The impact of endoscopic ultrasound on the management and outcome of patients with oesophageal cancer: an update of a systematic review.

AIM: To provide an updated systematic review concerning the impact of endoscopic ultrasound (EUS) in the modern era of oesophageal cancer staging. MATERIALS AND METHODS: To update the previous systematic review, databases including MEDLINE and EMBASE were searched and studies published from 2005 onwards were selected. Studies reporting primary data in patients with oesophageal or gastro-oesophageal junction cancer who underwent radiological staging and treatment, regardless of intent, were included. The primary outcome was the reported change in management after EUS. Secondary outcomes were recurrence rate and overall survival. Two reviewers extracted data from included articles. This study was registered with PROSPERO (CRD42021231852). RESULTS: Eighteen studies with 11,836 patients were included comprising 2,805 patients (23.7%) who underwent EUS compared to 9,031 (76.3%) without EUS examination. Reported change of management varied widely from 0% to 56%. When used, EUS fine-needle aspiration precluded curative treatment in 37.5%-71.4%. Overall survival improvements ranged between 121 and 639 days following EUS intervention compared to patients without EUS. Smaller effect sizes were observed in a randomised controlled trial, compared to larger differences reported in observational studies. CONCLUSION: Current evidence for the effectiveness of EUS in oesophageal cancer pathways is conflicting and of limited quality. In particular, the extent to which EUS adds value to contemporary cross-sectional imaging techniques is unclear and requires formal re-evaluation.

Variation in histopathological assessment and association with surgical quality indicators following oesophagectomy.

BACKGROUND: Histopathological outcomes, such as lymph node yield and margin positivity, are used to benchmark and assess surgical centre quality, and are reported annually by the National Oesophago-Gastric Cancer Audit (NOGCA) in England and Wales. The variation in pathological specimen assessment and how this affects these outcomes is not known. METHODS: A survey of practice was circulated to all tertiary oesophagogastric cancer centres across England and Wales. Questions captured demographic data, and information on how specimens were prepared and analysed. National performance data were retrieved from the NOGCA. Survey results were compared for tertiles of lymph node yield, and circumferential and longitudinal margins. RESULTS: Survey responses were received from 32 of 37 units (86 per cent response rate), accounting for 93.1 per cent of the total oesophagectomy volume in England and Wales. Only 5 of 32 units met or exceeded current guidelines on specimen preparation according to the Royal College of Pathologists guidelines. There was wide variation in how centres defined positive (R1) margins, and how margins and lymph nodes were assessed. Centres with the highest nodal yield were more likely to use systematic fat blocking, and to re-examine specimens when the initial load was low. Systematic blocking of lesser curve fat resulted in significantly higher rates of patients with at least 15 lymph nodes examined (91.4 versus 86.5 per cent; P = 0.027). CONCLUSION: Preparation and histopathological assessment of specimens varies significantly across institutions. This challenges the validity of currently used surgical quality metrics for oesophageal and other tumours.

Prediction of long-term survival after gastrectomy using random survival forests.

BACKGROUND: No well validated and contemporaneous tools for personalized prognostication of gastric adenocarcinoma exist. This study aimed to derive and validate a prognostic model for overall survival after surgery for gastric adenocarcinoma using a large national dataset. METHODS: National audit data from England and Wales were used to identify patients who underwent a potentially curative gastrectomy for adenocarcinoma of the stomach. A total of 2931 patients were included and 29 clinical and pathological variables were considered for their impact on survival. A non-linear random survival forest methodology was then trained and validated internally using bootstrapping with calibration and discrimination (time-dependent area under the receiver operator curve (tAUC)) assessed. RESULTS: The median survival of the cohort was 69 months, with a 5-year survival of 53.2 per cent. Ten variables were found to influence survival significantly and were included in the final model, with the most important being lymph node positivity, pT stage and achieving an R0 resection. Patient characteristics including ASA grade and age were also influential. On validation the model achieved excellent performance with a 5-year tAUC of 0.80 (95 per cent c.i. 0.78 to 0.82) and good agreement between observed and predicted survival probabilities. A wide spread of predictions for 3-year (14.8-98.3 (i.q.r. 43.2-84.4) per cent) and 5-year (9.4-96.1 (i.q.r. 31.7-73.8) per cent) survival were seen. CONCLUSIONS: A prognostic model for survival after a potentially curative resection for gastric adenocarcinoma was derived and exhibited excellent discrimination and calibration of predictions.

