Delay in Diagnostic Workup and Treatment of Esophageal Cancer

Introduction: Esophageal cancer should preferably be detected and treated at an early stage, but this may be prohibited by late onset of symptoms and delays in referral, diagnostic workup, and treatment. The aim of this study was to investigate the impact of these delays on outcome in patients with esophageal cancer. Methods: For 491 patients undergoing esophagectomy for cancer between 1991 and 2007, patients' short- and long-term outcome were analyzed according to different time intervals between onset of symptoms, diagnosis, and surgical treatment. Results: Length of prehospital delay (from onset of symptoms until endoscopic diagnosis) did not affect patient's short- or long-term outcome. A shorter hospital delay between establishing the diagnosis of esophageal cancer on endoscopy and surgery was associated with lower overall morbidity and in-hospital mortality. Patients of ASA classes I and II experienced a shorter hospital delay than patients of ASA classes III and IV. Length of hospital delay between endoscopic diagnosis and surgery did not affect pathological tumor-node-metastasis stage or R0-resection rate. Longer hospital delay did not result in worse survival: Overall survival after esophagectomy for cancer was not significantly different between patients with hospital delay 8 weeks (24. 7%, 21. 7%, and 32. 3%, respectively; p = 0. 12). Conclusion: A longer hospital delay (between endoscopic diagnosis and surgery) resulted in worse patient's short-term outcome (higher overall morbidity and mortality rates) but not in a worse long-term outcome (overall survival). This may be explained by a more time-consuming diagnostic workup in patients with a poorer physical status and not by tumor progression

Prognostic significance of the controlling nutritional status (CONUT) score in patients undergoing gastrectomy for gastric cancer: a systematic review and meta-analysis

Background: In recent years, the clinical evidence of the controlling nutritional status (CONUT) score has increased in patients with gastrointestinal cancers. The purp

Comparison of the 6th and 7th editions of the UICC-AJCC TNM classification for esophageal cancer

Background. The new 7th edition of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) tumor, node, metastasis (TNM) staging system is the ratification of data-driven recommendations from the Worldwide Esophageal Cancer Collaboration database. Generalizability remains questionable for single institutions. The present study serves as a validation of the 7th edition of the TNM system in a prospective cohort of patients with predominantly adenocarcinomas from a single institution. Methods

MicroRNA Profiling in Oesophageal Adenocarcinoma Cell Lines and Patient Serum Samples Reveals a Role for miR-451a in Radiation Resistance

Many patients with Oesophageal Adenocarcinoma (OAC) do not benefit from chemoradiotherapy treatment due to therapy resistance. To better understand the mechanisms involved in resistance and to find potential biomarkers, we investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in eight OAC cell lines, and miRNA expression profiling was performed via TaqMan OpenArray qPCR. miRNAs discovered were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to two or all three of the treatments. Target mRNA pathway analyses indicated several potential mechanisms of treatment resistance. miRNAs associated with the in vitro treatment responses were then investigated for association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in pre-treatment serums of patients with OAC. miR-451a was associated uniquely with resistance to radiation treatment in the cell lines, and with the response to nCRT in patient serums. Inhibition of miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p = 0.0003), and altered RNA expression. Pathway analysis of effected small non-coding RNAs and corresponding mRNA targets suggest potential mechanisms of radiation resistance in OAC

Arterial calcification is a risk factor for anastomotic leakage after esophagectomy: A systematic review and meta-analysis

Background: Leakage of the esophago-gastrostomy after esophagectomy with gastric tube reconstruction is a serious complication. Anastomotic leakage occurs in up to 20% of patients and a compromised perfusion of the gastric tube is thought to play an important role. This meta-analysis aimed to investigate whether arterial calcification is a risk factor for anastomotic leakage in esophageal surgery. Method: Embase, Medline, PubMed, Cochrane databases and Google scholar databases were systematically searched for studies that assessed arterial calcification of the thoracic aorta, celiac axis including its branches, or the superior mesenteric artery in patients that underwent esophagectomy with gastric tube reconstruction. The degree of calcification was classified as absent, minor or major. A “random-effects model” was used to calculate pooled Odds Ratios (OR) and 95% confidence intervals (CI). Heterogeneity was assessed using the Q-test and I2-test. Results: From the 456 articles retrieved, seven studies were selected including 1.860 patients. The median (range) of anastomotic leakage was 17.2% (12.7–24.8). Meta-analysis showed a statistically significant association between increased calcium score and anastomotic leakage for the thoracic aorta (OR 2.18(CI 1.42–3.34)), celiac axis (OR 1.62(CI 1.15–2.29)) and right post-celiac axis (common hepatic, gastroduodenal and right gastroepiploic arteries) (OR 2.69(CI 1.27–5.72)). Heterogeneity was observed for analysis on calcification of the thoracic aorta and celiac axis (I2 = 71% and 59%, respectively) but not for the right branches of the celiac axis (I2 = 0%). Conclusion: This meta-analysis, including good quality studies, showed a statistically significant association between arterial calcification and anastomotic leakage in patients who underwent esophagectomy with gastric tube reconstruction

