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Lancet. 2011 Mar 12;377(9769):905-13.
Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial.
Malfertheiner P, Bazzoli F, Delchier JC, Celinski K, Giguère M, Rivière M, Mégraud F; Pylera Study Group.
Gastroenterologie, Hepatologie und Infektiologie, Otto-von-Guericke-Universtitat, Magdeburg, Germany.
BACKGROUND: Helicobacter pylori is associated with benign and malignant diseases of the upper gastrointestinal tract, and increasing antibiotic resistance has made alternative treatments necessary. Our aim was to assess the efficacy and safety of a new, single-capsule treatment versus the gold standard for H pylori eradication.
METHODS: We did a randomised, open-label, non-inferiority, phase 3 trial in 39 sites in Europe, comparing the efficacy and safety of 10 days of quadruple therapy with omeprazole plus a single three-in-one capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline (quadruple therapy) versus 7 days of omeprazole, amoxicillin, and clarithromycin (standard therapy) in adults with recorded H pylori infection. Patients were randomly assigned treatment according to a predetermined list independently generated by Quintiles Canada (Ville St-Laurent, QC, Canada). Our study was designed as a non-inferiority trial but was powered to detect superiority. Our primary outcome was H pylori eradication, established by two negative (13)C urea breath tests at a minimum of 28 and 56 days after the end of treatment. Our assessment for non-inferiority was in the per-protocol population, with subsequent assessment for superiority in the intention-to-treat population (ie, all participants randomly assigned treatment). This study is registered with ClinicalTrials.gov, number NCT00669955.
FINDINGS: 12 participants were lost to follow-up and 101 were excluded from the per-protocol analysis. In the per-protocol population (n=339), the lower bound of the CI for treatment with quadruple therapy was greater than the pre-established non-inferiority margin of -10% (95% CI 15.1-32.3; p<0.0001). In the intention-to-treat population (n=440), eradication rates were 80% (174 of 218 participants) in the quadruple therapy group versus 55% (123 of 222) in the standard therapy group (p<0.0001). Safety profiles for both treatments were similar; main adverse events were gastrointestinal and CNS disorders.
INTERPRETATION: Quadruple therapy should be considered for first-line treatment in view of the rising prevalence of clarithromycin-resistant H pylori, especially since quadruple therapy provides superior eradication with similar safety and tolerability to standard therapy.
FUNDING: Axcan Pharma Inc.
Lancet. 2011 Aug 6;378(9790):507-14.
14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial.
Greenberg ER, Anderson GL, Morgan DR, Torres J, Chey WD, Bravo LE, Dominguez RL, Ferreccio C, Herrero R, Lazcano-Ponce EC, Meza-Montenegro MM, Pena R, Pena EM, Salazar-Martínez E, Correa P, Martínez ME, Valdivieso M, Goodman GE, Crowley JJ, Baker LH.
SWOG Statistical Center, Cancer Research and Biostatistics, Seattle, WA 98101-1468, USA.
BACKGROUND: Evidence from Europe, Asia, and North America suggests that standard three-drug regimens of a proton-pump inhibitor plus amoxicillin and clarithromycin are significantly less effective for eradication of Helicobacter pylori infection than are 5-day concomitant and 10-day sequential four-drug regimens that include a nitroimidazole. These four-drug regimens also entail fewer antibiotic doses than do three-drug regimens and thus could be suitable for eradication programmes in low-resource settings. Few studies in Latin America have been done, where the burden of H pylori-associated diseases is high. We therefore did a randomised trial in Latin America comparing the effectiveness of four-drug regimens given concomitantly or sequentially with that of a standard 14-day regimen of triple therapy.
METHODS: Between September, 2009, and June, 2010, we did a randomised trial of empiric 14-day triple, 5-day concomitant, and 10-day sequential therapies for H pylori in seven Latin American sites: Chile, Colombia, Costa Rica, Honduras, Nicaragua, and Mexico (two sites). Participants aged 21-65 years who tested positive for H pylori by a urea breath test were randomly assigned by a central computer using a dynamic balancing procedure to: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy); 5 days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy); or 5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole (sequential therapy). Eradication was assessed by urea breath test 6-8 weeks after randomisation. The trial was not masked. Our primary outcome was probablity of H pylori eradication. Our analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, registration number NCT01061437.
