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Objective The aim of this study is to identify preoperative patient-related prognostic factors for anastomotic leakage, mortality, and major complications in patients undergoing oncological esophagectomy. Background Esophagectomy is a high-risk procedure with an incidence of major complications around 25% and short-term mortality around 4%. Methods We systematically searched the Medline and Embase databases for studies investigating the associations between patient-related prognostic factors and anastomotic leakage, major postoperative complications (Clavien–Dindo ≥ IIIa), and/or 30-day/in-hospital mortality after esophagectomy for cancer. Results Thirty-nine eligible studies identifying 37 prognostic factors were included. Cardiac comorbidity was associated with anastomotic leakage, major complications, and mortality. Male sex and diabetes were prognostic factors for anastomotic leakage and major complications. Additionally, American Society of Anesthesiologists (ASA) score > III and renal disease were associated with anastomotic leakage and mortality. Pulmonary comorbidity, vascular comorbidity, hypertension, and adenocarcinoma tumor histology were identified as prognostic factors for anastomotic leakage. Age > 70 years, habitual alcohol usage, and body mass index (BMI) 18.5–25 kg/m2 were associated with increased risk for mortality. Conclusions Various patient-related prognostic factors are associated with anastomotic leakage, major postoperative complications, and postoperative mortality following oncological esophagectomy. This knowledge may define case-mix adjustment models used in benchmarking or auditing and may assist in selection of patients eligible for surgery or tailored perioperative care.

Introduction: Endoscopic pneumatic pyloric balloon dilation is a treatment option for early postoperative delayed gastric tube emptying following esophageal resection. This study aimed to determine the safety and effectiveness of endoscopic balloon dilation. Methods: Between 2015 and 2018, patients with delayed gastric emptying 8–10 days after esophageal resection with gastric tube reconstruction due to esophageal carcinoma were considered for inclusion. Inclusion criteria were ≥1 of the following: nasogastric tube production ≥500 mL/24 h, ≥300 mL gastric retention, ≥50% gastric tube dilatation on X-ray, or nasogastric tube replacement. Patients were excluded on evidence of anastomotic leakage or reintervention. Success was defined as the ability to expand intake without needing to replace the nasogastric tube. Dilation was performed using a 30-mm Rigiflex balloon. Results: Fifteen patients underwent pyloric dilation, 12 according to the study protocol. Treatment was performed at a median of 12 days (IQR 9–15) postoperatively. Success was achieved in 58%. At 3 months, 8 patients progressed to exclusively oral intake. The remaining 4 patients had supplementary nightly enteral tube feeding. There were no adverse events. Conclusion: Endoscopic balloon dilation of the pylorus is a safe, feasible therapy for early postoperative delayed gastric emptying. With a success rate of 58%, a clinical trial is a necessary next step.

OBJECTIVE: To evaluate changes in treatment and outcomes of esophagogastric cancer surgery after introduction of the DUCA. In addition, the presence of risk-averse behavior was assessed. SUMMARY OF BACKGROUND DATA: Clinical auditing is seen as an important quality improvement tool; however, its long-term efficacy remains largely unknown. In addition, critics claim that enhancements result from risk-averse behavior rather than positive effects of auditing. METHODS: DUCA data were used from registration start (1-1-2011) until 31-12-2018. Trends in patient, tumor, hospital and treatment characteristics were univariably assessed. Trends in short-term outcomes were investigated using multilevel multivariable logistic regression. Presence of risk aversion was described by the corrected proportion of patients undergoing surgery, using data from the Netherlands Cancer Registry. To evaluate the impact of centralization on time trends identified, the association between hospital volume and outcomes was investigated. RESULTS: This study included 6172 patients with esophageal and 3,690 with gastric cancer who underwent surgery. Pathological outcomes (lymph node yield, radicality) improved and futile surgery decreased over the years. In-hospital/30-day mortality decreased for esophagectomy (4.2% to 2.5%) and for gastrectomy (7.1% to 4.3%). Reinterventions, (minor) complications and readmissions increased. Risk aversion appeared absent. Between 2011-2018, annual median hospital volumes increased from 38 to 53 for esophagectomy and from 14 to 29 for gastrectomy. Higher hospital volumes were associated with several improved outcomes measures. CONCLUSIONS: During 8 years of auditing, outcomes improved, with no signs of risk-averse behavior. These improvements occurred in parallel with centralization. Feedback on postoperative complications remains the focus of the DUCA.

Background Anastomotic leakage has a great impact on clinical outcomes after esophagectomy. It has never been studied whether anastomotic leakage is of equal severity between different types of esophagectomy (i.e., transhiatal, McKeown and Ivor Lewis) in terms of postoperative mortality and morbidity. Methods All esophageal cancer patients with anastomotic leakage after transhiatal, McKeown or Ivor Lewis esophagectomy between 2011 and 2019 were selected from the Dutch Upper Gastrointestinal Cancer Audit (DUCA) registry. The primary outcome was 30-day/in-hospital mortality. Secondary outcomes included postoperative complications, re-operation and ICU readmission rate. Results Data from 1030 patients with anastomotic leakage after transhiatal (n=287), McKeown (n=397) and Ivor Lewis esophagectomy (n=346) were evaluated. The 30-day/in-hospital mortality rate was 4.5% in patients with leakage after transhiatal esophagectomy, 8.1% after McKeown and 8.1% after Ivor Lewis esophagectomy (P=0.139). After correction for confounders, leakage after transhiatal resection was associated with lower mortality (OR 0.152–0.699, P=0.004), but mortality after McKeown and Ivor Lewis esophagectomy was similar. Re-operation rate was 24.0% after transhiatal, 40.6% after McKeown and 41.3% after Ivor Lewis esophagectomy (PP Conclusion This study in patients with anastomotic leakage confirms a strong association between severity of clinical consequences and different types of esophagectomy. It supports the hypothesis that cervical leakage is generally less severe than intrathoracic leakage. The clinical impact of anastomotic leakage should be taken into account, in addition to its incidence, when different types of esophagectomy are compared by clinicians or researchers.

OBJECTIVES This study aimed to compare long-term survival following minimally invasive esophagectomy (MIE) versus open esophagectomy (OE) for esophageal cancer using a nationwide propensity-score matched cohort. SUMMARY BACKGROUND DATA MIE provides lower postoperative morbidity and mortality, and similar short-term oncological quality compared to OE. METHODS Data was acquired from the Dutch Upper Gastrointestinal Cancer Audit. Patients undergoing minimally invasive or open, transthoracic or transhiatal esophagectomy for primary esophageal cancer between 2011-2015 were included. A propensity-score matching analysis for MIE versus OE was performed separately for transthoracic and transhiatal esophagectomies. RESULTS A total of 1036 transthoracic MIE and OE patients, and 582 transhiatal MIE and OE patients were matched. Long-term survival was comparable for MIE and OE for both transthoracic and transhiatal procedures (5-year overall survival: transthoracic MIE 49.2% vs. OE 51.1%, p 0.695; transhiatal MIE 48.4% vs. OE 50.7%, p 0.832). For both procedures, MIE yielded more lymph nodes (transthoracic median 21 vs. 18, p < 0.001; transhiatal 15 vs. 13, p 0.007). Post-operative morbidity was comparable after transthoracic MIE and OE (60.8% vs. 64.9%, p 0.177), with a reduced length of stay after transthoracic MIE (median 12 vs. 15 days, p < 0.001). After transhiatal MIE, more postoperative complications (64.9% vs. 56.4%, p 0.034) were observed, without subsequent difference in length of stay. CONCLUSION Long-term survival after minimally invasive esophagectomy was equivalent to open in both propensity-score matched cohorts of patients undergoing transthoracic or transhiatal esophageal resections. Transhiatal minimally invasive esophagectomy was accompanied with more post-operative morbidity. Both transthoracic and transhiatal minimally invasive esophagectomy resulted in a more extended lymphadenectomy.