Outcome of Patients Treated Within and Outside a Randomized Clinical Trial on Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer

Background: Randomized clinical trials (RCTs) can provide a high level of evidence for medical decision making, but it is unclear if the results apply to patients treated outside such trials. Objective: The aim of this study was to retrospectively compare outcomes of patients with esophageal cancer treated within and outside an RCT. Methods: All patients receiving neoadjuvant chemoradiotherapy (nCRT) plus surgery for esophageal cancer between 2002 and 2008 (ChemoRadiotherapy for Esophageal cancer followed by Surgery Study [CROSS] cohort) who participated in multicenter, phase II–III trials were compared with patients who underwent the same treatment outside the trial between 2008 and 2013 (post-CROSS cohort). The differences between these cohorts were analyzed using t tests, while logistic regression models were used to evaluate adverse events. Overall and disease-free survival were calculated using the Kaplan–Meier method and Cox regression analyses. Results: A total of 208 CROSS patients and 173 post-CROSS patients were included in this study. Patients from the post-CROSS cohort were older, had more co morbidities, and had poorer performance status. Clinical N stage, but not cT stage, was worse in the post-CROSS cohort. There were no statistically significant differences in adverse events (pulmonary, cardiac, or anastomotic complications) or survival between the comparison cohorts. Conclusion: The outcomes of patients treated with nCRT plus esophagectomy for cancer have a high external consistency and can be extrapolated to the daily practice of physicians involved in the treatment and care of esophageal cancer patients

Population-Based Study on Risk Factors for Tumor-Positive Resection Margins in Patients with Gastric Cancer

Abstract Background Radical gastrectomy is the cornerstone of the treatment of locally advanced gastric cancer. This study was designed to evaluate factors associated with a tumor-positive resection margin after gastrectomy and to evaluate the influence of hospital volume. Methods In this Dutch cohort study, patients with junctional or gastric cancer who underwent curative gastrectomy between 2011 and 2017 were included. The primary outcome was incomplete tumor removal after the operation defined as the microscopic presence of tumor cells at the resection margin. The association of patient and disease characteristics with incomplete tumor removal was tested with multivariable regression analysis. The association of annual hospital volume with incomplete tumor removal was tested and adjusted for the patient- and disease characteristics. Results In total, 2799 patients were included. Incomplete tumor removal was seen in 265 (9.5%) patients. Factors associated with incomplete tumor removal were: tumor located in the entire stomach (odds ratio (OR) [95% confidence interval (CI): 3.38 [1.91–5.96] reference: gastroesophageal junction), cT3, cT4, cTx (1.75 [1.20–2.56], 2.63 [1.47–4.70], 1.60 [1.03–2.48], reference: cT0-2), pN+ (2.73 [1.96–3.80], reference: pN−), and diffuse and unknown histological subtype (3.15 [2.14–4.46] and 2.05 [1.34–3.13], reference: intestinal). Unknown differentiation grade was associated with complete tumor removal (0.50 [0.30–0.83], reference: poor/undifferentiated). Compared with a hospital volume of  39 resections were associated with lower probability for incomplete tumor removal (OR 0.56 [0.42–0.76] and 0.34 [0.18–0.64]). Conclusions Tumor location, cT, pN, histological subtype, and tumor differentiation are associated with incomplete tumor removal. The association of incomplete tumor removal with an annual hospital volume of < 20 resections may underline the need for further centralization of gastric cancer care in the Netherlands

Intrathoracic vs Cervical Anastomosis After Totally or Hybrid Minimally Invasive Esophagectomy for Esophageal Cancer A Randomized Clinical Trial

