A Population-based Study on Lymph Node Retrieval in Patients with Esophageal Cancer: Results from the Dutch Upper Gastrointestinal Cancer Audit

Background: For esophageal cancer, the number of retrieved lymph nodes (LNs) is often used as a quality indicator. The aim of this study is to analyze the number of retrieved LNs in The Netherlands, assess factors associated with LN yield, and explore the association with short-term outcomes. This is a population-based study on lymph node retrieval in patients with esophageal cancer, presenting results from the Dutch Upper Gastrointestinal Cancer Audit. Study Design: For this retrospective national cohort study, patients with esophageal carcinoma who underwent esophagectomy between 2011 and 2016 were included. The primary outcome was the number of retrieved LNs. Univariable and multivariable regression analyses were used to test for association with ≥ 15 LNs. Patients and Results: 3970 patients were included. Between 2011 and 2016, the median number of LNs increased from 15 to 20. Factors independently associated with ≥ 15 LNs were: 0–10 kg preoperative weight loss (versus: unknown weight loss, odds ratio [95% confidence interval]: 0.71 [0.57–0.88]), Charlson score 0 (versus: Charlson score 2: 0.76 [0.63–0.92]), cN2 category (reference: cN0, 1.32 [1.05–1.65]), no neoadjuvant therapy and neoadjuvant chemotherapy (reference: neoadjuvant chemoradiotherapy, 1.73 [1.29–2.32] and 2.15 [1.54–3.01]), minimally invasive transthoracic (reference: open transthoracic, 1.46 [1.15–1.85]), open transthoracic (versus open and minimally invasive transhiatal, 0.29 [0.23–0.36] and 0.43 [0.32–0.59]), hospital volume of 26–50 or > 50 resections/year (reference: 0–25, 1.94 [1.55–2.42] and 3.01 [2.36–3.83]), and year of surgery [reference: 2011, odds ratios (ORs) 1.48, 1.53, 2.28, 2.44, 2.54]. There was no association of ≥ 15 LNs with short-term outcomes. Conclusions: The number of LNs retrieved increased between 2011 and 2016. Weight loss, Charlson score, cN category, neoadjuvant therapy, surgical approach, year of resection, and hospital volume were all associated with increased LN yield. Retrieval of ≥ 15 LNs was not associated with increased postoperative morbidity/mortality

Biopsy proportion of tumour predicts pathological tumour response and benefit from chemotherapy in resectable oesophageal carcinoma –results from the UK MRC OE02 trial

Background Neoadjuvant chemotherapy followed by surgery is the standard of care for UK patients with locally advanced resectable oesophageal carcinoma (OeC). However, not all patients benefit from multimodal treatment and there is a clinical need for biomarkers which can identify chemotherapy responders. This study investigated whether the proportion of tumour cells per tumour area (PoT) measured in the pre-treatment biopsy predicts chemotherapy benefit for OeC patients. Patients and methods PoT was quantified using digitized haematoxylin/eosin stained pre-treatment biopsy slides from 281 OeC patients from the UK MRC OE02 trial (141 treated by surgery alone (S); 140 treated by 5-fluorouracil/cisplatin followed by surgery (CS)). The relationship between PoT and clinicopathological data including tumour regression grade (TRG), overall survival and treatment interaction was investigated. Results PoT was associated with chemotherapy benefit in a non-linear fashion (test for interaction, P=0·006). Only patients with a biopsy PoT between 40% and 70% received a significant survival benefit from neoadjuvant chemotherapy (N=129; HR (95%CI):1·94 (1·39-2·71), unlike those with lower or higher PoT (PoT70% (N=28, HR:0·65 (0·36-1·18)). High pre-treatment PoT was related to lack of primary tumour regression (TRG 4 or 5), P=0·0402. Conclusion This is the first study to identify in a representative subgroup of patients from a large randomized phase III trial in OeC patients that the proportion of tumour in the pre- chemotherapy biopsy predicts benefit from chemotherapy and may be a clinically useful biomarker for patient treatment stratification. Key message Proportion of tumour is a novel biomarker which can be measured in the pre- treatment diagnostic biopsy and which may enable the identification of chemotherapy responders and non-responders among patients with oesophageal carcinoma. Proportion of tumour could easily become part of the routine reporting of oesophageal cancer biopsies and may aid in managing patients with borderline resectable cancer

