National Institute for Health and Care Excellence (NICE) guidance on monitoring and management of Barrett's oesophagus and stage I oesophageal adenocarcinoma.

Barrett's oesophagus is the only known precursor to oesophageal adenocarcinoma, a cancer with very poor prognosis. The main risk factors for Barrett's oesophagus are a history of gastro-oesophageal acid reflux symptoms and obesity. Men, smokers and those with a family history are also at increased risk. Progression from Barrett's oesophagus to cancer occurs via an intermediate stage, known as dysplasia. However, dysplasia and early cancer usually develop without any clinical signs, often in individuals whose symptoms are well controlled by acid suppressant medications; therefore, endoscopic surveillance is recommended to allow for early diagnosis and timely clinical intervention. Individuals with Barrett's oesophagus need to be fully informed about the implications of this diagnosis and the benefits and risks of monitoring strategies. Pharmacological treatments are recommended for control of symptoms, but not for chemoprevention. Dysplasia and stage 1 oesophageal adenocarcinoma have excellent prognoses, since they can be cured with endoscopic or surgical therapies. Endoscopic resection is the most accurate staging technique for early Barrett's-related oesophageal adenocarcinoma. Endoscopic ablation is effective and indicated to eradicate Barrett's oesophagus in patients with dysplasia. Future research should focus on improved accuracy for dysplasia detection via new technologies and providing more robust evidence to support pathways for follow-up and treatment.

The AUGIS Survival Predictor: Prediction of Long-Term and Conditional Survival After Esophagectomy Using Random Survival Forests.

OBJECTIVE: The aim of this study was to develop a predictive model for overall survival after esophagectomy using pre/postoperative clinical data and machine learning. SUMMARY BACKGROUND DATA: For patients with esophageal cancer, accurately predicting long-term survival after esophagectomy is challenging. This study investigated survival prediction after esophagectomy using a RandomSurvival Forest (RSF) model derived from routine data from a large, well-curated, national dataset. METHODS: Patients diagnosed with esophageal adenocarcinoma or squamous cell carcinoma between 2012 and 2018 in England and Wales who underwent an esophagectomy were included. Prediction models for overall survival were developed using the RSF method and Cox regression from 41 patient and disease characteristics. Calibration and discrimination (time-dependent area under the curve) were validated internally using bootstrap resampling. RESULTS: The study analyzed 6399 patients, with 2625 deaths during follow-up. Median follow-up was 41 months. Overall survival was 47.1% at 5 years. The final RSF model included 14 variables and had excellent discrimination with a 5-year time-dependent area under the receiver operator curve of 83.9% [95% confidence interval (CI) 82.6%-84.9%], compared to 82.3% (95% CI 81.1%-83.3%) for the Cox model. The most important variables were lymph node involvement, pT stage, circumferential resection margin involvement (tumor at < 1 mm from cut edge) and age. There was a wide range of survival estimates even within TNM staging groups, with quintiles of prediction within Stage 3b ranging from 12.2% to 44.7% survival at 5 years. CONCLUSIONS: An RSF model for long-term survival after esophagectomy exhibited excellent discrimination and well-calibrated predictions. At a patient level, it provides more accuracy than TNM staging alone and could help in the delivery of tailored treatment and follow-up.

Diagnosis and treatment for gastro-oesophageal cancer in England and Wales: analysis of the National Oesophago-Gastric Cancer Audit (NOGCA) database 2012-2020.