Background: Transthoracic minimally invasive esophagectomy (MIE) is increasingly performed as part of curative multimodality treatment. There appears to be no robust evidence on the preferred location of the anastomosis after transthoracic MIE. Objective: To compare an intrathoracic with a cervical anastomosis in a randomized clinical trial. Design, Setting, and Participants: This open, multicenter randomized clinical superiority trial was performed at 9 Dutch high-volume hospitals. Patients with midesophageal to distal esophageal or gastroesophageal junction cancer planned for curative resection were included. Data collection occurred from April 2016 through February 2020. Intervention: Patients were randomly assigned (1:1) to transthoracic MIE with intrathoracic or cervical anastomosis. Main Outcomes and Measures: The primary end point was anastomotic leakage requiring endoscopic, radiologic, or surgical intervention. Secondary outcomes were overall anastomotic leak rate, other postoperative complications, length of stay, mortality, and quality of life. Results: Two hundred sixty-two patients were randomized, and 245 were eligible for analysis. Anastomotic leakage necessitating reintervention occurred in 15 of 122 patients with intrathoracic anastomosis (12.3%) and in 39 of 123 patients with cervical anastomosis (31.7%; risk difference, -19.4% [95% CI, -29.5% to -9.3%]). Overall anastomotic leak rate was 12.3% in the intrathoracic anastomosis group and 34.1% in the cervical anastomosis group (risk difference, -21.9% [95% CI, -32.1% to -11.6%]). Intensive care unit length of stay, mortality rates, and overall quality of life were comparable between groups, but intrathoracic anastomosis was associated with fewer severe complications (risk difference, -11.3% [-20.4% to -2.2%]), lower incidence of recurrent laryngeal nerve palsy (risk difference, -7.3% [95% CI, -12.1% to -2.5%]), and better quality of life in 3 subdomains (mean differences: dysphagia, -12.2 [95% CI, -19.6 to -4.7]; problems of choking when swallowing, -10.3 [95% CI, -16.4 to 4.2]; trouble with talking, -15.3 [95% CI, -22.9 to -7.7]). Conclusions and Relevance: In this randomized clinical trial, intrathoracic anastomosis resulted in better outcome for patients treated with transthoracic MIE for midesophageal to distal esophageal or gastroesophageal junction cancer. Trial Registration: Trialregister.nl Identifier: NL4183 (NTR4333)

Treatment of anastomotic leak after oesophagectomy for oesophageal cancer:large, collaborative, observational TENTACLE cohort study

Background: Anastomotic leak is a severe complication after oesophagectomy. Anastomotic leak has diverse clinical manifestations and the optimal treatment strategy is unknown. The aim of this study was to assess the efficacy of treatment strategies for different manifestations of anastomotic leak after oesophagectomy. Methods: A retrospective cohort study was performed in 71 centres worldwide and included patients with anastomotic leak after oesophagectomy (2011-2019). Different primary treatment strategies were compared for three different anastomotic leak manifestations: interventional versus supportive-only treatment for local manifestations (that is no intrathoracic collections; well perfused conduit); drainage and defect closure versus drainage only for intrathoracic manifestations; and oesophageal diversion versus continuity-preserving treatment for conduit ischaemia/necrosis. The primary outcome was 90-day mortality. Propensity score matching was performed to adjust for confounders. Results: Of 1508 patients with anastomotic leak, 28.2 per cent (425 patients) had local manifestations, 36.3 per cent (548 patients) had intrathoracic manifestations, 9.6 per cent (145 patients) had conduit ischaemia/necrosis, 17.5 per cent (264 patients) were allocated after multiple imputation, and 8.4 per cent (126 patients) were excluded. After propensity score matching, no statistically significant differences in 90-day mortality were found regarding interventional versus supportive-only treatment for local manifestations (risk difference 3.2 per cent, 95 per cent c.i. -1.8 to 8.2 per cent), drainage and defect closure versus drainage only for intrathoracic manifestations (risk difference 5.8 per cent, 95 per cent c.i. -1.2 to 12.8 per cent), and oesophageal diversion versus continuity-preserving treatment for conduit ischaemia/necrosis (risk difference 0.1 per cent, 95 per cent c.i. -21.4 to 1.6 per cent). In general, less morbidity was found after less extensive primary treatment strategies. Conclusion: Less extensive primary treatment of anastomotic leak was associated with less morbidity. A less extensive primary treatment approach may potentially be considered for anastomotic leak. Future studies are needed to confirm current findings and guide optimal treatment of anastomotic leak after oesophagectomy.</p