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Simple Summary: In the current study, we have collected real-world population data from the Netherlands Cancer Registry of patients who underwent perioperative anthracyclin triplets or FLOT. Our study showed no significant overall survival improvement for FLOT-treated patients compared to anthracyclin triplets, despite more staging laparoscopies in the first group. However, FLOT patients demonstrated higher rates of neoadjuvant therapy completion, proceeding to adjuvant therapy, and increased pathological complete response rates. Even though survival difference failed to reach statistical significance, we believe that our findings hold significance as they mirror the outcomes observed in clinical practice, outside the controlled environment of a clinical trial. Background: The FLOT4-AIO trial (2019) showed improved survival with perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) compared to anthracyclin triplets in gastric cancer treatment. It is unclear whether these results extend to real-world scenarios in the Netherlands. This study aimed to compare outcomes of perioperative FLOT to anthracyclin triplets in a real-world Dutch gastric cancer population. Methods: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) gastric or gastro-esophageal junction carcinoma between 2015–2021 who received neoadjuvant FLOT or anthracyclin triplets were selected from the Netherlands Cancer Registry. The primary outcome was overall survival (OS), analyzed through multivariable Cox regression. Secondary outcomes included pathological complete response (pCR), neoadjuvant chemotherapy cycle completion, surgical resection rates, and adjuvant therapy. Results: Adjusted OS showed no significant survival benefit (HR = 0.88, 95% CI 0.77–1.01, p = 0.07), even though the median OS was numerically improved by 8 months with FLOT compared to anthracyclin triplets (48.1 vs. 39.9 months, p = 0.16). FLOT patients were more likely to undergo diagnostic staging laparoscopies (74.2% vs. 44.1%, p < 0.001), had higher rates of completing neoadjuvant chemotherapy (OR = 1.35, 95% CI 1.09–1.68, p = 0.007), receiving adjuvant therapy (OR = 1.34, 95% CI 1.08–1.66, p = 0.08), and achieving pCR (OR = 1.52, 95% CI 1.05–2.20, p = 0.03). No significant differences were observed in (radical) resection rates. Conclusion(s): Real-world data showed no significant OS improvement for FLOT-treated patients compared to anthracyclin triplets, despite more staging laparoscopies. However, FLOT patients demonstrated higher rates of neoadjuvant therapy completion, proceeding to adjuvant therapy, and increased pCR rates. Therefore, we recommend the continued use of neoadjuvant FLOT therapy in the current clinical setting. [ABSTRACT FROM AUTHOR]

Objective. We aimed to gain consensus on HCPs' perspectives on self-management support information needs of patients with esophageal cancer during the preoperative phase. Methods. Based on the literature, observations of clinical consultations, and hospital patient information leaflets, a survey was created. HCPs were surveyed twice about their opinion on importance of information, from "not essential" to "absolutely essential," using Delphi methods. Topics were included in the second round if predetermined criteria were met. To be included in the final list, topics had to meet criteria for consensus and stability. Results. 64 information items and 6 sources of support were identified. Survey response rates were 59% (68 out of 116, first round) and 75% thereafter. The final list included 33 topics, including logistical information, expectations for future health condition, complications, follow-up care, nutrition during treatment, and nutrition during recovery as topics with 100% agreement. Consensus on the source of support was reached for face-to-face contact, written information, information video, and a case manager. Conclusion. This study provides a list of important topics, from the perspectives of HCPs, to guide the systematic provision of education to support EC patients' self-management during the preoperative phase. Additionally, the most preferred sources of support were face-to-face contact and a case manager. [ABSTRACT FROM AUTHOR]

