurred being 30 months (range: 1842) in nine patients [20]. In seven patients, new lesions developed within the rst year after initial treatment. Metachronous lesions were not associated with H. pylori infection status, location of the primary tumor, or gross appearance of the lesion. The rate of recurrence or incidence of metachro-

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nous GC is not dependent from the patients age, although there is a higher mortality related to comorbidities in patients older than 75 years [21]. If the long-term outcome of patients after EMR or surgical gastrectomy for early GC was compared, there was no signicant difference concerning cancer-related death or local recurrence of the disease [22]. Owing to the limited nature of the endoscopic procedure, there was a higher risk of metachronous cancer for the EMR group (HR 6.72; 95% CI: 2.0022.58). There was no impact on overall survival as retreatment of these patients was highly effective. However, showing similar complication rates, patients undergoing EMR stayed signicantly shorter in the hospital (8 vs. 15 days, p < .001) and the costs of care were signicantly longer compared to the surgery group (2049$ vs 4042$, p < .001). During the last year, several meta-analyses have been published comparing the outcome and the related risks of laparoscopically assisted distal gastrectomy versus the traditional open surgical procedure including mainly randomized controlled trials [2325]. Throughout the published data, the results are quite congruent. Whereas the overall mortality was similar for both procedures, there were lower overall complications, shorter duration of hospital stay, and lower surgery-related blood loss, but increased operation time for patients undergoing the laparoscopical procedure. Another important factor was a signicantly higher harvest of lymph nodes for patients undergoing open distal gastrectomy. Further retrospective studies from Asia as well as one prospective trial from Italy conrmed the major aspects of these data [26 28]. The rate of recurrence or metachronous metastases was similar for both procedures. A study from Korea assessed the benet of extensive surgery even in case of advanced, metastatic GC in 274 patients [29]. Patients were stratied into three groups either receiving complete gross resection, debulking gastrectomy, or systemic chemotherapy without debulking. Multivariate analysis of overall survival revealed a hazard ratio (HR) for death of 0.27 (p < .001) in the group that had received complete gross resection and of 0.64 (p = .024) in the group with debulking surgery compared to patients receiving systemic treatment only. These results indicate that radical surgery might be of benet for some highly selected patients, but prospective trials are needed for further validation of this approach. In another study, neoadjuvant chemotherapy in combination with cytoreductive surgery and intraperitoneal chemotherapy was compared to systemic chemotherapy alone (n = 20) [30]. Mean overall survival for the patients receiving multimodal treatment was 17.4 months compared to 11.1 months in the chemo-

therapy-only group. By the multimodal approach, 0.52 life-years could be gained, resulting in a gain of 0.49 QALYs, but incremental costs were 175,164 US-$ per QALY. Two major studies from France assessed the impact of platinum and 5-uorouracil (5-FU)-based perioperative chemotherapy on the outcome of patients with either GC including Adenocarcinoma at the Esophago Gastric Junction (AEG) or selected patients with signet ring cell cancer [31,32]. In a phase III trial on 224 patients with GC and AEG, perioperative chemotherapy was a favorable factor for overall survival in multivariate analysis [32]. Additional systemic treatment resulted in a 5-year survival of 38% versus 24% in the surgery-only group and a HR for death of 0.69 (95% CI: 0.500.95). The curative resection rate was also higher in patients who received systemic treatment (84% vs 73%, p = .04) with similar postoperative morbidity. In contrast, in patients with signet ring cell cancer, perioperative chemotherapy was an independent predictive factor for poor survival (HR 1.4; 95% CI. 1.1 1.9) [31]. In a multicentric trial from East Asia (37 centers in South Korea, Taiwan, and China), the effect of adjuvant treatment with oxaliplatin and capecitabine on diseasefree survival was assessed in patients after surgery including D2-lymphadenectomy for stage II-III-B GC [33]. The trial was stopped after an interim analysis for efcacy. During a median follow-up period of 34.2 months, it was shown that the 3-year disease-free survival was 74% in patients receiving adjuvant therapy compared to 59% in patients who received only surgery (HR 0.56; 95% CI: 0.440.72). However, a higher rate of III and IV adverse events was observed under systemic treatment (56% vs 6%). Similar results were obtained in the phase III ACTS-GC trial from Japan, evaluating the effect of adjuvant treatment with the oral 5-FU analogue S1 after D2-gastrectomy for GC [34]. The 5-year overall survival (OS) was 71.7% in patients receiving adjuvant treatment compared to 61.1% in the surgery-only group (HR 0.669; 95% CI: 0.5400.828). A retrospective analysis of data from 10,251 patients in the US American SEER database evaluated the effect of pre- or post-surgery radiation in patients undergoing surgical gastrectomy for GC [35]. Concerning the entire cohort, there was no survival benet for patients receiving any kind of radiation. Selective assessment of patients with positive lymph node involvement revealed improved median overall and 5-year survival rates (pre-op. radiation: p = .0261; post-op. radiation: p < .001). However, retrieval of more than 15 lymph nodes during primary surgery was an independent predictor of survival in multivariate analysis.