Preoperative image-guided identification of response to neoadjuvant chemoradiotherapy in esophageal cancer (PRIDE):a multicenter observational study

BACKGROUND: Nearly one third of patients undergoing neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal cancer have a pathologic complete response (pCR) of the primary tumor upon histopathological evaluation of the resection specimen. The primary aim of this study is to develop a model that predicts the probability of pCR to nCRT in esophageal cancer, based on diffusion-weighted magnetic resonance imaging (DW-MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and (18)F-fluorodeoxyglucose positron emission tomography with computed tomography ((18)F-FDG PET-CT). Accurate response prediction could lead to a patient-tailored approach with omission of surgery in the future in case of predicted pCR or additional neoadjuvant treatment in case of non-pCR. METHODS: The PRIDE study is a prospective, single arm, observational multicenter study designed to develop a multimodal prediction model for histopathological response to nCRT for esophageal cancer. A total of 200 patients with locally advanced esophageal cancer - of which at least 130 patients with adenocarcinoma and at least 61 patients with squamous cell carcinoma - scheduled to receive nCRT followed by esophagectomy will be included. The primary modalities to be incorporated in the prediction model are quantitative parameters derived from MRI and (18)F-FDG PET-CT scans, which will be acquired at fixed intervals before, during and after nCRT. Secondary modalities include blood samples for analysis of the presence of circulating tumor DNA (ctDNA) at 3 time-points (before, during and after nCRT), and an endoscopy with (random) bite-on-bite biopsies of the primary tumor site and other suspected lesions in the esophagus as well as an endoscopic ultrasonography (EUS) with fine needle aspiration of suspected lymph nodes after finishing nCRT. The main study endpoint is the performance of the model for pCR prediction. Secondary endpoints include progression-free and overall survival. DISCUSSION: If the multimodal PRIDE concept provides high predictive performance for pCR, the results of this study will play an important role in accurate identification of esophageal cancer patients with a pCR to nCRT. These patients might benefit from a patient-tailored approach with omission of surgery in the future. Vice versa, patients with non-pCR might benefit from additional neoadjuvant treatment, or ineffective therapy could be stopped. TRIAL REGISTRATION: The article reports on a health care intervention on human participants and was prospectively registered on March 22, 2018 under ClinicalTrials.gov Identifier: NCT03474341

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: A stepped-wedge cluster randomised trial

Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. Methods: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. Discussion: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care

Hunting for dark halo substructure using submilliarcsecond-scale observations of macrolensed radio jets

Dark halo substructure may reveal itself through secondary, small-scale gravitational lensing effects on light sources that are macrolensed by a foreground galaxy. Here, we explore the prospects of using Very Long Baseline Interferometry (VLBI) observations of multiply-imaged quasar jets to search for submilliarcsecond-scale image distortions produced by various forms of dark substructures in the 1e3-1e8 Msolar mass range. We present lensing simulations relevant for the angular resolutions attainable with the existing European VLBI Network (EVN), the global VLBI array, and an upcoming observing mode in which the Atacama Large Millimeter Array (ALMA) is connected to the global VLBI array. While observations of this type would not be sensitive to standard cold dark matter subhalos, they can be used to detect more compact forms of halo substructure predicted in alternative structure formation scenarios. By mapping ~5 strongly lensed systems, it should be possible to detect or robustly rule out primordial black holes in the 1e3-1e6 Msolar mass range if they constitute >1% percent of the dark matter in these lenses. Ultracompact minihalos are harder to detect using this technique, but 1e6-1e8 Msolar ultracompact minihalos could in principle be detected if they constitute >10% of the dark matter.Comment: 13 pages, 8 figures; v.2 accepted for publication in MNRA

Reporting National Outcomes After Esophagectomy and Gastrectomy According to the Esophageal Complications Consensus Group (ECCG)

