S. Michael Griffin

Guidelines for the management of oesophageal and gastric cancer

Over the past decade the Improving Outcomes Guidance (IOG) document has led to service re-configuration in the NHS and there are now 41 specialist centres providing oesophageal and gastric cancer care in England and Wales. The National Oesophago-Gastric Cancer Audit, which was supported by the British Society of Gastroenterology, the Association of Upper Gastrointestinal Surgeons (AUGIS) and the Royal College of Surgeons of England Clinical Effectiveness Unit, and sponsored by the Department of Health, has been completed and has established benchmarks for the service as well as identifying areas for future improvements.1–3 The past decade has also seen changes in the epidemiology of oesophageal and gastric cancer. The incidence of lower third and oesophago-gastric junctional adenocarcinomas has increased further, and these tumours form the most common oesophago-gastric tumour, probably reflecting the effect of chronic gastro-oesophageal reflux disease (GORD) and the epidemic of obesity. The increase in the elderly population with significant co-morbidities is presenting significant clinical management challenges. Advances in understanding of the natural history of the disease have increased interest in primary and secondary prevention strategies. Technology has improved the options for diagnostic and therapeutic endoscopy and staging with cross-sectional imaging. Results from medical and clinical oncology trials have established new standards of practice for both curative and palliative interventions. The quality of patient experience has become a significant component of patient care, and the role of the specialist nurse is fully intergrated. These many changes in practice and patient management are now routinely controlled by established multidisciplinary teams (MDTs) which are based in all hospitals managing these patients. The original guidelines described the management of oesophageal and gastric cancer within existing practice. This paper updates the guidance to include new evidence and to embed it within the framework of the current UK National Health Service (NHS) Cancer …

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Early complications after Ivor Lewis subtotal esophagectomy with two-field lymphadenectomy: Risk factors and management

BACKGROUND Esophageal resection represents a major surgical and physiologic insult carrying major morbidity and mortality. We present the results of esophagectomy in a specialist unit with emphasis on early complications and their management. STUDY DESIGN From January 4, 1990 through January 6, 2000, 228 patients have undergone Ivor Lewis subtotal esophagectomy with two-field lymphadenectomy for malignancy under the care of one surgeon. The median age was 64 years (range 39 to 77 years), with a male to female ratio of 2.3:1 and a predominance of adenocarcinoma (n = 146) compared with squamous cell carcinoma (n = 75) and other tumors (n = 7). Detailed prospective data were collected on preoperative status, operative parameters, and postoperative complications. RESULTS Median ICU stay was 1 day (range 1 to 47 days) and the median postoperative hospital stay in patients surviving surgery (n= 219) was 13 days (range 9 to 159 days). There were 119 separate postoperative complications occurring in 45% of patients (102 of 228), comprising predominantly pulmonary morbidity. Major respiratory complications (17%) were significantly associated with poor preoperative spirometry (p = 0.002) and a history of smoking (p = 0.03). Seven percent of patients (16 of 228) suffered cardiovascular or thromboembolic complications. Major surgical complications occurred in 10% of patients (22 of 228) including mediastinal leaks in 4%. Isolated anastomotic leaks (2%) were successfully treated conservatively in all cases; extensive leaks from ischemic gastric conduits (1%) or gastrotomy dehiscence (1%) underwent further exploration and either local repair or resection and exclusion. Reoperation for hemostasis was required in 3% (6 of 228) and only 1% of patients (2 of 228) developed chyle leaks. Thirty-day mortality was 2%, rising to 4% for in-hospital mortality. The nine fatalities were significantly older (p = 0.02) than those who survived and 67% (6 of 9) had suffered primary surgical complications. CONCLUSIONS Overall morbidity after radical esophagectomy is high, but early recognition and aggressive management of complications can minimize subsequent mortality. Concentration of facilities and surgical expertise in specialist units together with more careful patient selection can decrease mortality further.

A randomized controlled clinical trial of palliative therapies for patients with inoperable esophageal cancer.

OBJECTIVES:A dramatic rise in incidence, an aging population, and expensive palliative treatments have led to an escalating burden on clinicians managing inoperable esophageal cancer with only limited evidence of effectiveness. This study compares the clinical effectiveness and cost-effectiveness of self-expanding metal stents (SEMSs) with other palliative therapies to aid clinicians in making an evidence-based treatment choice.METHODS:We conducted a prospective, multicenter, randomized, controlled, clinical trial with 215 patients followed until death or study closure. The primary outcome measures were dysphagia, quality of life (QL) 6 weeks following treatment, and total cost of treatment. Secondary outcome measures included treatment-associated morbidity, mortality, survival, and cost-effectiveness. An intention-to-treat analysis was carried out.RESULTS:There was a significant difference in mean dysphagia grade between treatment arms 6 weeks following treatment (P=0.046), with worse swallowing reported by rigid stent–treated patients (mean dysphagia score difference=−0.49; 95% confidence interval (CI) −0.10 to −0.89, P=0.014). Global QL scores were lower at both 1 and 6 weeks following treatment for patients treated by SEMSs (mean difference QL index week 1=−0.66; 95% CI: −0.02 to −1.30, P=0.04; mean difference QL index week 6=−1.01; 95% CI −0.30 to −1.72, P=0.006). These findings were associated with higher post-procedure pain scores in the SEMS patient group (mean difference of the European Organisation for Research and Treatment of Cancer QLQ C-30 pain symptom score at week 1=11.13; 95% CI: 2.89–19.4; P=0.01). Although mean EQ-5D QL values differed between the treatments (P<0.001), this difference dissipated following generation of quality-adjusted life year values. Total costs varied between treatment arms but these findings canceled out when SEMSs were compared with non-SEMS therapies (95% CI −845.15–1,332.62). These results were robust to sensitivity analysis. There were no differences in the in-hospital mortality or early complication rates, but late complications were more frequent after rigid stenting (risk ratio=2.47; 95% CI 1.88–3.04). There was a survival advantage for non-stent-treated patients (log-rank statistic=4.21, P=0.04).CONCLUSIONS:The treatment choice for patients with inoperable esophageal cancer should be between a SEMS or a non-stent treatment after consideration has been given to both patient and tumor characteristics and clinician and patient preferences.