In this study the authors used a large nationwide dataset from England and Wales and tried to make a predictive model that estimated how long patients would survive after surgery for gastric cancer. They found that using a machine learning methodology provided excellent results and accuracy in predictions, significantly in excess of any other published model and traditional staging methods. The model will be useful to provide individualized prediction of survival to patients and in the future could be used to stratify treatments.

Machine learning to predict early recurrence after oesophageal cancer surgery.

BACKGROUND: Early cancer recurrence after oesophagectomy is a common problem, with an incidence of 20-30 per cent despite the widespread use of neoadjuvant treatment. Quantification of this risk is difficult and existing models perform poorly. This study aimed to develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multinational cohort and machine learning approaches. METHODS: Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in one Dutch and six UK oesophagogastric units were analysed. Using clinical characteristics and postoperative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and extreme gradient boosting (XGB). Finally, a combined (ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model. RESULTS: A total of 812 patients were included. The recurrence rate at less than 1 year was 29·1 per cent. All of the models demonstrated good discrimination. Internally validated areas under the receiver operating characteristic (ROC) curve (AUCs) were similar, with the ensemble model performing best (AUC 0·791 for ELR, 0·801 for RF, 0·804 for XGB, 0·805 for ensemble). Performance was similar when internal-external validation was used (validation across sites, AUC 0·804 for ensemble). In the final model, the most important variables were number of positive lymph nodes (25·7 per cent) and lymphovascular invasion (16·9 per cent). CONCLUSION: The model derived using machine learning approaches and an international data set provided excellent performance in quantifying the risk of early recurrence after surgery, and will be useful in prognostication for clinicians and patients.

ANTECEDENTES: la recidiva precoz del cáncer tras esofaguectomía es un problema frecuente con una incidencia del 20-30% a pesar del uso generalizado del tratamiento neoadyuvante. La cuantificación de este riesgo es difícil y los modelos actuales funcionan mal. Este estudio se propuso desarrollar un modelo predictivo para la recidiva precoz después de la cirugía para el adenocarcinoma de esófago utilizando una gran cohorte multinacional y enfoques con aprendizaje automático. MÉTODOS: Se analizaron pacientes consecutivos sometidos a esofaguectomía por adenocarcinoma y que recibieron tratamiento neoadyuvante en 6 unidades de cirugía esofagogástrica del Reino Unido y 1 de los Países Bajos. Con la utilización de características clínicas y la histopatología postoperatoria se generaron modelos mediante regresión de red elástica (elastic net regression, ELR) y métodos de aprendizaje automático Random Forest (RF) y XG boost (XGB). Finalmente, se generó un modelo combinado (Ensemble) de dichos métodos. La importancia relativa de los factores respecto al resultado se calculó como porcentaje de contribución al modelo. RESULTADOS: En total se incluyeron 812 pacientes. La tasa de recidiva a menos de 1 año fue del 29,1%. Todos los modelos demostraron una buena discriminación. Las áreas bajo la curva ROC (AUC) validadas internamente fueron similares, con el modelo Ensemble funcionando mejor (ELR = 0,791, RF = 0,801, XGB = 0,804, Ensemble = 0,805). El rendimiento fue similar cuando se utilizaba validación interna-externa (validación entre centros, Ensemble AUC = 0,804). En el modelo final, las variables más importantes fueron el número de ganglios linfáticos positivos (25,7%) y la invasión linfovascular (16,9%). CONCLUSIÓN: El modelo derivado con la utilización de aproximaciones con aprendizaje automático y un conjunto de datos internacional proporcionó un rendimiento excelente para cuantificar el riesgo de recidiva precoz tras la cirugía y será útil para clínicos y pacientes a la hora de establecer un pronóstico.

Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma.

BACKGROUND: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma. METHODS: A questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Records of consecutive patients undergoing oesophagogastric resection at seven centres between January 2000 and December 2013 were reviewed. Pathological response to neoadjuvant chemotherapy was assessed using the Mandard Tumour Regression Grade (TRG) and lymph node downstaging. RESULTS: TRG (8 of 11 centres) was the most widely used system to assess response to neoadjuvant chemotherapy, but there was discordance on how it was used in practice. Of 1392 patients, 1293 had TRG assessment; data were available for clinical and pathological nodal status (cN and pN) in 981 patients, and TRG, cN and pN in 885. There was a significant difference in survival between responders (TRG 1-2; median overall survival (OS) not reached) and non-responders (TRG 3-5; median OS 2·22 (95 per cent c.i. 1·94 to 2·51) years; P < 0·001); the hazard ratio was 2·46 (95 per cent c.i. 1·22 to 4·95; P = 0·012). Among local non-responders, the presence of lymph node downstaging was associated with significantly improved OS compared with that of patients without lymph node downstaging (median OS not reached versus 1·92 (1·68 to 2·16) years; P < 0·001). CONCLUSION: A clinically meaningful local response to neoadjuvant chemotherapy was restricted to the small minority of patients (14·8 per cent) with TRG 1-2. Among local non-responders, a subset of patients (21·3 per cent) derived benefit from neoadjuvant chemotherapy by lymph node downstaging and their survival mirrored that of local responders.

Systematic review and meta-analysis of immunohistochemical prognostic biomarkers in resected oesophageal adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma (OAC) is one of the fastest rising malignancies with continued poor prognosis. Many studies have proposed novel biomarkers but, to date, no immunohistochemical markers of survival after oesophageal resection have entered clinical practice. Here, we systematically review and meta-analyse the published literature, to identify potential biomarkers. METHODS: Relevant articles were identified via Ovid medline 1946-2013. For inclusion, studies had to conform to REporting recommendations for tumor MARKer (REMARK) prognostic study criteria. The primary end-point was a pooled hazard ratio (HR) and variance, summarising the effect of marker expression on prognosis. RESULTS: A total of 3059 articles were identified. After exclusion of irrelevant titles and abstracts, 214 articles were reviewed in full. Nine molecules had been examined in more than one study (CD3, CD8, COX-2, EGFR, HER2, Ki67, LgR5, p53 and VEGF) and were meta-analysed. Markers with largest survival effects were COX-2 (HR=2.47, confidence interval (CI)=1.15-3.79), CD3 (HR=0.51, 95% CI=0.32-0.70), CD8 (HR=0.55, CI=0.31-0.80) and EGFR (HR=1.65, 95% CI=1.14-2.16). DISCUSSION: Current methods have not delivered clinically useful molecular prognostic biomarkers in OAC. We have highlighted the paucity of good-quality robust studies in this field. A genome-to-protein approach would be better suited for the development and subsequent validation of biomarkers. Large collaborative projects with standardised methodology will be required to generate clinically useful biomarkers.

A prospective comparison of totally minimally invasive versus open Ivor Lewis esophagectomy.