Data on the age-specific incidence of esophageal cancer are lacking. Our aim was to investigate the age-stratified incidence, treatment, and survival trends of esophageal cancer in the Netherlands, with a focus on adults <50 years. Patients diagnosed with esophageal cancer were included from the nationwide Netherlands Cancer Registry (1989–2018). Follow-up data were available until 31 December 2018. Annual percentage changes of incidence were analyzed according to age group (<50, 50–74, and ≥75 years) and histology type: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). Treatment trends and relative survival rates (RSR) were estimated by age and stage grouping. A total 59,584 patients were included. In adults <50 years, EAC incidence tripled (mean increase per year: males 1.5%, females 3%), while the incidence of ESCC decreased (mean decrease per year: males −5.3%, females −4.3%). Patients <50 years more often presented with advanced disease stages compared to older patients and were more likely to receive multimodality treatments. Most patients <50 years with potentially curable disease were treated with neoadjuvant chemoradiotherapy followed by surgery compared to patients 50–74 and ≥75 years (74% vs. 55% vs. 15%, respectively; p <.001), and received more frequent systemic therapy once staged with palliative disease (72% vs. 54% vs. 19%, respectively; p <.001). The largest RSR improvement was seen in patients <50 years with early-stage (five years: +47%), potentially curable (five years: +22%), and palliative disease (one year: +11%). Over time, a trend of increasing survival difference was seen between patients <50 and ≥75 years with potentially curable (five-year difference: 17% to 27%) and palliative disease (one-year difference: 11% to 20%). The incidence of EAC is increasing in adults <50 years in the Netherlands. Differences in the use of multimodality treatments with curative or life-prolonging intent in different age categories may account for increasing survival gaps. [ABSTRACT FROM AUTHOR]

With increasing interest in organ-preserving strategies for potentially curable esophageal cancer, real-world data is needed to understand the impact of pathological tumor response after neoadjuvant chemoradiotherapy (CRT) on patient outcome. The objective of this study is to assess the association between pathological tumor response following CROSS neoadjuvant CRT and long-term overall survival (OS) in a nationwide cohort. All patients diagnosed in the Netherlands with potentially curable esophageal cancer between 2009 and 2017, and treated with neoadjuvant CRT followed by esophagectomy were included. Through record linkage with the nationwide Dutch Pathology Registry (PALGA), pathological data were obtained. The primary outcome was pathological tumor response based on ypTNM, classified into pathological complete response (ypT0N0) and incomplete responders (ypT0N+, ypT+N0, and ypT+N+). Multivariable logistic and Cox regression models were used to identify predictors of pathological complete response (pCR) and survival. A total of 4946 patients were included. Overall, 24% achieved pCR, with 19% in adenocarcinoma and 42% in squamous cell carcinoma. Patients with pCR had a better estimated 5-year OS compared to incomplete responders (62% vs. 38%, p<.001). Of the patients with incomplete response, ypT+N+ patients (32% of total population) had the lowest estimated 5-year OS rate, followed by ypT0N+ and ypT+ N0 (22%, 47%, and 49%, respectively, p<.001). Adenocarcinoma, well to moderate differentiation, cT3-4, cN+, signet ring cell differentiation and lymph node yield (≥15) were associated with lower likelihood of pCR. In this population-based study, pathological tumor response based on the ypTNM-stage was associated with different prognostic subgroups. A quarter of patients achieved ypT0N0 with favorable long-term survival, while one-third had an ypT+N+ response with very poor survival. The association between pathological tumor response and long-term survival could help in more accurate assessments of individual prognosis and treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Following esophagectomy, esophageal cancer patients experience a clinically relevant deterioration of health-related quality of life, both on the short- and long-term. With the currently growing number of esophageal cancer survivors, the burden of disease- and treatment-related complaints and symptoms becomes more relevant. This emphasizes the need for interventions aimed at improving quality of life. Beneficial effects of post-operative physical exercise have been reported in several cancer types, but so far comparable evidence in esophageal cancer patients is lacking. The aim of this study is to investigate effects of physical exercise on health-related quality of life in esophageal cancer patients following surgery.Methods: The Physical ExeRcise Following Esophageal Cancer Treatment (PERFECT) study is a multicenter randomized controlled trial including 150 esophageal cancer patients after surgery with curative intent. Patients are randomly allocated to an exercise group or usual care group. The exercise group participates in a 12-week combined aerobic and resistance exercise program, supervised by a physiotherapist near the patient's home-address. In addition, participants in the exercise group are requested to be physically active for at least 30 min per day, every day of the week. Participants allocated to the usual care group are asked to maintain their habitual physical activity pattern. The primary outcome is health-related quality of life (EORTC-QLQ-C30). Secondary outcomes include esophageal cancer specific quality of life, fatigue, anxiety and depression, sleep quality, work-related factors, cardiorespiratory fitness (VO2peak), muscle strength, physical activity, malnutrition risk, anthropometry, blood markers, recurrence of disease and survival. All questionnaire outcomes, diaries and accelerometers are assessed at baseline, post-intervention (12 weeks post-baseline) and 24 weeks post-baseline. Physical fitness, anthropometry and blood markers are assessed at baseline and post-intervention. In addition, adherence and safety are monitored throughout the exercise program.Discussion: This randomized controlled trial investigates effects of physical exercise versus usual care in esophageal cancer patients after surgery. As the design of the exercise program closely resembles daily practice, this study can contribute both to evidence on effects of exercise in esophageal cancer patients, and to potential implementation strategies.Trial Registration: Trial registration:Netherlands Trial Registry NTR5045 Date of trial registration: January 19th, 2015 Date and version study protocol: February 2017, version 1. [ABSTRACT FROM AUTHOR]