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As the outcome of patients with advanced GC is still poor, several regimens of systemic chemotherapy have been further assessed concerning their effectiveness in the palliative setting. In the Austrian GASTRIC-II trial, the combination of oxaliplatin, irinotecan, and cetuximab has been applied in 51 patients with advanced GC [36]. In 35 patients accessible for response evaluation, there was an overall response rate (ORR) of 23% with a median time to progression (TTP) of 24.8 weeks and a median OS of 38.1 weeks for patients with wild-type status of the K-ras gene. Main toxicity was acceptable, however, with neutropenia in 35% (III in nine and IV in one patient, respectively), thrombocytopenia in 33%, anemia in 73%, peripheral polyneuropathy in 37%, nausea in 45%, diarrhea in 57%, and fatigue in 37% of patients. In a Chinese phase II trial, a modied XELIRI (capecitabine plus irinotecan; Xeloda, Roche Pharmaceuticals, Basel, Switzerland) regimen was reported to be adequately safe and effective (ORR 43.7%) median TTP 5.6 months, OS 11.0 months)) [37]. Grade III/IV adverse events were neutropenia (15.6%), anorexia (9.4%), nausea (9.4%), vomiting (6.3%), and diarrhea (6.3%). Despite strong data from earlier studies supporting the addition of docetaxel to platinum/5-FU-based regimens, there are still phase II trials with conicting results. A study from Turkey could not demonstrate a signicant effect by addition of docetaxel on neither median OS (6.5 vs 8.7 months) or TTP (4.4 vs 65.2 months) in a cohort of 70 patients [38]. However, a Greek study demonstrated ORR of 59% and a median survival of 18.0 months for patients receiving docetaxel, oxaliplatin, and capecitabine with acceptable toxicity [39]. Promising results have been reported from a Japanese trial evaluating the efcacy of systemic treatment with paclitaxel in patients with malignant ascites (ORR 41.7%, 1-year survival 29.2%, no severe toxicity) [40]. The effect of sunitinib as second-line treatment in patients with GC has been assessed in a German phase II trial [41]. The overall response rate was 3.9% with a PFS of 1.28 months, an OS of 5.81 months, and a 1-year survival rate of 23.7%. These results do not support the application of sunitinib in this setting. Efforts are made to use the rapidly developing biostatistical approaches of gene-coexpression network proling for the identication of novel target genes or promising candidate compounds for the treatment of advanced GC [42].

Helicobacter pylori and Colorectal Cancer Risk

Several studies have suggested that chronic infection with H. pylori may moderately increase the risk for

colorectal cancer [4345]. The background for this hypothesis is that infection with H. pylori leads to an increase of plasma gastrin levels. Hypergastrinemia stimulates mucosal cell proliferation. Chronic H. pylori infection results in gastric atrophy, cell mutation, and transformation of gastric mucosal cells into gastrinproducing cells, which also express gastrin receptors serving to stimulate cell proliferation and tumor growth [4648]. Two meta-analysis reported that there is a modest increase in the risk of colorectal cancer owing to H. pylori infection [49,50]. However, the studies had several weaknesses as thus included a small sample size of studies with high heterogeneity and made note or confounding controls. Recently, a large populationbased case control study was conducted in Germany to investigate the association between H. pylori and colorectal cancer [51]. Serum anti-H. pylori antibodies and anti-CagA antibodies were measured in 1712 patients with colorectal cancer and 1669 controls. There was a high H. pylori seroprevalence in the study population (mean age 69 years) with more than 40% in both arms. Overall, H. pylori infection was more prevalent in colorectal cancer cases (46.1%) than in controls (40.1%). The authors performed a stratied analysis which showed risk elevation to be essentially conned to leftsided colorectal cancer, with an odds ratio (OR) of 1.22 (95% CI: 1.021.45). The results of this large population-based study suggest that H. pylori infection may be associated with an increased risk for the selected group after the neoplasia of the left colorectum. Colorectal cancer development is based on the adenoma-carcinoma sequence. Thus, a study investigated correlation between H. pylori infection or chronic atrophic gastritis (CAG) and risk of colorectal adenoma [52]. In this study, H. pylori infection was a risk factor for adenoma as a whole. The analysis of distal adenoma cases showed that adenoma risk was signicantly increased in the presence of H. pylori infection when chronic atrophic gastritis was present. In a large cross-sectional study from Korea, 2195 eligible subjects undergoing screening colonoscopy have been evaluated for the prevalence of H. pylori infection [53]. H. pylori-positive individuals presented a signicantly higher prevalence of colorectal adenomas compared to subjects without the infection (25.3 vs. 20.1%, p = .004). H. pylori seropositivity was an independent risk factor for overall colorectal adenoma in the multivariate analysis (OR = 1.36, 95% CI: 1.101.68). The authors further included a meta-analysis on the actual data published on this issue [53]. Ten studies and 15,863 patients have been included in the analysis resulting in a pooled OR for colorectal adenoma related to H. pylori infection of 1.58 (95% CI: 1.321.88).

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Overall, H. pylori infection leads to a small increase of the risk to develop colorectal adenoma and subsequently colorectal cancer.

Conclusion
Gastric cancer still remains the major challenge of H. pylori-related diseases. Effective screening and prevention strategies need to be improved. Endoscopic treatment of early GC allows a better cure with preservation of a good quality of life compared to open radical surgery. Advances in palliative treatment proceed only at slow pace. Recent meta-analyses support the role of H. pylori in colorectal carcinogenesis, with specic pathobiologic mechanisms still to be dened.

Acknowledgements and Disclosures

Competing interests: the authors have no competing interests.

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