BACKGROUND: The National Oesophago-Gastric Cancer Audit (NOGCA) captures patient data from diagnosis to end of primary treatment for all patients with oesophagogastric (OG) cancer in England and Wales. This study assessed changes in patient characteristics, treatments received, and outcomes for OG cancer surgery for the period 2012-2020, and examined which factors may have led to changes in clinical outcomes over this time. METHODS: Patients diagnosed with OG cancer between April 2012 and March 2020 were included. Descriptive statistics were used to summarize patient demographics, disease site, type, and stage, patterns of care, and outcomes over time. The treatment variables of unit case volume, surgical approach, and neoadjuvant therapy were included. Regression models were used to examine associations between surgical outcomes (duration of stay and mortality), and patient and treatment variables. RESULTS: In total, 83 393 patients diagnosed with OG cancer during the study period were included. Patient demographics and cancer stage at diagnosis showed little change over time. Altogether, 17 650 patients underwent surgery as part of radical treatment. These patients had increasingly more advanced cancers, and a greater likelihood of pre-existing comorbidity in more recent years. Significant decreases in mortality rates and duration of stay were noted, along with improvements in oncological outcomes (nodal yields and margin positivity rates). Following adjustment for patient and treatment variables, increasing audit year and trust volume were associated, respectively, with improved postoperative outcomes: lower 30-day mortality (odds ratio (OR) 0.93 (95 per cent c.i. 0.88 to 0.98) and OR 0.99 (95 per cent c.i. 0.99-0.99)) and lower 90-day mortality (OR 0.94 (95 per cent c.i. 0.91 to 0.98) and OR 0.99 (95 per cent c.i. 0.99-0.99)), and a reduction in duration of postoperative stay (incidence rate ratio (IRR) 0.98 (95 per cent c.i. 0.97 to 0.98) and IRR 0.99 (95 per cent c.i. 0.99 to 0.99)). CONCLUSION: Outcomes of OG cancer surgery have improved over time, despite little evidence of improvements in early diagnosis. The underlying drivers for improvements in outcome are multifactorial.

Impact of postoperative chemotherapy on survival for oesophagogastric adenocarcinoma after preoperative chemotherapy and surgery.

BACKGROUND: Perioperative chemotherapy is widely used in the treatment of oesophagogastric adenocarcinoma (OGAC) with a substantial survival benefit over surgery alone. However, the postoperative part of these regimens is given in less than half of patients, reflecting uncertainty among clinicians about its benefit and poor postoperative patient fitness. This study estimated the effect of postoperative chemotherapy after surgery for OGAC using a large population-based data set. METHODS: Patients with adenocarcinoma of the oesophagus, gastro-oesophageal junction or stomach diagnosed between 2012 and 2018, who underwent preoperative chemotherapy followed by surgery, were identified from a national-level audit in England and Wales. Postoperative therapy was defined as the receipt of systemic chemotherapy within 90 days of surgery. The effectiveness of postoperative chemotherapy compared with observation was estimated using inverse propensity treatment weighting. RESULTS: Postoperative chemotherapy was given to 1593 of 4139 patients (38.5 per cent) included in the study. Almost all patients received platinum-based triplet regimens (4004 patients, 96.7 per cent), with FLOT used in 3.3 per cent. Patients who received postoperative chemotherapy were younger, with a lower ASA grade, and were less likely to have surgical complications, with similar tumour characteristics. After weighting, the median survival time after postoperative chemotherapy was 62.7 months compared with 50.4 months without chemotherapy (hazard ratio 0.84, 95 per cent c.i. 0.77 to 0.94; P = 0.001). CONCLUSION: This study has shown that postoperative chemotherapy improves overall survival in patients with OGAC treated with preoperative chemotherapy and surgery.

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

OBJECTIVE: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785). DESIGN: EGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients. RESULTS: EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA. CONCLUSION: EGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.

Resource optimization for cancer pathways with aggregate diagnostic demand: a perishable inventory approach.

This work proposes a novel framework for planning the capacity of diagnostic tests in cancer pathways that considers the aggregate demand of referrals from multiple cancer specialties (sites). The framework includes an analytic tool that recursively assesses the overall daily demand for each diagnostic test and considers general distributions for both the incoming cancer referrals and the number of required specific tests for any given patient. By disaggregating the problem with respect to each diagnostic test, we are able to model the system as a perishable inventory problem that can be solved by means of generalized G/D/C queuing models, where the capacity [Formula: see text] is allowed to vary and can be seen as a random variable that is adjusted according to prescribed performance measures. The approach aims to provide public health and cancer services with recommendations to align capacity and demand for cancer diagnostic tests effectively and efficiently. Our case study illustrates the applicability of our methods on lung cancer referrals from UK's National Health Service.

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

Development and validation of a prognostic model incorporating texture analysis derived from standardised segmentation of PET in patients with oesophageal cancer.