FINDINGS: 1463 participants aged 21-65 years were randomly allocated a treatment: 488 were treated with 14-day standard therapy, 489 with 5-day concomitant therapy, and 486 with 10-day sequential therapy. The probability of eradication with standard therapy was 82.2% (401 of 488), which was 8.6% higher (95% adjusted CI 2.6-14.5) than with concomitant therapy (73.6% [360 of 489]) and 5.6% higher (-0.04% to 11.6) than with sequential therapy (76.5% [372 of 486]). Neither four-drug regimen was significantly better than standard triple therapy in any of the seven sites.
INTERPRETATION: Standard 14-day triple-drug therapy is preferable to 5-day concomitant or 10-day sequential four-drug regimens as empiric therapy for H pylori infection in diverse Latin American populations.
FUNDING: Bill & Melinda Gates Foundation, US National Institutes of Health.
Am J Gastroenterol. 2011 Feb;106(2):254-60.
Esophageal adenocarcinoma incidence in individuals with gastroesophageal reflux: synthesis and estimates from population studies.
Rubenstein JH, Scheiman JM, Sadeghi S, Whiteman D, Inadomi JM.
Veterans Affairs Center of Excellence for Clinical Management Research, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
OBJECTIVES: Recent advances in the management of Barrett's esophagus may kindle enthusiasm for screening for esophageal adenocarcinoma (EAC). Symptoms of gastroesophageal reflux disease (GERD) are recognized as relative risks for EAC. However, the absolute incidence of EAC in specific populations with GERD is unknown. We aimed to estimate the symptom-, age-, and sex-specific incidences of EAC, and place these incidences in the perspective of other cancers for which screening is endorsed.
METHODS: A Markov computer model utilizing published and publicly available data was created to estimate the age- and sex-specific incidences of EAC in American white non-Hispanics with GERD symptoms.
RESULTS: The incidence of EAC in men younger than 50 years with GERD symptoms is very low (for instance, at the age of 35 years, incidence=1.0/100,000), and their incidence of colorectal cancer is relatively much higher (for instance, at the age of 35 years, incidence of colorectal cancer is 6.7-fold greater). The incidence of EAC in older men with weekly GERD symptoms is substantial (for instance, at the age of 70 years, incidence=60.8/100,000 person-years), but their incidence of colorectal cancer is at least threefold greater. The incidence of EAC in women with GERD is extremely low, and similar to that of breast cancer in men (for instance, 3.9/100,000 person-years at the age of 60 years).
CONCLUSIONS: Screening for EAC should not be performed in men younger than 50 years or in women because of very low incidences of cancer, regardless of the frequency of GERD symptoms. In white men with weekly GERD over the age of 60 years, the incidence of EAC is substantial, and might warrant screening if that practice is particularly accurate, safe, effective, and inexpensive.
J Natl Cancer Inst. 2011 Jul 6;103(13):1049-57.
Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study.
Bhat S, Coleman HG, Yousef F, Johnston BT, McManus DT, Gavin AT, Murray LJ.
Centre for Public Health, Queens University Belfast, Institute of Clinical Sciences Building, Belfast BT12 6BA, Northern Ireland, UK.
BACKGROUND: Barrett's esophagus (BE) is a premalignant lesion that predisposes to esophageal adenocarcinoma. However, the reported incidence of esophageal adenocarcinoma in patients with BE varies widely. We examined the risk of malignant progression in patients with BE using data from the Northern Ireland Barrett's esophagus Register (NIBR), one of the largest population-based registries of BE worldwide, which includes every adult diagnosed with BE in Northern Ireland between 1993 and 2005. Subjects and
METHODS: We followed 8522 patients with BE, defined as columnar lined epithelium of the esophagus with or without specialized intestinal metaplasia (SIM), until the end of 2008. Patients with incident adenocarcinomas of the esophagus or gastric cardia or with high-grade dysplasia of the esophagus were identified by matching the NIBR with the Northern Ireland Cancer Registry, and deaths were identified by matching with records from the Registrar General's Office. Incidence of cancer outcomes or high-grade dysplasia was calculated as events per 100 person-years (% per year) of follow-up, and Cox proportional hazard models were used to determine incidence by age, sex, length of BE segment, presence of SIM, macroscopic BE, or low-grade dysplasia. All P values were from two-sided tests.