Introduction: Esophagectomy for cancer can be performed in a two-stage procedure with an intrathoracic anastomosis: the Ivor Lewis esophagectomy. A growing incidence of distal and gastroesophageal junction adenocarcinomas and increasing use of minimally invasive techniques have prompted interest in this procedure. The aim of this study was to assess short-term results of minimally invasive Ivor Lewis esophagectomy (MIE-IL).Methods: A retrospective cohort study was performed from June 2007 until September 2014, including patients that underwent MIE-IL for distal esophageal and gastroesophageal junction cancer in six different hospitals in the Netherlands and Spain. Data were collected with regard to operative techniques, pathology and postoperative complications.Results: In total, 282 patients underwent MIE-IL, of which 90.2 % received neoadjuvant therapy. Anastomotic leakage was observed in 43 patients (15.2 %), of whom 13 patients (4.6 %) had empyema, necessitating thoracotomy for decortication. With an aggressive treatment of complications, the 30-day and in-hospital mortality rate was 2.1 %. An R0-resection was obtained in 92.5 % of the patients. After neoadjuvant therapy, 20.1 % of patients had a complete response.Conclusions: Minimally invasive Ivor Lewis esophagectomy for distal esophageal and gastroesophageal junction adenocarcinomas is an upcoming approach for reducing morbidity caused by laparotomy and thoracotomy. Anastomotic leakage rate is still high possibly due to technical diversity of anastomotic techniques, and a high percentage of patients treated by neoadjuvant chemoradiotherapy. An aggressive approach to complications leads to a low mortality of 2.1 %. Further improvement and standardization in the anastomotic technique are needed in order to perform a safe intrathoracic anastomosis. [ABSTRACT FROM AUTHOR]

Background: An important parameter for survival in patients with esophageal carcinoma is lymph node status. The distribution of lymph node metastases depends on tumor characteristics such as tumor location, histology, invasion depth, and on neoadjuvant treatment. The exact distribution is unknown. Neoadjuvant treatment and surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy has not been reached. The aim of this study is to determine the distribution of lymph node metastases in patients with resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed. This can be the foundation for a uniform worldwide staging system and establishment of the optimal surgical strategy for esophageal cancer patients.Methods: The TIGER study is an international observational cohort study with 50 participating centers. Patients with a resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed in participating centers will be included. All lymph node stations will be excised and separately individually analyzed by pathological examination. The aim is to include 5000 patients. The primary endpoint is the distribution of lymph node metastases in esophageal and esophago-gastric junction carcinoma specimens following transthoracic esophagectomy with at least 2-field lymphadenectomy in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and (disease free) survival.Discussion: The TIGER study will provide a roadmap of the location of lymph node metastases in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and survival. Patient-tailored treatment can be developed based on these results, such as the optimal radiation field and extent of lymphadenectomy based on the primary tumor characteristics.Trial Registration: NCT03222895 , date of registration: July 19th, 2017. [ABSTRACT FROM AUTHOR]