OBJECTIVE: This international multicenter study by the Upper GI International Robotic Association aimed to gain insight in current techniques and outcomes of RAMIE worldwide.BACKGROUND: Current evidence for RAMIE originates from single-center studies, which may not be generalizable to the international multicenter experience.METHODS: Twenty centers from Europe, Asia, North-America, and South-America participated from 2016 to 2019. Main endpoints included the surgical techniques, clinical outcomes, and early oncological results of ramie.RESULTS: A total of 856 patients undergoing transthoracic RAMIE were included. Robotic surgery was applied for both the thoracic and abdominal phase (45%), only the thoracic phase (49%), or only the abdominal phase (6%). In most cases, the mediastinal lymphadenectomy included the low paraesophageal nodes (n=815, 95%), subcarinal nodes (n = 774, 90%), and paratracheal nodes (n = 537, 63%). When paratracheal lymphadenectomy was performed during an Ivor Lewis or a McKeown RAMIE procedure, recurrent laryngeal nerve injury occurred in 3% and 11% of patients, respectively. Circular stapled (52%), hand-sewn (30%), and linear stapled (18%) anastomotic techniques were used. In Ivor Lewis RAMIE, robot-assisted hand-sewing showed the highest anastomotic leakage rate (33%), while lower rates were observed with circular stapling (17%) and linear stapling (15%). In McKeown RAMIE, a hand-sewn anastomotic technique showed the highest leakage rate (27%), followed by linear stapling (18%) and circular stapling (6%).CONCLUSION: This study is the first to provide an overview of the current techniques and outcomes of transthoracic RAMIE worldwide. Although these results indicate high quality of the procedure, the optimal approach should be further defined.

Background Esophagectomy is the key component of curative esophageal cancer treatment. Textbook outcome is a composite measure describing an optimal perioperative course, including variables related to radical resection, including at least 15 lymph nodes, and an uncomplicated postoperative course without hospital readmission. This study assessed clinicopathologic predictors of textbook outcome and the association of textbook outcome with survival in 2 tertiary referral centers. Methods All patients with esophageal cancer who underwent esophagectomy with gastric tube reconstruction and curative intent between 2007 and 2016 were included. Patients with carcinoma in situ and patients undergoing a salvage or nonelective procedure were excluded. The primary end point was the association of textbook outcome of esophageal cancer surgery with long-term survival. Secondary end points were clinicopathologic predictors of textbook outcome. Results In total, 1065 patients were included, of whom 327 achieved textbook outcome (30.7%). Squamous cell carcinoma (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.39 to 0.80), hybrid approach (OR, 0.30; 95% CI, 0.10 to 0.89), and American Society of Anesthesiologists (ASA) class II or higher predicted worse textbook rates (ASA class II: OR, 0.33, 95% CI, 0.22 to 0.49; ASA class III or IV: OR, 0.68; 95% CI, 0.48 to 0.96), whereas neoadjuvant therapy predicted a better textbook rate (OR, 1.58; 95% CI, 1.08 to 2.31). Superior overall (hazard ratio, 0.77; 95% CI, 0.64 to 0.93) and disease-free survival (hazard ratio, 0.80; 95% CI, 0.67 to 0.96) were observed in the textbook outcome group. Conclusions Achieved textbook outcome was associated with better overall and disease-free survival, thus illustrating the association of improved short-term outcomes and long-term survival and the importance of pursuing textbook outcome.

Background This study aimed to describe the incidence of failure to cure (a composite outcome measure defined as surgery not meeting its initial aim), and the impact of hospital variation in the administration of neoadjuvant therapy on this outcome measure. Methods All patients in the Dutch Upper Gastrointestinal Cancer Audit undergoing curatively intended gastric cancer surgery in 2011–2019 were included. Failure to cure was defined as (1) ‘open-close’ surgery; (2) irradical surgery (R1/R2); or (3) 30-day/in-hospital mortality. Case-mix-corrected funnel plots, based on multivariable logistic regression analyses, investigated hospital variation. The impact of a hospital’s tendency to administer neoadjuvant chemotherapy on the heterogeneity in failure to cure between hospitals was assessed based on median odds ratios and multilevel logistic regression analyses. Results Some 3862 patients from 28 hospitals were included. Failure to cure was noted in 22.3% (hospital variation: 14.5–34.8%). After case-mix correction, two hospitals had significantly higher-than-expected failure to cure rates, and one hospital had a lower-than-expected rate. The failure to cure rate was significantly higher in hospitals with a low tendency to administer neoadjuvant chemotherapy. Approximately 29% of hospital variation in failure to cure could be attributed to different hospital policies regarding neoadjuvant therapy. Conclusions Failure to cure has an incidence of 22% in patients undergoing gastric cancer surgery. Higher failure to cure rates were seen in centers administering less neoadjuvant chemotherapy, which confirms the Dutch guideline recommendation on the administration of neoadjuvant chemotherapy. Failure to cure provides short loop feedback and can be used as a quality indicator in surgical audits.

Purpose: The CROSS trial established neoadjuvant chemoradiotherapy (nCRT) for patients with resectable esophageal adenocarcinoma (rEAC). In the PERFECT trial, we investigated the feasibility and efficacy of nCRT combined with programmed-death ligand-1 (PD-L1) inhibition for rEAC. Patients and Methods: Patients with rEAC received nCRT according to the CROSS regimen combined with five cycles of atezolizumab (1,200 mg). The primary endpoint was the feasibility of administering five cycles of atezolizumab in ≥75% patients. A propensity score–matched nCRT cohort was used to compare pathologic response, overall survival, and progression-free survival. Exploratory biomarker analysis was performed on repeated tumor biopsies. Results: We enrolled 40 patients of whom 85% received all cycles of atezolizumab. Immune-related adverse events of any grade were observed in 6 patients. In total, 83% proceeded to surgery. Reasons for not undergoing surgery were progression (n = 4), patient choice (n = 2), and death (n = 1). The pathologic complete response rate was 25% (10/40). No statistically significant difference in response or survival was found between the PERFECT and the nCRT cohort. Baseline expression of an established IFNγ signature was higher in responders compared with nonresponders (P = 0.043). On-treatment nonresponders showed either a high number of cytotoxic lymphocytes (CTL) with a transcriptional signature consistent with expression of immune checkpoints, or a low number of CTLs. Conclusions: Combining nCRT with atezolizumab is feasible in patients with rEAC. On the basis of our exploratory biomarker study, future studies are necessary to elucidate the potential of neoadjuvant immunotherapy in patient subgroups. See related commentary by Catenacci, p. 3269

Background: Studies on the value of a staging laparoscopy in detecting metastases in gastric cancer patients show great variation. This study investigates the avoidable surgery rate in patients with and without a staging laparoscopy scheduled for surgery with curative intent. Methods: This population-based cohort study included all patients with an intentional resection for a potentially curable gastric adenocarcinoma, between 2011 and 2016, registered in the Dutch Upper GI Cancer audit. Patients with and without a staging laparoscopy were compared. The primary outcome was the avoidable surgery rate (detection of metastases and/or locoregional non-resectable tumor during intentional gastrectomy). Secondary outcomes were the negative predictive value, postoperative morbidity and pathology parameters. Results: 2849 patients who underwent an intentional gastrectomy were included. 414 of 2849 (14.5%) patients underwent a staging laparoscopy before initiation of treatment. The avoidable surgery rate was 16.2% in the staging laparoscopy group, compared to 8.5% in the non-staging group (P < 0.001), resulting in a negative predictive value of 83.8%. The avoidable surgery rate remained significantly different after correction for possible confounders. The main reason for not executing the gastrectomy was the presence of distant metastasis in both groups. cT and cN stage were significantly higher in patients who underwent a staging laparoscopy. Conclusions: The staging laparoscopy group had a higher cTN and pTN stage, implicating selection of patients with more advanced disease for a staging laparoscopy. Despite the staging laparoscopy, a higher rate of avoidable surgery was found, suggesting a low sensitivity for detecting metastases or locoregional non-resectability in this patient group.

Background Chemoradiation followed by resection has been the standard therapy for resectable (cT1-4aN0-3M0) esophageal carcinoma in the Netherlands since 2010. The optimal surgical approach remains a matter of debate. Therefore, the purpose of this study was to compare the transhiatal and the transthoracic approach concerning morbidity, mortality and oncological quality. Methods Data was acquired from the Dutch Upper GI Cancer Audit. Patients who underwent esophagectomy with curative intent and gastric tube reconstruction for mid/distal esophageal or esophagogastric junction carcinoma (cT1-4aN0-3M0) from 2011 to 2016 were included. Patients who underwent a transthoracic and transhiatal esophagectomy were compared after propensity score matching. Results After propensity score matching, 1532 of 4143 patients were included for analysis. The transthoracic approach yielded more lymph nodes (transthoracic median 19, transhiatal median 14; p p = 0.044). The transthoracic group experienced more chyle leakage (9.7% vs. 2.7%, p p p = 0.003). The transthoracic group required a longer hospital stay (median 14 vs. 11 days, p p p = 0.009). Conclusions In a propensity score-matched cohort, the transthoracic esophagectomy provided a more extensive lymph node dissection, which resulted in a higher lymph node yield, at the cost of increased morbidity and short-term mortality.

