Christian Ell

Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial.

CONTEXT Gastroesophageal reflux disease (GERD) is a chronic, relapsing disease with symptoms that have negative effects on daily life. Two treatment options are long-term medication or surgery. OBJECTIVE To evaluate optimized esomeprazole therapy vs standardized laparoscopic antireflux surgery (LARS) in patients with GERD. DESIGN, SETTING, AND PARTICIPANTS The LOTUS trial, a 5-year exploratory randomized, open, parallel-group trial conducted in academic hospitals in 11 European countries between October 2001 and April 2009 among 554 patients with well-established chronic GERD who initially responded to acid suppression. A total of 372 patients (esomeprazole, n = 192; LARS, n = 180) completed 5-year follow-up. Interventions Two hundred sixty-six patients were randomly assigned to receive esomeprazole, 20 to 40 mg/d, allowing for dose adjustments; 288 were randomly assigned to undergo LARS, of whom 248 actually underwent the operation. MAIN OUTCOME MEASURE Time to treatment failure (for LARS, defined as need for acid suppressive therapy; for esomeprazole, inadequate symptom control after dose adjustment), expressed as estimated remission rates and analyzed using the Kaplan-Meier method. RESULTS Estimated remission rates at 5 years were 92% (95% confidence interval [CI], 89%-96%) in the esomeprazole group and 85% (95% CI, 81%-90%) in the LARS group (log-rank P = .048). The difference between groups was no longer statistically significant following best-case scenario modeling of the effects of study dropout. The prevalence and severity of symptoms at 5 years in the esomeprazole and LARS groups, respectively, were 16% and 8% for heartburn (P = .14), 13% and 2% for acid regurgitation (P < .001), 5% and 11% for dysphagia (P < .001), 28% and 40% for bloating (P < .001), and 40% and 57% for flatulence (P < .001). Mortality during the study was low (4 deaths in the esomeprazole group and 1 death in the LARS group) and not attributed to treatment, and the percentages of patients reporting serious adverse events were similar in the esomeprazole group (24.1%) and in the LARS group (28.6%). CONCLUSION This multicenter clinical trial demonstrated that with contemporary antireflux therapy for GERD, either by drug-induced acid suppression with esomeprazole or by LARS, most patients achieve and remain in remission at 5 years. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00251927.

Accuracy of staging in early oesophageal cancer using high resolution endoscopy and high resolution endosonography: a comparative, prospective, and blinded trial

Background and aims: The increasing use of endoscopic resection for curative treatment of early oesophageal cancers requires accurate staging before therapy. In a prospective blinded trial, we compared staging of early oesophageal carcinoma using high resolution endoscopy (HR-E) with staging using high resolution endosonography (HR-EUS). Patients and methods: A total of 100 patients (89 men, 11 women; mean age 63.9 (10.8) years (range 31–91)) with a suspicion of early oesophageal adenocarcinoma (n = 81) or squamous cell carcinoma (n = 19) were enrolled in the study. After endoscopic staging with high resolution video endoscopy by two experienced endoscopists, HR-EUS was performed by an experienced endosonographer who was blinded to the endoscopic assessment. Results of the staging examinations were correlated with the histology of the resected tumours. Results: Overall rates for accuracy of the endoscopic and endosonographic staging were 83.4% and 79.6%, respectively. Sensitivity for mucosal tumours (n = 68) was more than 90% (EUS 91.2%, endoscopy 94.1%) while sensitivity for submucosal tumours (n = 25) was lower, at 48% for EUS and 56% for endoscopic staging. A combination of the two techniques increased the sensitivity for submucosal tumours to 60%. Submucosal tumours in the tubular oesophagus were significantly better staged with HR-EUS than submucosal tumours close to the oesophagogastric junction (10/11 v 2/14; p<0.001). Tumours infiltrating the second and third submucosal layers were also more correctly diagnosed than tumours with slight infiltration of the first submucosal layer (sm1). Conclusions: The overall diagnostic accuracy of both HR-E and HR-EUS with a 20 MHz miniprobe in early oesophageal cancer was high (approximately 80%), with no significant differences between the two techniques. HR-E and HR-EUS provide a high level of diagnostic accuracy for mucosal tumours and submucosal tumours located in the tubular part of the oesophagus. With submucosal tumours located at the oesophagogastric junction or with infiltration of the first third of the submucosa however, the diagnostic accuracy of both techniques is not yet satisfactory.