RESULTS: After a mean of 7.0 years of follow-up, 79 patients were diagnosed with esophageal cancer, 16 with cancer of the gastric cardia, and 36 with high-grade dysplasia. In the entire cohort, incidence of esophageal or gastric cardia cancer or high-grade dysplasia combined was 0.22% per year (95% confidence interval [CI] = 0.19% to 0.26%). SIM was found in 46.0% of patients. In patients with SIM, the combined incidence was 0.38% per year (95% CI = 0.31 to 0.46%). The risk of cancer was statistically significantly elevated in patients with vs without SIM at index biopsy (0.38% per year vs 0.07% per year; hazard ratio [HR] = 3.54, 95% CI = 2.09 to 6.00, P < .001), in men compared with women (0.28% per year vs 0.13% per year; HR = 2.11, 95% CI = 1.41 to 3.16, P < .001), and in patients with low-grade dysplasia compared with no dysplasia (1.40% per year vs 0.17% per year; HR = 5.67, 95% CI = 3.77 to 8.53, P < .001).
CONCLUSION: We found the risk of malignant progression among patients with BE to be lower than previously reported, suggesting that currently recommended surveillance strategies may not be cost-effective.
N Engl J Med. 2011 Oct 13;365(15):1375-83.
Incidence of adenocarcinoma among patients with Barrett's esophagus.
Hvid-Jensen F, Pedersen L, Drewes AM, Sorensen HT, Funch-Jensen P.
Department of Surgical Gastroenterology L, Aarhus University Hospital, Aarhus, Denmark.
BACKGROUND: Accurate population-based data are needed on the incidence of esophageal adenocarcinoma and high-grade dysplasia among patients with Barrett's esophagus.
METHODS: We conducted a nationwide, population-based, cohort study involving all patients with Barrett's esophagus in Denmark during the period from 1992 through 2009, using data from the Danish Pathology Registry and the Danish Cancer Registry. We determined the incidence rates (numbers of cases per 1000 person-years) of adenocarcinoma and high-grade dysplasia. As a measure of relative risk, standardized incidence ratios were calculated with the use of national cancer rates in Denmark during the study period.
RESULTS: We identified 11,028 patients with Barrett's esophagus and analyzed their data for a median of 5.2 years. Within the first year after the index endoscopy, 131 new cases of adenocarcinoma were diagnosed. During subsequent years, 66 new adenocarcinomas were detected, yielding an incidence rate for adenocarcinoma of 1.2 cases per 1000 person-years (95% confidence interval [CI], 0.9 to 1.5). As compared with the risk in the general population, the relative risk of adenocarcinoma among patients with Barrett's esophagus was 11.3 (95% CI, 8.8 to 14.4). The annual risk of esophageal adenocarcinoma was 0.12% (95% CI, 0.09 to 0.15). Detection of low-grade dysplasia on the index endoscopy was associated with an incidence rate for adenocarcinoma of 5.1 cases per 1000 person-years. In contrast, the incidence rate among patients without dysplasia was 1.0 case per 1000 person-years. Risk estimates for patients with high-grade dysplasia were slightly higher.
CONCLUSIONS: Barrett's esophagus is a strong risk factor for esophageal adenocarcinoma, but the absolute annual risk, 0.12%, is much lower than the assumed risk of 0.5%, which is the basis for current surveillance guidelines. Data from the current study call into question the rationale for ongoing surveillance in patients who have Barrett's esophagus without dysplasia. (Funded by the Clinical Institute, University of Aarhus, Aarhus, Denmark.).
N Engl J Med. 2011 Oct 13;365(15):1437-8.
The problems with surveillance of Barrett's esophagus.