Objective: Investigate long-term survival, morbidity, mortality, and pathology results in patients following esophagectomy or total gastrectomy for gastroesophageal junction (GEJ) cancer. Background: Both a total gastrectomy and an esophagectomy may be valid treatment options in patients with GEJ cancer. Which procedure results in the most optimal patient outcome is not well studied. The aim of this study was to investigate the long-term survival, morbidity, mortality, and pathology results in patients following esophagectomy or total gastrectomy for GEJ cancer. Methods: A retrospective comparative cohort study of prospectively collected data from the Dutch Upper GI Cancer Audit combined with survival data of the Dutch medical insurance database was performed. Patients with GEJ cancer in whom a total gastrectomy or an esophagectomy was performed between 2011 and 2016 were compared. The primary outcome was 3-year overall survival. Postoperative morbidity, mortality, 3-year conditional survival, radicality of resection, and lymph node yield were secondary endpoints. Results: A total of 871 patients were included: 790 following esophagectomy and 81 following gastrectomy. The 3-year overall survival was 35.8% after esophagectomy and 28.4% after gastrectomy (hazard ratio 1.2, 95% confidence interval 0.721-1.836, P = 0.557). Postoperative morbidity, mortality, radicality of resection, lymph node yield, and 3-year conditional survival did not differ significantly between groups. Conclusion: A total gastrectomy and an esophagectomy for GEJ cancer show largely comparable results with regard to long-term survival, postoperative morbidity, mortality, and pathology results. If both procedures are feasible, other parameters such as surgeona s experience and quality of life should be considered when planning for surgery.

Objective: This study aimed to describe failure to cure in terms of incidence, hospital variation, and as an outcome parameter for salvage esophagectomy. Summary Background Data: Failure to cure is a composite outcome measure that could be used for hospital comparison in esophageal carcinoma care. Methods: All patients registered in the Dutch Upper GI Cancer Audit who underwent potentially curative esophageal carcinoma surgery in 2011 to 2018, were included in this nationwide cohort study. Failure to cure was defined as: 1) no surgical resection due to intraoperative metastasis or locally irresectable tumor, 2) macroscopically or microscopically incomplete resection, or 3) 30- day/in-hospital mortality. Association of baseline characteristics with failure to cure was analyzed using multivariable logistic regression in the total population and in salvage patients. Results: Some 5894 patients from 22 hospitals were included, of whom 630 (10.7%) had failure to cure (hospital variation [5.5%–19.1%]). Higher age, preoperative weight loss, higher ASA-score, higher N-stage, neoadjuvant chemotherapy, or no neoadjuvant therapy (compared with neoadjuvant chemoradiotherapy), open surgery, and resection before 2014 were associated with failure to cure. After case-mix correction, 2 hospitals had statistically significant higher failure to cure percentages, whereas 2 had lower percentages. Of 151 salvage esophagectomy patients, 32.5% had failure to cure. The failure to cure rate after salvage surgery was 27.6% in high-volume hospitals and 47.6% in medium-volume hospitals. Conclusions: The incidence of failure to cure was 10.7%. Given the significant hospital variation in the percentage of failure to cure, improvement is needed. Since salvage procedures are more often successful in high-volume hospitals, further centralization of this procedure is warranted

Objective To identify the most prevalent symptoms and those with greatest impact upon health-related quality of life (HRQOL) among esophageal cancer survivors. Background Long-term symptom burden after esophagectomy, and associations with HRQOL, are poorly understood. Patients and methods Between 2010 and 2016, patients from 20 European Centers who underwent esophageal cancer surgery, and were disease-free at least 1 year postoperatively were asked to complete LASER, EORTC-QLQ-C30, and QLQ-OG25 questionnaires. Specific symptom questionnaire items that were associated with poor HRQOL as identified by EORTC QLQ-C30 and QLQ-OG25 were identified by multivariable regression analysis and combined to form a tool. Results A total of 876 of 1081 invited patients responded to the questionnaire, giving a response rate of 81%. Of these, 66.9% stated in the last 6 months they had symptoms associated with their esophagectomy. Ongoing weight loss was reported by 10.4% of patients, and only 13.8% returned to work with the same activities.Three LASER symptoms were correlated with poor HRQOL on multivariable analysis; pain on scars on chest (odds ratio (OR) 1.27; 95% CI 0.97-1.65), low mood (OR 1.42; 95% CI 1.15-1.77) and reduced energy or activity tolerance (OR 1.37; 95% CI 1.18-1.59). The areas under the curves for the development and validation datasets were 0.81 ± 0.02 and 0.82 ± 0.09 respectively. Conclusion Two-thirds of patients experience significant symptoms more than 1 year after surgery. The 3 key symptoms associated with poor HRQOL identified in this study should be further validated, and could be used in clinical practice to identify patients who require increased support.

Introduction To optimally target physiotherapy treatment, knowledge of the pre- and postoperative course of functional status in patients undergoing esophagectomy is required. The aim of this prospective longitudinal study was to investigate the course of functional status in patients with esophageal cancer before and after esophagectomy. Materials and methods Functional status outcome measures of patients with esophageal cancer who underwent surgery between March 2012 and June 2016 were prospectively measured at 3 months and at 1 day before surgery and at 1 week and at 3 months after surgery. Analysis of repeated measurements with the mixed model approach was used to study changes over time. Results Hundred fifty-five patients were measured at 3 months and at 1 day before surgery, of which 109 (70.3%) at 1 week and 60 (38.7%) at 3 months after surgery. Mean (SD) age at surgery was 63.5 years (9.3), and 122 patients (78.7%) were male. The incidence of postoperative complications was 83 (53.5%). Three months postoperatively, functional status measures returned to baseline levels, except from handgrip strength (beta [95% CI] −6.2 [-11.3 to −1.1]; P = 0.02) and fatigue (4.7 [0.7to 8.7]; P = 0.02). No differences were observed in the course of functional status between patients with and without postoperative complications. Conclusion Functional status of patients undergoing esophagectomy returned to baseline values three months after surgery, despite the high incidence of postoperative complications. This requires rethinking the concept of prehabilitation, where clearly not all patients benefit from high functional status to prevent postoperative complications.

Summary Introduction The prognostic value of histomorphologic regression in primary esophageal cancer has been previously established, however the impact of lymph node (LN) response on survival still remains unclear. The aim of this review was to assess the prognostic significance of LN regression or downstaging following neoadjuvant therapy for esophageal cancer. Methods An electronic search was performed to identify articles evaluating LN regression or downstaging after neoadjuvant therapy. Random effects meta-analyses were performed to assess the influence of regression in the LNs and nodal downstaging on overall survival. Histomorphologic tumor regression in LNs was defined by the absence of viable cells or degree of fibrosis on histopathologic examination. Downstaged LNs were defined as pN0 nodes by the tumor, node, and metastasis classification, which were positive prior to treatment neoadjuvant. Results Eight articles were included, three of which assessed tumor regression (number of patients = 292) and five assessed downstaging (number of patients = 1368). Complete tumor regression (average rate of 29.1%) in the LNs was associated with improved survival, although not statistically significant (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.26–1.06; P = 0.17). LNs downstaging (average rate of 32.2%) was associated with improved survival compared to node positivity after neoadjuvant treatment (HR = 0.41, 95%CI = 0.22–0.77; P = 0.005). Discussion The findings of this meta-analysis have shown a survival benefit in patients with LN downstaging and are suggestive for considering LN downstaging to ypN0 as an additional prognostic marker in staging and in the comparative evaluation of differing neoadjuvant regimens in clinical trials. No statistically significant effect of histopathologic regression in the LNs on long-term survival was seen.

Background Sex differences in clinicopathological characteristics, treatment, and postoperative outcomes of gastric and esophageal cancer are largely undefined. This study aimed to compare tumor and treatment characteristics and outcomes of gastric and esophageal cancer surgery between male and female patients. Methods Patients after elective surgery for primary esophageal (EAC) or gastric adenocarcinoma (GAC) registered in the Dutch Upper GI Cancer Audit between 2011 and 2016 were included. The primary endpoint, 5-year relative survival with relative excess risk (RER), i.e., adjusted for the normal life expectancy, was compared between male and female patients with EAC and GAC. Results In total, 4937 patients were included (75% male) with a mean age of 66 years. cT and cN-stages showed a similar distribution in male and female patients. In females, antrum GAC was more frequent (47% vs. 38%, p p = 0.033). For GAC, less postoperative morbidity (33% vs. 38% p = 0.017) and less re-interventions (12% vs. 16%, p = 0.008) were observed in females, although they had inferior 5-year relative survival (49% vs. 56%, RER = 1.31, 95% CI 1.09–1.58, p = 0.004). No differences in relative survival of EAC were observed. Conclusions In addition to significant sex differences in tumor location, female patients with esophageal adenocarcinoma less frequently received neo-adjuvant therapy, and female patients with gastric adenocarcinoma had inferior relative survival. Further consideration and exploration of sex differences in surgical treatment and outcomes are necessary to improve tailored treatment and outcomes.