Comparing laparoscopic antireflux surgery with esomeprazole in the management of patients with chronic gastro-oesophageal reflux disease: a 3-year interim analysis of the LOTUS trial

Background: With the introduction of laparoscopic antireflux surgery (LARS) for gastro-oesophageal reflux disease (GORD) along with the increasing efficacy of modern medical treatment, a direct comparison is warranted. The 3-year interim results of a randomised study comparing both the efficacy and safety of LARS and esomeprazole (ESO) are reported. Methods: LOTUS is an open, parallel-group multicentre, randomised and controlled trial conducted in dedicated centres in 11 European countries. LARS was completed according to a standardised protocol, comprising a total fundoplication and a crural repair. Medical treatment comprised ESO 20 mg once daily, which could be increased stepwise to 40 mg once daily and then 20 mg twice daily in the case of incomplete GORD control. The primary outcome variable was time to treatment failure (Kaplan–Meier analysis). Treatment failure was defined on the basis of symptomatic relapse requiring treatment beyond that stated in the protocol. Results: 554 patients were randomised, of whom 288 were allocated to LARS and 266 to ESO. The two study arms were well matched. The proportions of patients who remained in remission after 3 years were similar for the two therapies: 90% of surgical patients compared with 93% medically treated for the intention to treat population, p = 0.25 (90% vs 95% per protocol). No major unexpected postoperative complications were experienced and ESO was well tolerated. However, postfundoplication complaints remain a problem after LARS. Conclusions: Over the first 3 years of this long-term study, both laparoscopic total fundoplication and continuous ESO treatment were similarly effective and well-tolerated therapeutic strategies for providing effective control of GORD.

Diagnostic accuracy of forceps biopsy versus polypectomy for gastric polyps: a prospective multicentre study

Aims: To determine whether an adequate histological diagnosis of gastric polyps can be attained on the basis of forceps biopsy. Patients and methods: In a prospective multicentre study, 194 patients with 222 endoscopically removable gastric polyps (≥5 mm) underwent forceps biopsy and complete polypectomy. Patients with fundic gland polyps and polyposis syndrome were not included. Specimens were evaluated by primary and reference pathologists, and the complication rate of gastric polypectomy was also determined. Results: Of the 222 polyps, histological examination of the polypectomy specimens revealed tumour-like lesions in 77% (10% focal foveolar hyperplasia, 59% hyperplastic polyps, 4% inflammatory fibroid polyps, 4% other polyps) and neoplasia in 19% (10% tubular adenoma, 2% tubulovillous adenoma, 1% high grade intraepithelial neoplasia, 6% adenocarcinoma). When biopsy results were compared, complete agreement was found in 124 cases (55.8%) and, in an additional 77 cases (34.7%), the clinically important differentiation between tumour-like lesions and neoplasia was possible. However, relevant differences were found by the reference pathologist in six cases (2.7%), the most common reason being failure of biopsy to reveal foci of carcinoma in hyperplastic polyps. Bleeding was observed after polypectomy in 16 patients (7.2%), in 15 of whom it was managed conservatively. Conclusions: We recommend complete removal by an experienced endoscopist of all epithelial gastric polyps larger than 5 mm after thorough individualised risk-benefit analysis.