OBJECTIVE: This nation-wide population-based study aimed to report postoperative morbidity and mortality after esophagectomy and gastrectomy in the Netherlands according to the definitions of the Esophagectomy Complications Consensus Group (ECCG). BACKGROUND: To standardize international outcome reporting in esophageal surgery, the ECCG developed a standardized outcomes set. METHODS: For this national cohort study, all patients undergoing esophagectomy or gastrectomy for cancer between 2016 and 2017 were selected from the Dutch Upper gastrointestinal Cancer Audit. In a random sample of hospitals, data completeness and accuracy were validated by reabstraction of the data. The investigated o

Impact of Age and Comorbidity on Choice and Outcome of Two Different Treatment Options for Patients with Potentially Curable Esophageal Cancer

Purpose. This study was designed to assess the impact of age and comorbidity on choice and outcome of definitive chemoradiotherapy (dCRT) or neoadjuvant chemoradiotherapy plus surgery. Methods. In this population-based study, all patients with potentially curable EC (cT1N?/cT2-3, TX, any cN, cM0) diagnosed in the South East of the Netherlands between 2004 and 2014 were included. Kaplan–Meier method with log-rank tests and multivariable Cox regression analysis were used to compare overall survival (OS). Results. A total of 702 patients was included. Age C 75 years and multiple comorbidities were associated with a higher probability for dCRT (odds ratio [OR] 8.58; 95% confidence interval [CI] 4.72–15.58; and OR 3.09; 95% CI 1.93–4.93). The strongest associations were found for the combination of hypertension plus diabetes (OR 3.80; 95% CI 1.97–7.32) and the combination of cardiovascular with pulmonary comorbidity (OR 3.18; 95% CI 1.57–6.46). Patients with EC who underwent dCRT had a poorer prognosis than those who underwent nCRT plus surgery, irrespective of age, number, and type of comorbidities. In contrast, for patients with squamous cell carcinoma with C 2 comorbidities or age C 75 years, OS was comparable between both groups (hazard ratio [HR] 1.52; 95% CI 0.78–2.97; and HR 0.73; 95% CI 0.13–4.14). Conclusions. Histological tumor type should be acknowledged in treatment choices for patients with esophageal cancer. Neoadjuvant chemoradiotherapy plus surgery should basically be advised as treatment of choice for operable esophageal adenocarcinoma patients. For patients with esophageal squamous cell carcinoma with C 2 comorbidities or age C 75 years, dCRT may be the preferred strategy

Case-mix adjustment for between-hospital comparisons in oesophageal and gastric cancer surgery

Background: Clinical and pathological outcomes of oesophagogastric cancer surgery are used for benchmarking hospital performance. The extent to which case-mix adjustment is required for valid hospital comparisons is unknown. This study aimed to develop distinct case-mix adjustment models for multiple outcomes of oesophageal and gastric cancer surgery, and to assess the impact of case-mix adjustment on between-hospital comparisons. Methods: We included all patients who underwent oesophagogastric cancer resections in the Netherlands between 2017 and 2022. We developed distinct case-mix adjustment models for ten outcomes. Model performance was evaluated with the area-under-the-receiving-operator-curve (AUC) and pseudo-R-squared, representing how strongly case-mix factors predict the outcomes. We used the Wald χ2 test to assess relative predictor importance per model. The impact of case-mix adjustment on between-hospital comparisons on outcome was quantified using unadjusted and adjusted observed/expected ratios. Results: In total, 4354 oesophageal cancer patients and 2109 gastric cancer patients were included. The most informative predictors in the models for oesophageal cancer were ASA-score, salvage surgery, peripheral vascular disease/aortic aneurysm, chronic lung disease, and tumour histology. For gastric cancer these were age, preoperative weight loss, tumour location, and clinical M-category. All case-mix models showed low to moderate performance, with AUCs ranging between 0.58 and 0.73 and between 0.58 and 0.74 for oesophageal and gastric cancer, respectively. Overall, case-mix adjustment had a limited impact on between-hospital comparisons, but more pronounced for 30-day mortality, failure-to-cure and failure-to-rescue. Conclusion: Given low to moderate model performance and the limited impact on between-hospital comparisons, case-mix adjustment may not always be necessary for valid benchmarking on outcomes in oesophagogastric cancer surgery.</p