Background Within the scope of value-based health care, this study aimed to analyze Dutch hospital performance in terms of length of hospital stay after esophageal cancer surgery and its association with 30-day readmission rates. Since both parameters are influenced by the occurrence of complications, this study only included patients with an uneventful recovery after esophagectomy. Methods All patients registered in the Dutch Upper Gastrointestinal Cancer Audit (DUCA) who underwent a potentially curative esophagectomy between 2015 and 2018 were considered for inclusion. Patients were excluded in case of an intraoperative/post-operative complication, readmission to the intensive care unit, or any re-intervention. Length of hospital stay was dichotomized around the national median into ‘short admissions’ and ‘long admissions’. Hospital variation was evaluated using a case-mix-corrected funnel plot based on multivariable logistic regression analyses. Association of length of hospital stay with 30-day readmission rates was investigated using the χ2-statistic. Results A total of 1007 patients was included. National median length of hospital stay was 9 days, ranging from 6.5 to 12.5 days among 17 hospitals. The percentage of ‘short admissions’ per hospital ranged from 7.7 to 93.5%. After correction for case-mix variables, 3 hospitals had significantly higher ‘short admission’ rates and 4 hospitals had significantly lower ‘short admission’ rates. Overall, 6.2% [hospital variation (0.0–13.2%)] of patients were readmitted. Hospital 30-day readmission rates were not significantly different between patients with a short length of hospital stay and those with a long length of hospital stay (5.5% versus 7.6%; p = 0.19). Conclusions Based on these nationwide audit data, median length of hospital stay after an uncomplicated esophagectomy was 9 days ranging from 6.5 to 12.5 days among Dutch hospitals. There was no association between length of hospital stay and readmission rates. Nationwide improvement might lead to a substantial reduction of hospital costs.

Background For esophagectomy, thoracic epidural analgesia (TEA) is the standard of care for perioperative pain management. Although effective, TEA is associated with moderate to serious adverse events such as hypotension and neurologic complications. Paravertebral analgesia (PVA) may be a safe alternative. The authors hypothesized that TEA and PVA are similar in efficacy for pain treatment in thoracolaparoscopic Ivor Lewis esophagectomy. Methods This retrospective cohort study compared TEA with PVA in two consecutive series of 25 thoracolaparoscopic Ivor Lewis esophagectomies. In this study, TEA consisted of continuous epidural bupivacaine and sufentanil infusion with a patient-controlled bolus function. In PVA, the catheter was inserted by the surgeon under thoracoscopic vision during surgery. Administration of PVA consisted of continuous paravertebral bupivacaine infusion after a bolus combined with patient-controlled analgesia using intravenous morphine. The primary outcome was the median highest recorded Numeric Pain Rating Scale (NRS) during the 3 days after surgery. The secondary outcomes were vasopressor consumption, fluid administration, and length of hospital stay. Results In both groups, the median highest recorded NRS was 4 or lower during the first three postoperative days. The patients with PVA had a higher overall NRS (mean difference, 0.75; 95% confidence interval 0.49–1.44). No differences were observed in any of the other secondary outcomes. Conclusion For the patients undergoing thoracolaparoscopic Ivor Lewis esophagectomy, TEA was superior to PVA, as measured by NRS during the first three postoperative days. However, both modes provided adequate analgesia, with a median highest recorded NRS of 4 or lower. These results could form the basis for a randomized controlled trial.

Curative treatment for patients with esophageal cancer consists of neoadjuvant treatment and radical surgical resection. Two different strategies exist; patients can either be treated with perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT). Both strategies improve 5-year survival rates, it is however not known if these treatments affect long-term Health-Related Quality of Life (HR-QoL) differently. The aim of this study was to compare HR-QoL between patients following CT and CRT followed by esophagectomy for esophageal cancer. Methods The LASER study database comprises data of a multicenter European study, with focus on HR-QoL among disease-free patients at least one year following an esophagectomy for esophageal or junctional cancer. Included patients completed the LASER, EORTC-QLQ-C30 and EORTC-QLQ-OG25 questionnaires. From this database we extracted patients either treated with CT or CRT for analysis. The primary endpoint was the mean difference in all long-term HR-QoL domains and LASER key symptom scores, using univariable and multivariable logistic regression analysis. The secondary endpoint was to compare the reported HR-QoL domain scores in the study population to the reference values of the general population. Results Among the 565 included patients, 349 (61.8%) received CRT, and 216 (38.2%) were treated with CT. The mean age was 63.7 years (±SD 8.6), and mean time since surgery was 4.3 years (±SD 1.7). After multivariable analysis, patients treated with CT reported worse outcomes on ‘Social Functioning’ (∆means 4.56, p-value Conclusion Significant differences in favor of CRT were observed in several long-term HR-QoL domains for patients following esophagectomy for cancer. However, none of the observed differences in the reported long-term HR-QoL domains between patients treated with CT or with CRT, were clinically relevant (∆means≠ ≥ 10 points). Selection of neoadjuvant therapy should therefore be based on patient characteristics.

The predictive value of postoperative albuminemia decrease (ΔAlb) has been increasingly evidenced in different types of major surgery but data on esophagectomy remain scarce. This study aimed to assess the predictive value of ΔAlb for adverse short-term outcomes after oncological esophagectomy. Methods Retrospective analysis of an international multicentric cohort of patients undergoing oncological esophagectomy between 2006–2017. Patients with missing pre- and postoperative albumin values were excluded from the analysis. Primary endpoint was postoperative morbidity according to Clavien classification. Secondary endpoints were Comprehensive Complication Index (CCI) and length of hospital stay (LoS). Results A total of 1046 patients were analyzed. Major complications were reported in 363 (34.7%) patients. Albuminemia showed a rapid postoperative decrease on postoperative day 1 (POD1) (ΔAlb POD1) with a median value of 11 g/L. ROC curve analysis determined a cut-off of 11 g/L for the prediction of overall complications. Patients with ΔAlb POD1 ≥ 11 g/L showed increased overall complications (p = 0.004), major complications (p = 0.009) and CCI (p = 0.006) while LoS was comparable (p = 0.099). On multivariable analysis, ΔAlb POD1 ≥ 11 g/L was an independent predictor of overall (OR: 1.55; 95% CI 1.09–2.21; p = 0.015) and major complications (OR: 1.43; 95% CI 1.09–1.89; p = 0.009). Conclusion Oncological esophagectomy induced a rapid decrease of albuminemia. ΔAlb POD1 ≥ 11 g/L was independently associated with the occurrence of overall and major postoperative complications. ΔAlb appears as a promising biomarker to detect patients at risk of adverse outcomes after oncological esophagectomy.

Orringer, McKeown and Ivor Lewis esophagectomy are the most commonly performed procedures for esophageal and gastro-esophageal junction cancer. Anastomotic leakage remains a major problem after all types of esophagectomy and it is currently unknown whether anastomotic leakage severity is different between the types of esophagectomy. The aim of this study was to investigate the relationship between surgical techniques and the severity of anastomotic leakage in patients after Orringer esophagectomy, McKeown esophagectomy or Ivor Lewis esophagectomy. Methods All esophageal and gastro-esophageal junction cancer patients with anastomotic leakage after Orringer, McKeown or Ivor Lewis esophagectomy between 2011 and 2019 were selected from the Dutch Upper Gastrointestinal Cancer Audit (DUCA). The primary outcome parameter was a composite endpoint of reoperation, intensive care unit (ICU) readmission and 30-day/in-hospital mortality. Secondary outcome parameters included postoperative complications, re-intervention rate, ICU and hospital length of stay. Results Data from 1034 patients with anastomotic leakage after Orringer (n = 287), McKeown (n = 397) and Ivor Lewis esophagectomy (n = 346) were evaluated. The primary endpoint occurred in 36.3% of patients with anastomotic leakage after Orringer esophagectomy, in 55.4% of patients with anastomotic leakage after McKeown esophagectomy and in 61.2% of patients with anastomotic leakage after Ivor Lewis esophagectomy (p Conclusion Consequences of anastomotic leakage are most severe after Ivor Lewis esophagectomy, moderately severe after McKeown esophagectomy and least severe after Orringer esophagectomy. This study demonstrated that not only the incidence, but also the severity of anastomotic leakage should be considered in current clinical practice and in studies that compare leakage rates between different surgical techniques of esophagectomy.