Photodynamic ablation of early cancers of the stomach by means of mTHPC and laser irradiation: preliminary clinical experience

Background—Radical surgical treatment has been the first choice for early gastric cancer, but high resolution endosonography allows in situ diagnosis with a high sensitivity and specifity and in consequence the option of local endoscopic treatment. Aims—To evaluate photodynamic therapy (PDT) usingmeso-tetrahydroxyphenylchlorin (mTHPC) as the photosensitiser in superficial gastric cancer. Methods—Twenty two patients with superficial early gastric cancer received mTHPC (0.075 mg/kg intravenously) and were treated 96 hours later with red light at 652 nm (20 J/cm2). Tumour response was assessed by endoscopy and extensive biopsy. Results—Endoscopies performed two to three days after PDT showed a haemorrhagic fibrinoid necrosis of the mucosal layer. Complete remission was achieved in 16/22 (73%) patients: 13/16 (80%) with intestinal type cancer and 3/6 (50%) with a diffuse Lauren’s carcinoma. The mean follow up period was 12 months and 20 months, respectively. An average of 1.8 treatment sessions was required. Severe side effects were not observed. Seven patients had mild to moderate skin photosensivity reactions; 12 had local pain after PDT for 1–10 days. Conclusion—PDT using mTHPC as the photosensitiser represents a safe and efficient method for topical treatment of early gastric cancer, especially of Lauren’s intestinal carcinoma. If the preliminary results can be verified in larger patient series and during long term follow up, local treatment of early cancers of the stomach by PDT could be considered as a therapeutic option for selected patients.

Standardization of Surgical Technique in Antireflux Surgery: The LOTUS Trial Experience

BackgroundTo date, it has been difficult to compare medical therapy for gastroesophageal reflux disease with that of surgical management from a scientific viewpoint, mainly because of the lack of standardization of the operative technique. This study was designed to identify a methodology for standardization of surgical technique and to measure the effectiveness of this standardization.MethodsSurgeons contributing to a major international multicenter trial comparing optimum medical therapy with surgical therapy for treatment of gastroesophageal reflux attempted to optimize their surgical techniques so that a realistic comparison could be made that may aid clinical decision-making. The surgeons met, shared their techniques using video, and produced a standardized set of criteria for the surgical centers and a common operative technique. Data collection methods ensured accuracy of the records of the procedure applied and the data were analyzed for consistency with set surgical standards.ResultsThere was a high degree of conformity (>95%) between the recommended method of performing a Nissen fundoplication as defined in the trial protocol, and variations were restricted to isolated individuals. The operations were completed without mortality, few conversions, and with very low postoperative morbidity.ConclusionsThis study has shown that, contrary to commonly held belief, surgeons are able to standardize their work for the purposes of measuring the outcome of an operative procedure within the context of a randomized, controlled trial.

Laser lithotripsy of difficult bile duct stones: results in 60 patients using a rhodamine 6G dye laser with optical stone tissue detection system

Introduction—Laser lithotripsy of bile duct stones has become a widely accepted endoscopic treatment modality for giant, impacted, or very hard stones. The procedure is usually carried out under direct endoscopic control in view of the potential risk of bile duct injuries in “blind” laser application. Aims—To investigate the use of a rhodamine 6G laser lithotriptor with an integrated optical stone tissue detection system (oSTDS). Methods—From 1 September 1991 to 7 March 1997, 60 patients with giant or impacted common bile duct stones refractory to endoscopic papillotomy stone extraction, and mechanical lithotripsy were treated via the endoscopic retrograde route using a rhodamine 6G dye laser (595 nm, 2.5 μs, 80–150 mJ pp, Lithognost Telemit/Baasel Corp., Germany) with integrated oSTDS. In case of tissue contact oSTDS cuts off the laser pulse after 190 ns (transmission of 5–8% of the total pulse energy). 47 patients (78.3%) were subjected tox ray targeting (oSTDS) alone, five (8.3%) to choledochoscope targeting alone, and eight (13.3%) to both techniques. Results—At the end of treatment 52 (87%) patients were completely stone-free. The only major complications included transient haemobilia, cholangitis, and pancreatitis in five patients. All five were successfully treated by conservative methods. Conclusions—Laser lithotripsy using the described rhodamine 6G dye laser with oSTDS seems to be safe and effective and allows “blind” fragmentation of difficult common bile duct stones under radiological control only.