The majority of esophagectomies in Western parts of the world are performed by a transthoracic approach reflecting the prevalence of adenocarcinoma of the lower esophagus or esophagogastric junction. Minimally invasive esophagectomy (MIE) has been reported in a variety of formats, but there are no series that directly compare totally minimally invasive thoracolaparoscopic 2 stage esophagectomy (MIE-2) with open Ivor Lewis (IVL). A prospective single-center cohort study of patients undergoing elective MIE-2 or IVL between January 2005 and November 2010 was performed. Short-term clinicopathologic outcomes were recorded using validated systems. One hundred and six patients (median age 66, range 36-85, 88 M : 18 F) underwent two-stage esophagectomy (53 MIE-2 and 53 IVL). Patient demographics (age, sex, body mass index, American Society of Anesthesiologists grade, tumor characteristics, neoadjuvant chemotherapy, and TNM stage) were comparable between the two groups. Outcomes for MIE-2 and IVL were comparable for anastomotic leak rates (5 [9%] vs. 2 [4%], P= 0.241), resection margin clearance (R0) (43 [81%] vs. 38 [72%], P= 0.253), median lymph node yield (19 vs. 18, P= 0.584), and median length of stay (12 [range 7-91] vs. 12 [range 7-101] days), respectively. Blood loss was significantly less for MIE-2 compared with IVL (median 300 [range 0-1250] mL vs. 400 [range 0-3000] mL, respectively, P= 0.021). MIE-2 in this series of selected patients supports its efficacy, when performed by an experienced minimally invasive surgical team. A well-designed multicenter trial addressing clinical effectiveness is now required.

Oesophageal cancer: The effect of early nutrition support on clinical outcomes.

BACKGROUND AND AIMS: Malnutrition is prevalent in oesophageal cancer. Evidence for the use of nutrition support and prehabilitation in this cohort is variable. The aim of this study was to examine the effect of early nutrition support and functional measures of nutritional status on post-operative outcomes in adult patients with oesophageal cancer. METHODS: Retrospective review of adults with oesophageal cancer undergoing oesophagectomy (n = 151). Early nutrition support was defined as: oral or enteral nutrition supplementation during neoadjuvant treatment. Late nutrition support defined as: oral or enteral nutrition supplementation prescribed post-operatively. Nutrition outcome measures were; percentage weight loss from 3 to 6 months prior to diagnosis, peri- and post-operatively, and pre-operative assessment of handgrip-strength (HGS). RESULTS: Pre-operative weight loss ≥10% was a significant predictor of mortality at 1 year (OR 2.84, 95%CI 1.03-7.83, p = 0.04) independent of tumour stage, adjuvant treatment, age and gender. Adults prescribed early nutrition support during neoadjuvant treatment experienced less weight loss at 12-months post-oesophagectomy compared to adults prescribed late oral nutrition support (p=<0.05). Pre-operative HGS measurements were not a useful predictor of postoperative complications (p = 0.2), length of stay (p = 0.9) or 90-day mortality (p = 0.6). CONCLUSIONS: Pre-operative weight loss ≥10% was associated with mortality. Early nutrition support was associated with less weight loss at 12-months post-operatively. Pre-operative HGS measures did not have prognostic value as a stand-alone measure. Future work should investigate the efficacy of early nutrition support in reducing both pre- and post-operative weight loss to improve nutritional status and surgical outcomes as part of a multimodal prehabilitation programme in adults with oesophageal cancer.

A minimum core outcome dataset for the reporting of preclinical chemotherapeutic drug studies: Lessons learned from multiple discordant methodologies in the setting of colorectal cancer.

In vivo studies in animal models are critical tools necessary to study the fundamental complexity of carcinogenesis. A constant strive to improve animal models in cancer exists, especially those investigating the use of chemotherapeutic effectiveness. In the present systematic review, colorectal cancer (CRC) is used as an example to highlight and critically evaluate the range of reporting strategies used when investigating chemotherapeutic agents in the preclinical setting. A systematic review examining the methodology and reporting of preclinical chemotherapeutic drug studies using CRC murine models was conducted. A total of 45 studies were included in this systematic review. The literature was found to be highly heterogeneous with various cell lines, animal strains, animal ages and chemotherapeutic compounds/regimens tested, proving difficult to compare outcomes between similar studies or indeed gain any significant insight into which chemotherapeutic regimen caused adverse events. From this analysis we propose a minimum core outcome dataset that could be regarded as a standardised way of reporting results from in vivo experimentation.