OBJECTIVES: This retrospective cohort study developed a prognostic model incorporating PET texture analysis in patients with oesophageal cancer (OC). Internal validation of the model was performed. METHODS: Consecutive OC patients (n = 403) were chronologically separated into development (n = 302, September 2010-September 2014, median age = 67.0, males = 227, adenocarcinomas = 237) and validation cohorts (n = 101, September 2014-July 2015, median age = 69.0, males = 78, adenocarcinomas = 79). Texture metrics were obtained using a machine-learning algorithm for automatic PET segmentation. A Cox regression model including age, radiological stage, treatment and 16 texture metrics was developed. Patients were stratified into quartiles according to a prognostic score derived from the model. A p-value < 0.05 was considered statistically significant. Primary outcome was overall survival (OS). RESULTS: Six variables were significantly and independently associated with OS: age [HR =1.02 (95% CI 1.01-1.04), p < 0.001], radiological stage [1.49 (1.20-1.84), p < 0.001], treatment [0.34 (0.24-0.47), p < 0.001], log(TLG) [5.74 (1.44-22.83), p = 0.013], log(Histogram Energy) [0.27 (0.10-0.74), p = 0.011] and Histogram Kurtosis [1.22 (1.04-1.44), p = 0.017]. The prognostic score demonstrated significant differences in OS between quartiles in both the development (X2 143.14, df 3, p < 0.001) and validation cohorts (X2 20.621, df 3, p < 0.001). CONCLUSIONS: This prognostic model can risk stratify patients and demonstrates the additional benefit of PET texture analysis in OC staging. KEY POINTS: • PET texture analysis adds prognostic value to oesophageal cancer staging. • Texture metrics are independently and significantly associated with overall survival. • A prognostic model including texture analysis can help risk stratify patients.

WITHDRAWN: Systemic treatments for metastatic cutaneous melanoma.

BACKGROUND: Systemic therapies for metastatic cutaneous melanoma, the most aggressive of all skin cancers, remain disappointing. Few lasting remissions are achieved and the therapeutic aim remains one of palliation.Many agents are used alone or in combination with varying degrees of toxicity and cost. It is unclear whether evidence exists to support these complex regimens over best supportive care / placebo. OBJECTIVES: To review the benefits from the use of systemic therapies in metastatic cutaneous melanoma compared to best supportive care/placebo, and to establish whether a 'standard' therapy exists which is superior to other treatments. SEARCH METHODS: Randomised controlled trials were identified from the MEDLINE, EMBASE and CCTR/CENTRAL databases. References, conference proceedings, and Science Citation Index/Scisearch were also used to locate trials. Cancer registries and trialists were also contacted. SELECTION CRITERIA: Randomised controlled trials of adults with histologically proven metastatic cutaneous melanoma in which systemic anti-cancer therapy was compared with placebo or supportive care. DATA COLLECTION AND ANALYSIS: Study selection was performed by two independent reviewers. Data extraction forms were used for studies which appeared to meet the selection criteria and, where appropriate, full text articles were retrieved and reviewed independently. MAIN RESULTS: No randomised controlled trials were found comparing a systemic therapy with placebo or best supportive care in metastatic cutaneous melanoma. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled clinical trials to show superiority of systemic therapy over best supportive care / placebo in the treatment of malignant cutaneous melanoma.Given that patients with metastatic melanoma frequently receive systemic therapy, it is our pragmatic view that a future systematic review could compare any systemic treatment, or combination of treatments, to single agent dacarbazine.

Update on Neoadjuvant Regimens for Patients with Operable Oesophageal/Gastrooesophageal Junction Adenocarcinomas and Squamous Cell Carcinomas.

Survival outcomes following multimodal treatment of operable oesophageal and gastrooesophageal cancer remain disappointingly poor. Although an appreciation of the impact of both tumour location and histological subtype is now shaping the design of clinical trials, there has been a lack of consensus of the optimal neoadjuvant treatment strategy. This update article will review recent advances in the use of both neoadjuvant chemotherapy and chemoradiotherapy. The emerging role of PET imaging to direct appropriate neoadjuvant treatment regimens and the additive benefit of biological agents are also discussed.

Management of Barrett's high-grade dysplasia: initial results from a population-based national audit.