Monitoring the changing pattern of esophago-gastric cancer: data from a UK regional cancer registry

Objectives: The aim of this study was to evaluate the reliability and adequacy of the existing system of cancer registration in the United Kingdom to monitor past and future trends in esophago-gastric cancer incidence. Methods: The Northern and Yorkshire UK Cancer Registry was interrogated for all cases of esophageal and gastric cancer occurring between 1984 and 1993. Data concerning year of registration, subsite, histology, sex, and ages were recorded and analyzed. Results: A total of 22,300 cases were identified from an estimated population of 6.7 million. The overall age- and sex-standardized incidence of gastric cancer fell over the 10-year period from 12.8 to 10.5 per 100,000 (p < 0.001) while esophageal cancer increased from 4.6 to 5.4 cases per 100,000 (p = 0.006). Adenocarcinoma of the gastric cardia increased in proportion from 29.1% to 52.2% (p < 0.0001), 70.4% of esophageal and 71% of gastric cancer registrations were recorded without details of subsite. For 25% of esophageal cancers and 36% of gastric cancers there was no histological information. Conclusions: While the trend toward an increasing incidence of adenocarcinoma at the esophago-gastric junction reported in earlier studies appears to be confirmed, the high incidence of imprecise subsite reporting of cancer registry data illustrated in this study should make us look critically at the findings of other cancer registry data. Recognition of cancer of the esophago-gastric junction as distinct from other gastric and esophageal subsites may improve accuracy of recording and allow cancer registry data to more accurately monitor the changes in esophago- gastric cancer incidence in subsequent analyses.

Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial

Summary Background Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Methods In this multicentre, randomised, open-label phase 2–3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1–21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203. Findings Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5–54·9) in the chemotherapy alone group and 48·1% (43·2–52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91–1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). Interpretation The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. Funding Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.

Lung Transplantation, Gastroesophageal Reflux, and Fundoplication

Lung transplantation is an accepted treatment strategy for end-stage lung disease; however, bronchiolitis obliterans syndrome is a major cause of morbidity and mortality. This review explores the role of gastroesophageal reflux disease in bronchiolitis obliterans syndrome and the evidence suggesting the benefits of anti-reflux surgery in improving lung function and survival. There is a high prevalence of gastroesophageal reflux in patients post lung transplantation. This may be due to a high preoperative incidence, vagal damage and immunosuppression. Reflux in these patients is associated with a worse outcome, which may be due to micro-aspiration. Anti-reflux surgery is safe in selected lung transplant recipients; however there has been one report of a postoperative mortality. Evidence is conflicting but may suggest a benefit for patients undergoing anti-reflux surgery in terms of lung function and survival; there are no controlled studies. The precise indications, timing, and choice of fundoplication are yet to be defined, and further studies are required.

The response of early gastric cancer to proton-pump inhibitors.

To the Editor: Early diagnosis is paramount in the successful treatment of gastric cancer.1 We have found that empirical treatment with a proton-pump inhibitor can delay the diagnosis as occurred i...

Self-expanding metal stents in the palliation of small bowel stenosis secondary to recurrent gastric cancer☆☆☆★

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The trefoil factor interacting protein TFIZ1 binds the trefoil protein TFF1 preferentially in normal gastric mucosal cells but the co- expression of these proteins is deregulated in gastric cancer

The gastric tumour suppressor trefoil protein TFF1 is present as a covalently bound heterodimer with a previously uncharacterised protein, TFIZ1, in normal human gastric mucosa. The purpose of this research was firstly to examine the molecular forms of TFIZ1 present, secondly to determine if TFIZ1 binds other proteins apart form TFF1 in vivo, thirdly to investigate if TFIZ1 and TFF1 are co-regulated in normal gastric mucosa and fourthly to determine if their co-regulation is maintained or disrupted in gastric cancer. We demonstrate that almost all human TFIZ1 is present as a heterodimer with TFF1 and that TFIZ1 is not bound to either of the other two trefoil proteins, TFF2 and TFF3. TFIZ1 and TFF1 are co-expressed by the surface mucus secretory cells throughout the stomach and the molecular forms of each protein are affected by the relative abundance of the other. TFIZ1 expression is lost consistently, early and permanently in gastric tumour cells. In contrast, TFF1 is sometimes expressed in the absence of TFIZ1 in gastric cancer cells and this expression is associated with metastasis (lymph node involvement: p = 0.007). In conclusion, formation of the heterodimer between TFIZ1 and TFF1 is a specific interaction that occurs uniquely in the mucus secretory cells of the stomach, co-expression of the two proteins is disrupted in gastric cancer and expression of TFF1 in the absence of TFIZ1 is associated with a more invasive and metastatic phenotype. This indicates that TFF1 expression in the absence of TFIZ1 expression has potentially deleterious consequences in gastric cancer.