Background: Anastomotic leakage (0–30%) after esophagectomy is a severe complication and is associated with considerable morbidity and mortality. The aim of this study was to determine which treatment for anastomotic leakage after esophagectomy have the best clinical outcome, based on the currently available literature. Methods: A systematic literature search was performed in Medline, Embase, and Web of Science until April 2017. All studies reporting on the specific treatment of cervical or intrathoracic anastomotic leakage following esophagectomy with gastric tube reconstruction for esophageal or cardia cancer were included. The primary outcome parameter was postoperative mortality. Methodological quality was assessed by the Newcastle-Ottawa Quality Assessment Scale. Results: Nineteen retrospective cohort studies including 273 patients were identified. Methodological quality of all studies was poor to moderate. Mortality rates of intrathoracic anastomotic leakages in the treatment groups were as follows: conservative (14%), endoscopic stent (8%), endoscopic drainage (8%), endoscopic vacuum-assisted closure system (0%), and surgery treatment group (50%). Mortality rates of cervical anastomotic leakages in the treatment groups were as follows: conservative (8%), endoscopic stent (29%), and endoscopic dilatation (0%). Discussion: Due to small cohorts, heterogeneity between studies, and lack of data regarding leakage characteristics, no evidence supporting a specific treatment for anastomotic leakage after esophagectomy was found. A severity score based on leakage characteristics instead of treatment given is essential for determining the optimal treatment of anastomotic leakage. In the absence of robust evidence-based treatment guidelines, we suggest customized treatment depending on sequelae of the leak and clinical condition of the patient. PrDepartment of Surgery, Radboudumc, P.O.B. 9101/618 NLactical advices are provided. Trial registration: Registration number PROSPERO: CRD42016032374. [ABSTRACT FROM AUTHOR]

Background Neoadjuvant chemoradiotherapy (nCRT) followed by resection of the tumor with two field lymphadenectomy is a standard treatment for esophageal cancer. After nCRT, however, in more than 70% of patients no lymph node metastases are found, suggesting extensive overtreatment. Tumor-targeted fluorescence imaging is a promising technique to detect lymph node metastases intra-operatively and guide personalized resection. The aim of this study is to identify potential viable tumor markers for fluorescence imaging of lymph node metastases in patients with esophageal adenocarcinoma (EAC). Methods Immunohistochemistry (IHC) was performed on tissue microarrays from EAC's patients that underwent surgical resection between 2007 and 2016. Patients were subdivided in five groups, non-pretreated patients with and without metastatic lymph nodes, complete responders, partial responders and non-responders after nCRT. Five membranous markers, c-MET, CAIX, EGFR, EpCAM, HER2, and two cytoplasmic markers, VEGF-A and VEGF-A receptor were included. Tumor marker expression was scored on intensity (none (0), slight (1), moderate (2), strong (3)) and the percentage of positive cells (estimation). Threshold for positive detection rate was defined as an intensity of ≥ 2 in more than 10% the cells. Results EpCAM showed the highest expression in metastastic lymph nodes, with a median intensity of 3 (range 2–3) in > 70% of the tumor cells. Expression was found in 37 out of 39 EAC's (95%). VEGF-A and CAIX expression was observed in 28 of 33 (85%) and 10 of 33 (30%) of metastatic lymph nodes and 34 of 39 (87%) and 17 of 39 (44%) in the primary EAC's, respectively. For the other tumor biomarkers the detection rate ranged between 0 and 11% for metastatic lymph nodes and primary EAC's. Only EpCAM and VEGF-A showed weak, non-specific staining in the fibrotic tissue. Conclusion High expression rates in primary EAC and metastatic lymph nodes were observed using immunohistochemical antibodies for EpCAM, VEGF-A and CA-IX, making these clinically relevant viable EAC tumor markers. A phase 1 dose finding study targeting VEGF-A by Bevacizumab-800-CW in patient with EAC is in preparation. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]