BACKGROUND AND AIMS: Previous studies reported significant variation in the management of patients with Barrett's esophagus. However, these are based on self-reported clinical practice. The aim of this study was to examine the management of high-grade dysplasia in Barrett's esophagus in England by using patient-level data and to compare practice with guidelines. METHODS: From April 2012 to March 2013, National Health Service (NHS) trusts in England prospectively collected data on patients newly diagnosed with high-grade dysplasia (HGD) of the esophagus as part of the National Oesophago-Gastric Cancer Audit. Data were collected on patient characteristics, diagnosis and endoscopic findings, treatment planning, and therapy. RESULTS: Between April 2012 and March 2013, NHS trusts reported 465 cases of HGD. Diagnosis was confirmed by a second pathologist in 79.4% of cases (270/340), and 86.0% (374/465) had their treatment planned at a multidisciplinary team meeting. A total of 290 patients (62.4%) were managed endoscopically (frequently with endoscopic resection or radiofrequency ablation), whereas 26 patients (5.6%) had esophagectomy. The proportion of patients managed by surveillance varied by age (P < .001), ranging from 19.5% in patients aged <65 years to 63.8% in patients aged ≥85 years. More patients received active treatment if their cases were discussed at a multidisciplinary meeting (73.5% vs 44.3%; P < .001) or managed at higher-volume trusts (87.8% vs 55.4%; P < .001). CONCLUSIONS: There was marked variation in the management of HGD across England, with a third of patients receiving no active treatment. Patients discussed at a specialist multidisciplinary meeting or managed in high-volume trusts were more likely to receive active treatment.

Gastric Cancers Missed During Endoscopy in England.

BACKGROUND & AIMS: Single-center studies have estimated that 4.6% to 25.8% of gastric cancers are missed at endoscopy. We performed a population-based study to make a more precise estimate of factors associated with missed lesions in England. METHODS: We performed a retrospective population-based observational cohort study of 2727 patients diagnosed with gastric cancer from April 2011 through March 2012 in England, using linked records from 3 national data sets. The primary outcome was the proportion of patients who had undergone endoscopy in the 3 to 36 months before a diagnosis of gastric cancer. We determined this proportion for the entire cohort and for subgroups. RESULTS: Of the 2727 patients in the cohort, 8.3% (95% confidence interval, 7.2%-9.3%) underwent endoscopic evaluation in the 3 to 36 months before their diagnosis of gastric cancer. An endoscopy within 3 to 36 months of diagnosis was associated with a diagnosis of early stage cancer (stages 0 or 1, 11.5%; stage 2, 7.9%; stages 3 or 4, 6.9%; P = .01 for stage 0 or 1 vs stage 2 or greater), younger age at diagnosis (<55 y, 13.3% vs ≥55 y, 7.8%; P = .03), and female sex (10% of women vs 7.3% of men; P = .01). Gastric ulcers were detected in 15% of endoscopies performed at any time in the 3 years before cancer diagnosis, and in 64% of endoscopies performed 3 to 6 months before a diagnosis of gastric cancer. CONCLUSIONS: Based on a retrospective analysis of medical records in England, in 8.3% of patients with gastric cancer, their cancer was missed at endoscopy within the 3 previous years. A previous endoscopy detected benign gastric ulcers more frequently than any other lesion in patients who later were diagnosed with gastric cancer.

NEOSCOPE: a randomised Phase II study of induction chemotherapy followed by either oxaliplatin/capecitabine or paclitaxel/carboplatin based chemoradiation as pre-operative regimen for resectable oesophageal adenocarcinoma.