Background: Identifying predictors of anastomotic leakage can contribute to prevention of this common complication after esophagectomy. This study identified predictors for anastomotic leakage and assessed the influence of anastomotic leakage on short-term outcomes and long-term survival. Methods: A retrospective cohort study was conducted of consecutive patients who underwent esophagectomy in the Amsterdam University Medical Centers, location Amsterdam Medical Center, between 1993 and 2019. Multilevel logistic and Cox regression models were used to assess predictors for anastomotic leakage and survival, and an operation year-level random effects was considered for the unmeasured characteristics at year of operation. Results: Included were 1539 patients, and anastomotic leakage developed in 288 (19%). Predictors for developing anastomotic leakage after a transthoracic esophagectomy were a higher body mass index and a cervical anastomosis. Diabetes mellitus type 2 and chronic obstructive pulmonary disease were predictors for anastomotic leakage after a transhiatal esophagectomy. Median intensive care unit and hospital stay was longer for patients with anastomotic leakage than for patients without anastomotic leakage (both P < .001 for transthoracic esophagectomy, P = .010 and P < .001, respectively, for transhiatal esophagectomy). A higher percentage of patients with anastomotic leakage died within 30 days (3.8% vs 1.9%, P = .050). However, anastomotic leakage did not significantly influence long-term survival (hazard ratio, 0.994; 95% CI, 0.849-1.176; P = .994). Conclusions: Higher body mass index, cervical anastomosis, diabetes mellitus, and chronic obstructive pulmonary disease are predictors for anastomotic leakage after esophagectomy. Anastomotic leakage is associated with worse short-term outcomes, but long-term survival was not influenced. Future studies should focus on patient optimization, accurate patient selection, and development of tools in risk assessment.

Deep neuromuscular blockade (NMB) can improve surgical conditions and possibly pain after low-risk laparoscopic surgery. We hypothesized that targeting a deep level of NMB by a continuous compared with an on-demand infusion of rocuronium could improve surgical conditions in patients undergoing thoraco-laparoscopic esophagectomy. In this single-centre, randomized-controlled, double-blind trial, patients received either a continuous infusion of rocuronium 0.6 mg·kg−1·hr−1 (intervention) or NaCl 0.9% (control). Both surgeon and anesthesiologist were blinded to group assignment and the train-of-four measurements. Open-label rocuronium was given if requested (i.e., on-demand) by the surgeon. At the end of surgery, sugammadex was given if necessary to reverse the NMB. The primary outcome was the quality of surgical conditions during the abdominal phase of the operation as measured by the surgical rating scale (SRS). Secondary outcomes included the thoracic SRS, number of on-demand boluses, intraoperative surgical events, pain scores (up to 12 hr postoperatively), and duration of surgery. The median [interquartile range] abdominal SRS was not different between the intervention (4 [4–5]) and control (4 [4–5]) groups (median difference, 0; 95% confidence interval, 0 to 0; P = 0.45). The thoracic SRS was 4 [4–4] in both groups (P = 0.23). The median number of rocuronium bolus requests was higher in the control group compared with the intervention group (3 [3–6] vs 1 [0–2], respectively; P 0.05), or duration of surgery (P = 0.95). Continuous rocuronium infusion did not improve surgical conditions when boluses of rocuronium were available on-demand. No major benefits in other outcomes were seen. EUDRACT (2014-002147-18); registered 19 May, 2014 and clinicaltrials.gov (NCT02320734); registered 18 December, 2014.

Esophagectomy with gastric tube reconstruction is a highly complex surgical procedure. With regard to mobilization of the stomach and optimal gastric tube preparation and anastomosis, there are several important intraoperative steps that can influence the outcome of the operation. This study aims to describe the optimal mobilization of the stomach for gastric tube reconstruction and explore the best place in the gastric tube for intrathoracic anastomosis after esophagectomy. A search of the literature was performed and results are described in a descriptive review. Based on literature and our own experience we describe important operating steps for laparoscopic stomach mobilisation for gastric tube reconstruction. Steps to create additional length include preserving the left gastroepiploic artery, transecting the right gastric artery, extended duodenal mobilization, and duodenal diversion with roux-Y reconstruction. Several techniques for intrathoracic anastomosis are described in literature. Several imaging techniques, of which fluorescence imaging is the most commonly used, are available to assess the vascularization of the gastric tube and to assist in determining the best place in the gastric tube for intra thoracic anastomosis. Although there is little evidence of exact technique on stomach mobilization and location for an intrathoracic anastomosis, many techniques are used by different authors with varying results.

Objective: We examined the association between surgical hospital volume and both overall survival (OS) and disease-free survival (DFS) using data obtained from the international CRITICS (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) trial. Summary Background Data: In the CRITICS trial, patients with resectable gastric cancer were randomized to receive preoperative chemotherapy followed by adequate gastrectomy and either chemotherapy or chemoradiotherapy. Methods: Patients in the CRITICS trial who underwent a gastrectomy with curative intent in a Dutch hospital were included in the analysis. The annual number of gastric cancer surgeries performed at the participating hospitals was obtained from the Netherlands Cancer Registry; the hospitals were then classified as low-volume (1 – 20 surgeries/year) or high-volume (≥21 surger-surgeries/year) and matched with the CRITICS trial data. Univariate and multivariate analyses were then performed to evaluate the hazard ratio (HR) between hospital volume and both OS and DFS. Results: From 2007 through 2015, 788 patients were included in the CRITICS trial. Among these 788 patients, 494 were eligible for our study; the median follow-up was 5.0 years. Five-year OS was 59.2% and 46.1% in the high-volume and low-volume hospitals, respectively. Multivariate analysis revealed that undergoing surgery in a high-volume hospital was associated with higher OS [HR ¼ 0.69, 95% confidence interval (CI) ¼ 0.50 – 0.94, P ¼ 0.020] and DFS (HR ¼ 0.73, 95% CI: 0.54 – 0.99, P ¼ 0.040). Conclusions: In the CRITICS trial, hospitals with a high annual volume of gastric cancer surgery were associated with higher overall and DFS. These findings emphasize the value of centralizing gastric cancer surgeries in the Western world.

The current study aims to examine the impact of extracapsular lymph node involvement (EC-LNI) on survival for both esophageal adenocarcinoma (AC) and squamous cell carcinoma (SCC) treated with neoadjuvant chemoradiation therapy (nCRT) followed by surgery. Studies have demonstrated the negative prognostic value of EC-LNI in primary surgery, but its impact after nCRT remains unclear. From the databases of 6 European high-volume centers 1505 patients with R0 resections were withheld. Oncologic variables, including ypT, ypN, number of positive lymph nodes, and lymph node capsular status: EC-LNI and intracapsular lymph node involvement (IC-LNI), were examined. Statistical analysis was performed by Cox proportional hazards modeling. In SCC 182 patients (31.6%) had positive lymph nodes, of whom 60 (33.0%) showed EC-LNI. In AC 391 patients (42.1%) had positive lymph nodes, of whom 147 (37.6%) showed EC-LNI. Overall 5-year survival (O5YS) in SCC was 42.0%. Presence of EC-LNI meant a significantly worse O5YS than IC-LNI or pN0 (10.6%, 39.5%, and 47.4%, respectively; P < 0.05). O5YS in AC was 41.2%. No significant difference was observed between EC-LNI and IC-LNI (P = 0.322). In the multivariate analysis, among the examined possible prognosticators, presence of EC-LNI showed the highest hazard ratio (2.29, confidence interval: 1.52-3.47) as an independent prognosticator for overall survival in SCC, but it was not in AC. Based on this international multicenter study, the presence of EC-LNI after nCRT is at least as important as N-stage for survival and EC-LNI is the strongest prognosticator for overall survival in SCC but not in AC

Summary Textbook outcome for esophageal cancer surgery is a composite quality measure including 10 short-term surgical outcomes reflecting an uneventful perioperative course. Achieved textbook outcome is associated with improved long-term survival. This study aimed to update the original textbook outcome based on international consensus. Forty-five international expert esophageal cancer surgeons received a personal invitation to evaluate the 10 items in the original textbook outcome for esophageal cancer surgery and to rate 18 additional items divided over seven subcategories for their importance in the updated textbook outcome. Items were included in the updated textbook outcome if ≥80% of the respondents agreed on inclusion. In case multiple items within one subcategory reached ≥80% agreement, only the most inclusive item with the highest agreement rate was included. With a response rate of 80%, 36 expert esophageal cancer surgeons, from 34 hospitals, 16 countries, and 4 continents responded to this international survey. Based on the inclusion criteria, the updated quality indicator ‘textbook outcome for esophageal cancer surgery’ should consist of: tumor-negative resection margins, ≥20 lymph nodes retrieved and examined, no intraoperative complication, no complications Clavien–Dindo ≥III, no ICU/MCU readmission, no readmission related to the surgical procedure, no anastomotic leakage, no hospital stay ≥14 days, and no in-hospital mortality. This study resulted in an international consensus-based update of a quality measure, textbook outcome for esophageal cancer surgery. This updated textbook outcome should be implemented in quality assurance programs for centers performing esophageal cancer surgery, and could standardize quality measures used internationally.