In patients with Barrett's esophagus, the native squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium that is subject to dysplasia and mutation into esophageal adenocarcinoma. The incidence of esophageal adenocarcinoma, a particularly lethal form of cancer, increased by a factor of 6 in the United States between 1975 and 2001. Identified risk factors for esophageal adenocarcinoma are Barrett's esophagus, frequent heartburn, white race, older age, male sex, and obesity. Among these, the most important risk and the one offering the greatest opportunity for a cancer-prevention strategy is Barrett's esophagus. Consequently, substantial resources are expended on endoscopically identifying and monitoring Barrett's esophagus to control the "epidemic" of esophageal adenocarcinoma. However, the usefulness of this strategy is determined by a set of risk and effectiveness estimates, and crucial among these is the estimate of the risk that esophageal adenocarcinoma will develop in patients with nondysplastic Barrett's esophagus. In their report of an epidemiologic study from Denmark in this issue of the Journal, Hvid-Jensen et al. suggest that the risk is much lower than previously estimated, profoundly questioning the usefulness of the screening and surveillance strategy.
The link between Barrett's esophagus and esophageal adenocarcinoma was well established by the 1970s. Early estimates suggested that the risk of esophageal adenocarcinoma among patients with Barrett's esophagus was 0.8% per year, or about one case per 125 patient-years — an increase by a factor of 30 or 40 relative to the risk in the general population. Since then, this risk estimate has been progressively lowered. It was first reduced to about one case per 200 patient-years with the recognition that publication bias (overemphasis of studies with small numbers of patients) had resulted in a systematic overestimation of the risk.3 The risk estimate was further downgraded to about one case per every 300 patient-years in a recent meta-analysis in which a number of oversights in earlier meta-analyses were corrected, such as inclusion of prevalent cancers, inclusion of patients with dysplasia, and duplicate counting. Now we have two very large, population-based studies that further reduce the risk estimate. A report capturing the entire population of Northern Ireland (1.7 million persons) with a mean follow-up of 7 years estimated the risk of esophageal adenocarcinoma to be 0.13%, or one case per 769 patient-years. Hvid-Jensen et al. accessed a high-quality database encompassing the entire population of Denmark (5.4 million persons) to derive a risk estimate of 0.12%, or one case per 860 patient-years. With the use of that estimate, the relative risk of esophageal adenocarcinoma for a patient with Barrett's esophagus as compared with the general population was 11.3, a substantial drop from the increase by a factor of 30 or 40 estimated in early reports.
So the problems with the screening and surveillance strategy for patients with Barrett's esophagus lie not in the logic but in the numbers. An abundance of evidence points to frequent heartburn and Barrett's esophagus as risk factors for esophageal adenocarcinoma. However, the magnitude of the risk is small. Even after the precipitous increase in cases of esophageal adenocarcinoma in recent years, this cancer occurs infrequently in the United States, with only an estimated 8000 cases in 2004. Furthermore, an estimated 40% of patients with esophageal adenocarcinoma report no history of frequent heartburn.6 Hence, the target of a protocol for screening and surveillance of patients with Barrett's esophagus in the United States would be about 5000 cases of esophageal adenocarcinoma per year. On the other hand, the population at risk for esophageal adenocarcinoma because of frequent heartburn is very large. The 2010 U.S. census counted about 121 million Americans older than 45 years of age. Among these, an estimated 6% (7.3 million persons) have frequent heartburn, 5 to 15% of whom are likely to have Barrett's esophagus.7 Consequently, the probability that esophageal adenocarcinoma will be detected with the use of endoscopy is only about 1 of every 1460 screening endoscopic examinations, but 146 patients with Barrett's esophagus will be detected in the process.
Endoscopy is unquestionably effective in detecting Barrett's esophagus. The problem is that as our knowledge of the biologic characteristics of Barrett's esophagus has matured, the significance of the lesion has dwindled. In fact, patients with Barrett's esophagus have the same life expectancy as does the general population, and esophageal cancer proves to be an uncommon cause of death in patients with Barrett's esophagus, regardless of surveillance. Furthermore, currently available evidence has not shown that the current strategy of screening and surveillance of patients with Barrett's esophagus is cost-effective or reduces mortality from esophageal adenocarcinoma. As reinforced by the elegant epidemiologic data reported by Hvid-Jensen et al., the problems with surveillance of Barrett's esophagus lie in the numbers.