BACKGROUND: Both oxaliplatin/capecitabine-based chemoradiation (OXCAP-RT) and carboplatin-paclitaxel based radiation (CarPac-RT) are active regimens in oesophageal adenocarcinoma, but no randomised study has compared their efficacy and toxicity. This randomised phase II "pick a winner" trial will identify the optimum regimen to take forward to a future phase III trial against neo-adjuvant chemotherapy, the current standard in the UK. METHODS/DESIGN: Patients with resectable adenocarcinoma of the oesophagus or Siewert Type 1-2 gastro-oesophageal junction (GOJ), ≥T3 and/or ≥ N1 are eligible for the study. Following two cycles of induction OXCAP chemotherapy (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m(2) D1-21, q 3 wk), patients are randomised 1:1 to OXCAP-RT (oxaliplatin 85 mg/m(2) Day 1,15,29; capecitabine 625 mg/m(2) twice daily on days of RT; RT-45 Gy/25 fractions/5 weeks) or CarPac-RT (Carboplatin AUC2 and paclitaxel 50 mg/m2 Day 1,8,15,22,29; RT-45 Gy/25 fractions/5 weeks). Restaging CT/PET-CT is performed 4-6 weeks after CRT, and a two-phase oesophagectomy with two-field lymphadenectomy is performed six to eight weeks after CRT. The primary end-point is pathological complete response rate (pCR) at resection and will include central review. Secondary endpoints include: recruitment rate, toxicity, 30-day surgical morbidity/mortality, resection margin positivity rate and overall survival (median, 3- and 5-yr OS. 76 patients (38/arm) gives 90% power and one-sided type 1 error of 10% if patients on one novel treatment have a response rate of 35% while the second treatment has a response rate of 15%. A detailed RT Quality Assurance (RTQA) programme includes a detailed RT protocol and guidance document, pre-accrual RT workshop, outlining exercise, and central evaluation of contouring and planning. This trial has been funded by Cancer Research UK (C44694/A14614), sponsored by Velindre NHS Trust and conducted through the Wales Cancer Trials Unit at Cardiff University on behalf of the NCRI Upper GI CSG. DISCUSSION: Following encouraging results from previous trials, there is an interest in neo-adjuvant chemotherapy and CRT containing regimens for treatment of oesophageal adenocarcinoma. NEOSCOPE will first establish the efficacy, safety and feasibility of two different neo-adjuvant CRT regimens prior to a potential phase III trial. TRIAL REGISTRATION: Eudract No: 2012-000640-10. ClinicalTrials.gov: NCT01843829 .

A population-based, retrospective, cohort study of esophageal cancer missed at endoscopy.

BACKGROUND AND STUDY AIMS: Several studies have suggested that a significant minority of esophageal cancers are missed at endoscopy The aim of this study was to estimate the proportion of esophageal cancers missed at endoscopy on a national level, and to investigate the relationship between miss rates and patient and tumor characteristics. PATIENTS AND METHODS: This retrospective, population-based, cohort study identified patients diagnosed with esophageal cancer between April 2011 and March 2012 in England, using two linked databases (National Oesophago-Gastric Cancer Audit and Hospital Episode Statistics). The main outcome was the rate of previous endoscopy within 3 - 36 months of cancer diagnosis. This was calculated for the overall cohort and by patient characteristics, including tumor site and disease stage. RESULTS: A total of 6943 new cases of esophageal cancer were identified, of which 7.8 % (95 % confidence interval 7.1 - 8.4) had undergone endoscopy in the 3 - 36 months preceding diagnosis. Of patients with stage 0/1 cancers, 34.0 % had undergone endoscopy in the 3 - 36 months before diagnosis compared with 10.0 % of stage 2 cancers and 4.5 % of stage 3/4 cancers. Of patients with stage 0/1 cancers, 22.1 % were diagnosed after ≥ 3 endoscopies in the previous 3 years. Patients diagnosed with an upper esophageal lesion were more likely to have had an endoscopy in the previous 3 - 12 months (P = 0.040). The most common diagnosis at previous endoscopy was an esophageal ulcer (48.2 % of investigations). CONCLUSION: Esophageal cancer may be missed at endoscopy in up to 7.8 % of patients who are subsequently diagnosed with cancer. Endoscopists should make a detailed examination of the whole esophageal mucosa to avoid missing subtle early cancers and lesions in the proximal esophagus. Patients with an esophageal cancer may be misdiagnosed as having a benign esophageal ulcer.

Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial.

BACKGROUND: In the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer. METHODS: In this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m(2) on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m(2) twice daily on days 1-21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0-1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m(2) once per week) or capecitabine (830 mg/m(2) twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987. FINDINGS: 114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6-73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4-63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9-19·2) in the capecitabine group and 13·4 months (95% CI 11·0-15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18-0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1-89·5) in the capecitabine group and 64·2 (95% CI 46·4-77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2-14·6) in the capecitabine group and 10·4 months (95% CI 8·9-12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32-1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3-4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy. Of the 34 patients in the capecitabine group who received chemoradiotherapy, 25 (74%) received the full protocol dose of radiotherapy, compared with 26 (68%) of 38 patients in the gemcitabine group. Quality-of-life scores were not significantly different between the treatment groups. INTERPRETATION: Our results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer. However, these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small. FUNDING: Cancer Research UK.

Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

BACKGROUND: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. METHODS: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. FINDINGS: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). INTERPRETATION: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. FUNDING: Amgen, UK National Institute for Health Research Biomedical Research Centre.

Performance on a relational integration task is impaired during hangover.

Recently, researchers have proposed an updated model of executive functions that includes relational integration, the mental ability to bind information into more complex structures. Hangover is known to disrupt other core components of executive functions, but little is known about how it influences relational integration. Therefore, this study aimed to investigate how hangover influences performance on a relational integration task. Twenty-seven participants completed an online relational integration task, mood and emotion regulation questionnaires during a hangover and no-hangover condition in this naturalistic design study. Results indicated that relational integration was impaired in hangover (p < 0.001, ηp2 = 0.562) relative to the no-hangover condition. In addition, participants experienced greater difficulties in regulating emotions (p < 0.001, d = 0.85) and lower mood (p < 0.001, d = 0.88) during hangover. These results suggest that relational integration is impaired in hangover and add weight to the argument that cognitive impairments in hangover may be due to the hangover-related impact on domain-general processing resources.

Modelling lung cancer diagnostic pathways using discrete event simulation.

The United Kingdom has one of the poorest lung cancer survival rates in Europe. In this study, to help design and evaluate a single lung cancer pathway (SCP) for Wales, existing diagnostic pathways and processes have been mapped and then modelled with a discrete event simulation. The validated models have been used to provide key performance indicators and to examine different diagnostic testing strategies. Under the current diagnostic pathways, the mean time to treatment was 72 days for surgery patients, 56 days for chemotherapy patients, and 61 days for radiotherapy patients. Our research demonstrated that by ensuring that the patient attends their first outpatient appointment within 7 days and streamlining the diagnostic tests would have the potential to remove approximately 11 days from the current lung cancer pathway resulting in a 21% increase in patients receiving treatment within the Welsh Government set target of 62 days.

Reporting of short-term clinical outcomes after esophagectomy: a systematic review.

OBJECTIVE: This review summarizes reporting of complications of esophageal cancer surgery. BACKGROUND: Accurate assessment of morbidity and mortality after surgery for cancer is essential to compare centers, allow data synthesis, and inform clinical decision-making. A lack of defined standards may distort clinically relevant treatment effects. METHODS: Systematic literature searches identified articles published between 2005 and 2009 reporting morbidity and mortality after esophagectomy for cancer. Data were analyzed for frequency of complication reporting and to check whether outcomes were defined and classified for severity and whether a validated system for grading complications was used. Information about reporting outcomes adjusting for baseline risk factors was collated, and a descriptive summary of the results of included outcomes was undertaken. RESULTS: Of 3458 abstracts, 224 full papers were reviewed and 122 were included (17 randomized trials and 105 observational studies), reporting outcomes of 57,299 esophagectomies. No single complication was reported in all papers, and 60 (60.6%) did not define any of the measured complications. Anastomotic leak was the most commonly reported morbidity, assessed in 80 (80.1%) articles, defined in 28 (28.3%), but 22 different descriptions were used. Five papers (5.1%) categorized morbidity with a validated grading system. One hundred fifteen papers reported postoperative mortality rates, 25 defining the term using 10 different definitions. In-hospital mortality was the most commonly used term for postoperative death, with 6 different interpretations of this phrase. Eighteen papers adjusted outcomes for baseline risk factors and 60 presented baseline measures of comorbidity. CONCLUSIONS: Outcome reporting after esophageal cancer surgery is heterogeneous and inconsistent, and it lacks methodological rigor. A consensus approach to reporting clinical outcomes should be considered, and at the minimum it is recommended that a "core outcome set" is defined and used in all studies reporting outcomes of esophageal cancer surgery. This will allow meaningful cross study comparisons and analyses to evaluate surgery.