Memory metal stents for palliation of malignant obstruction of the oesophagus and cardia.

Thirty patients with incurable malignant obstruction of the oesophagus and cardia were treated with self expanding oesophageal memory metal stents (Ultraflex) in a prospective study. The endoprostheses were successfully placed in all patients. Within one week after implantation dysphagia had improved in 25 of 30 patients (83%). Stent expansion was incomplete within one week after implantation in 12 of 30 patients (40%). After an average of two dilatation sessions eight of 12 stents had expanded completely. Five patients complained of retrosternal pain and three of them suffered from heartburn over several days despite acid inhibition. Major problems in the follow up period occurred in 10 of 30 patients (30%) and included late perforation (one) and tumour ingrowth/overgrowth (nine). All of these complications were treated endoscopically. Improvement of the dysphagia of the patients with tumour ingrowth/overgrowth lasted for about eight weeks (median; range: 2-38 weeks). Until November 1994 six of 30 patients were still alive with a survival time of 309 days (median; range: 103-368 days). It is concluded that oesophageal memory metal stents are easy to implant, prove effective in the palliation of malignant oesophageal obstructions, and have a low risk of severe complications. The only disadvantages are that incomplete initial stent expansion as well as tumour ingrowth/overgrowth occurred in nearly one third of the patients.

Long-term safety of proton pump inhibitor therapy assessed under controlled, randomised clinical trial conditions: data from the SOPRAN and LOTUS studies.

Control of chronic gastro‐oesophageal reflux disease may be achieved either by anti‐reflux surgery (ARS) or by long‐term medical therapy with proton pump inhibitors (PPIs). The primary efficacy results of the SOPRAN study, comparing long‐term omeprazole use with open ARS, and the LOTUS study, comparing long‐term esomeprazole use with laparoscopic ARS, have been reported. A secondary objective of these studies was to address the long‐term safety of these respective therapeutic strategies and thereby provide a valid scientific platform for assessing long‐term PPI safety.

Long-Term Outcome of Microscopic Esophagitis in Chronic GERD Patients Treated With Esomeprazole or Laparoscopic Antireflux Surgery in the LOTUS Trial

OBJECTIVES:Gastroesophageal reflux disease (GERD)-associated changes in esophageal histology have been reported mainly after short-term medical antireflux therapy, and few individual lesions have been examined. We report detailed histological findings from the LOTUS study, at baseline and at 1 and 3 years after laparoscopic antireflux surgery (LARS) or esomeprazole treatment in patients with chronic GERD.METHODS:LOTUS is a long-term, open, parallel-group, multicenter, randomized, controlled trial conducted in 11 European countries that compared LARS (n=248) with esomeprazole 20–40 mg daily (n=266). Biopsies from the distal esophagus 2 cm above the Z-line and at the Z-line were taken at baseline, and 1 and 3 years. The following lesions were assessed: basal cell hyperplasia (BCH), papillary elongation (PE), intercellular space dilatations (ISDs), intraepithelial eosinophils (EOSs), neutrophils, and necrosis/erosion. A severity score (SS, range 0–2) was calculated by taking the average score of all assessable lesions.RESULTS:All lesions were more severe on Z-line biopsies than at 2 cm, and almost all improved significantly from baseline to 1 and 3 years. The average SS (from 2 cm to Z-line) changed from 0.95 to 0.57 (1 year) and to 0.49 (3 years) on esomeprazole, and from 0.91 to 0.56 (1 year) and to 0.52 (3 years) after LARS (P<0.001 for both treatments at 1 and 3 years, with no significant difference between treatments). The proportions of patients with severe histological changes decreased from approximately 50% at baseline to 11% at 3 years.CONCLUSIONS:Both continuous esomeprazole treatment and laparoscopic fundoplication are associated with significant and similar overall improvement in microscopic esophagitis after 1 year that is maintained at 3 years.