We assessed the feasibility of adjuvant S-1 and oxaliplatin following neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Patients treated with nCRT (paclitaxel, carboplatin) and esophagectomy received six 21-day cycles with oxaliplatin (130 mg/m2) on day 1 and S-1 (25 mg/m2 twice daily) on days 1–14. The primary endpoint was feasibility, defined as ≥50% completing treatment. We performed exploratory propensity-score matching to compare survival, ERCC1 and Thymidylate Synthase (TS) immunohistochemistry analyses, proteomics biomarker discovery and 5-FU pharmacokinetic analyses. Forty patients were enrolled and 48% completed all adjuvant cycles. Median dose intensity was 98% for S-1 and 62% for oxaliplatin. The main reason for early discontinuation was toxicity (67%). The median recurrence-free and overall survival were 28.3 months and 40.8 months, respectively (median follow-up 29.1 months). Survival was not significantly prolonged compared to a matched cohort (p = 0.09). Patients with ERCC1 negative tumor expression had significantly better survival compared to ERCC1 positivity (p = 0.01). Our protein signature model was predictive of survival [p = 0.04, Area under the curve (AUC) 0.80]. Moreover, 5-FU pharmacokinetics significantly correlated with treatment-related toxicity. To conclude, six cycles adjuvant S-1 and oxaliplatin were not feasible in pretreated esophageal adenocarcinoma. Although the question remains whether additional treatment with chemotherapy should be provided in the adjuvant setting, subgroups such as patients with ERCC1 negativity could potentially benefit from adjuvant SOX based on our exploratory biomarker research.

There are four ways to perform the esophagojejunal anastomosis after a total gastrectomy: the conventional circular stapler (described in Chap. 36), the circular Orvil® device anastomosis and the linear stapler side-to-side anastomosis are here described, and the hand-sewn anastomosis (reported in Chap. 39).

Item does not contain fulltext BACKGROUND: Esophagectomy is a technically challenging procedure, associated with significant morbidity. The introduction of minimally invasive esophagectomy (MIE) has reduced postoperative morbidity. OBJECTIVE: Although the short-term effect on complications is increasingly being recognized, the impact on long-term survival remains unclear. This study aims to investigate the association between postoperative complications following MIE and long-term survival. METHODS: Data were collected from the EsoBenchmark Collaborative composed by 13 high-volume, expert centers routinely performing MIE. Patients operated between June 1, 2011 and May 31, 2016 were included. Complications were graded using the Clavien-Dindo (CD) classification. To correct for short-term effects of postoperative complications on mortality, patients who died within 90 days postoperative were excluded. Primary endpoint was 5-year overall survival. RESULTS: A total of 915 patients were included with a mean follow-up time of 30.8 months (standard deviation 17.9). Complications occurred in 542 patients (59.2%) of which 50.2% had a CD grade ≥III complication [ie, (re)intervention, organ dysfunction, or death]. The incidence of anastomotic leakage (AL) was 135 of 915 patients (14.8%) of which 84 patients were classified as a CD grade ≥III. Multivariable analysis showed a significantly deteriorated long-term survival in all patients with AL [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.25-2.24]. This inverse relation was most distinct when AL was scored as a CD grade ≥III (HR 1.83, 95% CI 1.30-2.58). For all other complications, no significant association with long-term survival was found. CONCLUSION: The occurrence and severity of AL, but not overall complications, after MIE negatively affect long-term survival of esophageal cancer patients.

Introduction: Minimally invasive techniques show improved short-term and comparable long-term outcomes compared to open techniques in the treatment of gastric cancer and improved survival has been seen with the implementation of multimodality treatment. Therefore, focus of research has shifted towards optimizing treatment regimens and improving quality of life. Materials and methods: A randomized trial was performed in thirteen hospitals in Europe. Patients were randomized between open total gastrectomy (OTG) or minimally invasive total gastrectomy (MITG) after neoadjuvant chemotherapy. This study investigated patient reported outcome measures (PROMs) on health-related quality of life (HRQoL) following OTG or MITG, using the Euro-Qol-5D (EQ-5D) and the European Organization for Research and Treatment of Cancer (EORTC) questionnaires, modules C30 and STO22. Due to multiple testing a p-value < 0.001 was deemed statistically significant. Results: Between January 2015 and June 2018, 96 patients were included in this trial. Forty-nine patients were randomized to OTG and 47 to MITG. A response compliance of 80% was achieved for all PROMs. The EQ5D overall health score one year after surgery was 85 (60–90) in the open group and 68 (50–83.8) in the minimally invasive group (P = 0.049). The median EORTC-QLQ-C30 overall health score one year postoperatively was 83,3 (66,7–83,3) in the open group and 58,3 (35,4–66,7) in the minimally invasive group (P = 0.002). This was not statistically significant. Conclusion: No differences were observed between open total gastrectomy and minimally invasive total gastrectomy regarding HRQoL data, collected using the EQ-5D, EORTC QLQ-C30 and EORTC-QLQ-STO22 questionnaires.

Immunotherapy is a new anti-cancer treatment option, showing promising results in clinical trials. To investigate potential immune biomarkers in esophageal adenocarcinoma (EAC), we explored immune landscape patterns in the tumor microenvironment before and after neoadjuvant chemoradiation (nCRT). Sections from matched pretreatment biopsies and post-nCRT resection specimens (n = 188) were stained for (1) programmed death-ligand 1 (PD-L1, CD274); (2) programmed cell death protein 1 (PD-1, CD279), forkhead box P3 (FOXP3), CD8, pan-cytokeratin multiplex; and (3) an MHC class I, II duplex. The densities of tumor-associated immune cells (TAICs) were calculated using digital image analyses and correlated to histopathological nCRT response [tumor regression grade (TRG)], survival, and post-nCRT immune patterns. PD-L1 positivity defined by a combined positive score of >1 was associated with a better response post-nCRT (TRG 1–3 versus 4, 5, p = 0.010). In addition, high combined mean densities of CD8 +, FOXP3 +, and PD-1 + TAICs in the tumor epithelium and stroma of biopsies were associated with a better response (TRG 1–3 versus 4, 5, p = 0.025 and p = 0.044, respectively). Heterogeneous TAIC density patterns were observed post-nCRT, with significantly higher CD8 + and PD-1 + TAIC mean densities compared with biopsies (both p = 0.000). Three immune landscape patterns were defined post-nCRT: ‘inflamed’, ‘invasive margin’, and ‘desert’, of which ‘inflamed’ was the most frequent (57%). Compared with matched biopsies, resection specimens with ‘inflamed’ tumors showed a significantly higher increase in CD8 + density compared with non-inflamed tumors post-nCRT (p = 0.000). In this cohort of EAC patients, higher TAIC densities in pretreatment biopsies were associated with response to nCRT. This warrants future research into the potential of the tumor-immune landscape for patient stratification and novel (immune) therapeutic strategies.

The anastomosis will be performed after complete mediastinal lymphadenectomy and mobilization of the esophagus. The abdominal lymphadenectomy and gastric tube creation have been performed earlier, by laparoscopy during the abdominal phase.

Since intensive care unit (ICU) admission and chemotherapy use near death impair the quality of life, we studied the prevalence of both and their correlation with hospital volume in incurable gastroesophageal cancer patients as both impair the quality of life. We analyzed all Dutch patients with incurable gastroesophageal cancer who died in 2017&ndash, 2018. National insurance claims data were used to determine the prevalence of ICU admission and chemotherapy use (stratified on previous chemotherapy treatment) at three and one month(s) before death. We calculated correlations between hospital volume (i.e., the number of included patients per hospital) and both outcomes. We included 3748 patients (mean age: 71.4 years, 71.4% male). The prevalence of ICU admission and chemotherapy use were, respectively, 5.6% and 21.2% at three months and 4.2% and 8.0% at one month before death. Chemotherapy use at three and one months before death was, respectively, 4.3 times (48.0% vs. 11.2%) and 3.7 times higher (15.7% vs. 4.3%), comparing patients with previous chemotherapy treatment to those without. Hospital volume was negatively correlated with chemotherapy use in the final month (rweighted = &minus, 0.23, p = 0.04). ICU admission and chemotherapy use were relatively infrequent. Oncologists in high-volume hospitals may be better equipped in selecting patients most likely to benefit from chemotherapy.

Background Minimally invasive esophagectomy with two-field lymphadenectomy is standard of care for T1b esophageal adenocarcinoma (EAC) with a high risk of lymph node metastasis. Sentinel node navigation surgery (SNNS) is a well-known concept to tailor the extent of lymphadenectomy. The aim of this study was to evaluate the feasibility and safety of SNNS with a hybrid tracer (technetium-99 m/indocyanine green/nanocolloid) for patients with high-risk T1b EAC. Methods In this prospective, multicenter pilot study, 5 patients with high-risk T1b EAC were included. The tracer was injected endoscopically around the endoscopic resection scar the day before surgery, followed by preoperative imaging (lymphoscintigraphy/SPECT-CT). During surgery, first the SNs were localized and resected based on preoperative imaging and intraoperative gammaprobe- and fluorescence-based detection, followed by esophagectomy. Primary endpoints were the percentage of patients with detectable SNs, concordance between preoperative and intraoperative SN detection, and the additive value of indocyanine green. Results SNs could be identified and resected in all patients (median 3 SNs per patient, range 2–7). There was a high concordance between preoperative and intraoperative SN detection. In 2 patients additional peritumoral SNs were identified with fluorescence-based detection. None of the resected lymph nodes showed signs of (micro)metastases and no nodal metastases were detected in the surgical resection specimen. Conclusions SNNS using technetium-99 m/indocyanine green/nanocolloid seems feasible and safe in patients with high-risk T1b EAC. Indocyanine green fluorescence seems to be of additive value for detection of peritumoral SNs. Whether this approach can optimize selection for esophagectomy needs to be studied in future research.

Background: The distribution of lymph node metastases in esophageal adenocarcinoma following neoadjuvant chemoradiation (nCRTx) is unclear, but may have consequences for radiotherapy and surgery. The aim of this study was to define the distribution of lymph node metastases and relation to the radiation field in patients following nCRTx and esophagectomy. Methods: Between April 2014 and August 2015 esophageal adenocarcinoma patients undergoing transthoracic esophagectomy with 2-field lymphadenectomy following nCRTx were included in this prospective observational study. Lymph node stations according to AJCC 7 were separately investigated. The location of lymph node metastases in relation to the radiation field was determined. The primary endpoint was the distribution of lymph node metastases and relation to the radiation field, the secondary endpoints were high-risk stations and risk factors for lymph node metastases and relation to survival. Results: Fifty consecutive patients were included. Lymph node metastases were found in 60% of patients and most frequently observed in paraesophageal (28%), left gastric artery (24%), and celiac trunk (18%) stations. Fifty-two percent had lymph node metastases within the radiation field. The incidence of lymph node metastases correlated significantly with ypT-stage (p = 0.002), cT-stage (p = 0.005), lymph angioinvasion (p = 0.004), and Mandard (p = 0.002). The number of lymph node metastases was associated with survival in univariable analysis (HR 1.12, 95% CI 1.068–1.173, p ' 0.001). Conclusions: Esophageal adenocarcinoma frequently metastasizes to both the mediastinal and abdominal lymph node stations. In this study, more than half of the patients had lymph node metastases within the radiation field. nCRTx is therefore not a reason to minimize lymphadenectomy in patients with esophageal adenocarcinoma.

In this study, four optical techniques&mdash, Optical Coherence Tomography, Sidestream Darkfield Microscopy, Laser Speckle Contrast Imaging, and Fluorescence Angiography (FA)&mdash, were compared on performing an intraoperative quantitative perfusion assessment of the gastric conduit during oesophagectomy. We hypothesised that the quantitative parameters show decreased perfusion towards the fundus in the gastric conduit and in patients with anastomotic leakage. In a prospective study in patients undergoing oesophagectomy with gastric conduit reconstruction, measurements were taken with all four optical techniques at four locations from the base towards the fundus in the gastric conduit (Loc1, Loc2, Loc3, Loc4). The primary outcome included 14 quantitative parameters and the anastomotic leakage rate. Imaging was performed in 22 patients during oesophagectomy. Ten out of 14 quantitative parameters significantly indicated a reduced perfusion towards the fundus of the gastric conduit. Anastomotic leakage occurred in 4/22 patients (18.4%). At Loc4, the FA quantitative values for &ldquo, T1/2&rdquo, and &ldquo, mean slope&rdquo, differed between patients with and without anastomotic leakage (p = 0.025 and p = 0.041, respectively). A quantitative perfusion assessment during oesophagectomy is feasible using optical imaging techniques, of which FA is the most promising for future research.

Metastatic lymphatic mapping in esophageal cancer is important to determine the optimal extent of the radiation field in case of neoadjuvant chemoradiotherapy and lymphadenectomy when esophagectomy is indicated. The objective of this review is to identify the distribution pattern of metastatic lymphatic spread in relation to histology, tumor location, and T-stage in patients with esophageal cancer. Embase and Medline databases were searched by two independent researchers. Studies were included if published before July 2019 and if a transthoracic esophagectomy with a complete 2- or 3-field lymphadenectomy was performed without neoadjuvant therapy. The prevalence of lymph node metastases was described per histologic subtype and primary tumor location. Fourteen studies were included in this review with a total of 8952 patients. We found that both squamous cell carcinoma and adenocarcinoma metastasize to cervical, thoracic, and abdominal lymph node stations, regardless of the primary tumor location. In patients with an upper, middle, and lower thoracic squamous cell carcinoma, the lymph nodes along the right recurrent nerve are often affected (34%, 24% and 10%, respectively). Few studies describe the metastatic pattern of adenocarcinoma. The current literature is heterogeneous in the classification and reporting of lymph node metastases. This complicates evidence-based strategies in neoadjuvant and surgical treatment.

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 outcomes in the present study were postoperative complications, major complications (Clavien-Dindo grade ≥III), and 30-day mortality, according to definitions of the ECCG. RESULTS: A total of 2545 patients from 22 hospitals were included. The completeness of the Dutch Upper gastrointestinal Cancer Audit was estimated at 99.8%. Data accuracy on different items was 94% to 100%. After esophagectomy, 1046 of 1617 patients (65%) had a postoperative complication including 468 patients (29%) with a major complication. Most common complications were pneumonia (21%), esophago-enteric leak from anastomosis, staple line or localized conduit necrosis (19%), and atrial dysrhythmia (15%). The 30-day mortality was 1.7%. After gastrectomy, 397 of 928 patients (42%) had a postoperative complication including 180 patients (19%) with a major complication. Most common complications were pneumonia (12%), esophago-enteric leak from anastomosis, staple line or localized conduit necrosis (9%), and acute delirium (5%). The 30-day mortality was 4.4%. CONCLUSIONS: Reporting complications according to the ECCG platform is feasible in the Netherlands and facilitates international benchmarking.

PURPOSE Approximately 15% to 43% of esophageal adenocarcinomas (EACs) are human epidermal growth factor receptor 2 (HER2) positive. Because dual-agent HER2 blockade demonstrated a survival benefit in breast cancer, we conducted a phase II feasibility study of trastuzumab and pertuzumab added to neoadjuvant chemoradiotherapy (nCRT) in patients with EAC. PATIENTS AND METHODS Patients with resectable HER2-positive EAC received standard nCRT with carboplatin and paclitaxel and 41.4 Gy of radiotherapy, with 4 mg/kg of trastuzumab on day 1, 2 mg/kg per week during weeks 2 to 6, and 6 mg/kg per week during weeks 7, 10, and 13 and 840 mg of pertuzumab every 3 weeks. The primary end point was feasibility, defined as ≥ 80% completion of treatment with both trastuzumab and pertuzumab. An exploratory comparison of survival with a propensity score–matched cohort receiving standard nCRT was performed, as were exploratory pharmacokinetic and biomarker analyses. RESULTS Of the 40 enrolled patients (78% men; median age, 63 years), 33 (83%) completed treatment with trastuzumab and pertuzumab. No unexpected safety events were observed. R0 resection was achieved in all patients undergoing surgery, with pathologic complete response in 13 patients (34%). Three-year progression-free and overall survival (OS) were 57% and 71%, respectively (median follow-up, 32.1 months). Compared with the propensity score–matched cohort, a significantly longer OS was observed with HER2 blockade (hazard ratio, 0.58; 95% CI, 0.34 to 0.97). Results of pharmacokinetic analysis and activity on [18F]fluorodeoxyglucose positron emission tomography scans did not correlate with survival or pathologic response. Patients with HER2 3+ overexpression or growth factor receptor–bound protein 7 (Grb7) –positive tumors at baseline demonstrated significantly better survival ( P = .007) or treatment response ( P = .016), respectively. CONCLUSION Addition of trastuzumab and pertuzumab to nCRT in patients with HER2-positive EAC is feasible and demonstrates potentially promising activity compared with historical controls. HER2 3+ overexpression and Grb7 positivity are potentially predictive for survival and treatment response, respectively.

For resectable adenocarcinoma (AC) of the gastro-oesophageal junction (GEJ), several treatment options are available including: perioperative chemotherapy and neoadjuvant chemoradiotherapy (nCRT) [...

Background Surgical resection with adequate lymphadenectomy is regarded the only curative option for gastric cancer. Regarding minimally invasive techniques, mainly Asian studies showed comparable oncological and short-term postoperative outcomes. The incidence of gastric cancer is lower in the Western population and patients often present with more advanced stages of disease. Therefore, the reproducibility of these Asian results in the Western population remains to be investigated. Methods A randomized trial was performed in thirteen hospitals in Europe. Patients with an indication for total gastrectomy who received neoadjuvant chemotherapy were eligible for inclusion and randomized between open total gastrectomy (OTG) or minimally invasive total gastrectomy (MITG). Primary outcome was oncological safety, measured as the number of resected lymph nodes and radicality. Secondary outcomes were postoperative complications, recovery and 1-year survival. Results Between January 2015 and June 2018, 96 patients were included in this trial. Forty-nine patients were randomized to OTG and 47 to MITG. The mean number of resected lymph nodes was 43.4 ± 17.3 in OTG and 41.7 ± 16.1 in MITG (p = 0.612). Forty-eight patients in the OTG group had a R0 resection and 44 patients in the MITG group (p = 0.617). One-year survival was 90.4% in OTG and 85.5% in MITG (p = 0.701). No significant differences were found regarding postoperative complications and recovery. Conclusion These findings provide evidence that MITG after neoadjuvant therapy is not inferior regarding oncological quality of resection in comparison to OTG in Western patients with resectable gastric cancer. In addition, no differences in postoperative complications and recovery were seen.

Objective The microscopic tumor spread (MS) beyond the macroscopic tumor borders of esophageal tumors is crucial for determining the clinical target volume (CTV) in radiotherapy. The question arises whether current voluminous CTV margins of 3–5 cm around the macroscopic gross tumor volume (GTV) to account for MS are still accurate when fiducial markers are used for GTV determination. We aimed to pathologically validate the use of fiducial markers placed on the (echo)endoscopically determined tumor border (EDTB) as a surrogate for macroscopic tumor borders and to analyse the MS beyond EDTBs. Methods Thirty-three consecutive esophageal cancer patients treated with neo-adjuvant chemoradiotherapy after (echo)endoscopic fiducial marker implantation at cranial and caudal EDTB were included in this study. Fiducial marker positions were detected in the surgical specimens under CT guidance and demarcated with beads, and subsequently analysed for macroscopic tumor spread and MS beyond the demarcations. A logistic regression analysis was performed to determine predicting factors for MS beyond EDTB. Results A total of 60 EDTBs were examined in 32 patients. In 50% of patients no or only partial regression of tumor in response to therapy (≥Mandard 3) or higher was seen (i.e., residual tumor group) and included for MS analysis. None had macroscopic tumor spread beyond EDTBs. In the residual tumor group, only 20 and 21% of the cranial and caudal EDTBs were crossed with a maximum of 9 mm and 16 mm MS, respectively. This MS was corrected for each individual determined contraction rate (mean: 93%). Presence of MS beyond EDTB was significantly associated with initial tumor length (p = 0.028). Conclusion Our results validate the use of fiducial markers on EDTB as a surrogate for macroscopic tumor and indicate that CTV margins around the GTV to compensate for MS along the esophageal wall can be limited to 1–1.5 cm, when the GTV is determined with fiducial markers.

Background: Radiomic features retrieved from standard CT-images have shown prognostic power in several tumor sites. In this study, we investigated the prognostic value of pretreatment CT radiomic features to predict overall survival of esophageal cancer patients after chemoradiotherapy. Material and methods: Two datasets of independent centers were analyzed, consisting of esophageal cancer patients treated with concurrent chemotherapy (Carboplatin/Paclitaxel) and 41.4Gy radiotherapy, followed by surgery if feasible. In total, 1049 radiomic features were calculated from the primary tumor volume. Recursive feature elimination was performed to select the 40 most relevant predictors. Using these 40 features and six clinical variables as input, two random forest (RF) models predicting 3-year overall survival were developed. Results: In total 165 patients from center 1 and 74 patients from center 2 were used. The radiomics-based RF model yielded an area under the curve (AUC) of 0.69 (95%CI 0.61-0.77), with the top-5 most important features for 3-year survival describing tumor heterogeneity after wavelet filtering. In the validation dataset, the RF model yielded an AUC of 0.61 (95%CI 0.47-0.75). Kaplan Meier plots were significantly different between risk groups in the training dataset (p = .027) and borderline significant in the validation dataset (p = .053). The clinical RF model yielded AUCs of 0.63 (95%CI 0.54-0.71) and 0.62 (95%CI 0.49-0.76) in the training and validation dataset, respectively. Risk groups did not reach a significant correlation with pathological response in the primary tumor. Conclusions: A RF model predicting 3-year overall survival based on pretreatment CT radiomic features was developed and validated in two independent datasets of esophageal cancer patients. The radiomics model had better prognostic power compared to the model using standard clinical variables.

Aim To identify predictors for anastomotic leakage after esophagectomy and to determine the influence of anastomotic leakage on short-term and long-term survival. Background and methods Identifying predictors of anastomotic leakage after esophagectomy may contribute to its prevention. The influence of anastomotic leakage on long-term survival is unclear. A retrospective cohort study was conducted in consecutive patients who underwent an esophagectomy with reconstruction in the Amsterdam UMC, location AMC, between January 1993 and January 2019. Logistic regression and Cox regression models were used to assess predictors for anastomotic leakage and to assess survival. Results 1747 patients were included, of which 326 (18.7%) developed anastomotic leakage. Independent predictors of cervical anastomotic leakage were diabetes mellitus, cT4-stage and a gastroesophageal junction tumor. ASA grade 3-5, a non-radical resection, pT2-stage, pN+ and hand sewn anastomosis were independent predictors of intrathoracic anastomotic leakage (table 1). 30-day mortality was 2% in patients without, and 4% of patients with anastomotic leakage (p=0.076). Anastomotic leakage did not significantly influence long-term survival when corrected for confounders (HR 0.96 95%CI 0.81 – 1.14, p=0.618). Conclusion Independent risk factors for anastomotic leakage after esophagectomy are diabetes mellitus, cT4-stage and a gastroesophageal junction tumor for cervical anastomosis, and ASA grade 3-5, a non-radical resection, pT2-stage, pN+ and hand sewn anastomosis for intrathoracic anastomosis. 30-day mortality was higher in the anastomotic leakage group. We found no correlation between anastomotic leakage and long term survival.

Trastuzumab, a monoclonal antibody against HER2, has become standard of care for metastatic HER2-overexpressing esophagogastric adenocarcinoma and is currently investigated as (neo)adjuvant treatment option in HER2-positive esophagogastric adenocarcinoma. The HER2 status is commonly determined on archived material of the primary tumor. However, this status may change over the course of treatment or disease progression. The aim of this study was to assess the dynamics of HER2 status in esophageal adenocarcinoma (EAC) in patients with resectable and recurrent disease, and to determine the associations of these changes with clinical outcome. Discordance, defined as any change in HER2 status between matched biopsy and post-neoadjuvant chemoradiation therapy resection specimen (N = 170), or between matched resection specimen and recurrence of patients not eligible for curative treatment (N = 61), was determined using the standardized HER2 status scoring system. Clinically relevant positive discordance was defined as a change to HER2 positive status, as this would imply eligibility for HER2-targeted therapy. A difference in HER2 status between biopsy and resection specimen and resection specimen and metachronous recurrence was observed in 2.1% (n = 3) and 3.3% (n = 2) of the paired cases, respectively. Clinically relevant discordance was detected in 1.4% (n = 2) of the resectable patients and 1.6% (n = 1) of the patients with recurrent disease. Patients with HER2-positive status tumors before start of neoadjuvant treatment showed better overall survival, but not statistically significant. No association between HER2 status discordance and survival was found. Clinically relevant HER2 status discordance was observed and in order to prevent under-treatment of patients, the assessment of HER2 status in the metastatic setting should preferably be performed on the most recently developed lesions if the previous HER2 assessment on archival material of the primary tumor was negative.