Prediction of Morbidity and Mortality After Esophagectomy: A Systematic Review.

BACKGROUND: Esophagectomy for esophageal cancer has a complication rate of up to 60%. Prediction models could be helpful to preoperatively estimate which patients are at increased risk of morbidity and mortality. The objective of this study was to determine the best prediction models for morbidity and mortality after esophagectomy and to identify commonalities among the models. PATIENTS AND METHODS: A systematic review was performed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and was prospectively registered in PROSPERO ( https://www.crd.york.ac.uk/prospero/ , study ID CRD42022350846). Pubmed, Embase, and Clarivate Analytics/Web of Science Core Collection were searched for studies published between 2010 and August 2022. The Prediction model Risk of Bias Assessment Tool was used to assess the risk of bias. Extracted data were tabulated and a narrative synthesis was performed. RESULTS: Of the 15,011 articles identified, 22 studies were included using data from tens of thousands of patients. This systematic review included 33 different models, of which 18 models were newly developed. Many studies showed a high risk of bias. The prognostic accuracy of models differed between 0.51 and 0.85. For most models, variables are readily available. Two models for mortality and one model for pulmonary complications have the potential to be developed further. CONCLUSIONS: The availability of rigorous prediction models is limited. Several models are promising but need to be further developed. Some models provide information about risk factors for the development of complications. Performance status is a potential modifiable risk factor. None are ready for clinical implementation.

Extent and Boundaries of Lymph Node Stations During Minimally Invasive Esophagectomy: A Survey Among Dutch Esophageal Surgeons.

BACKGROUND: The optimal extent of lymph node dissection (LND) and the anatomic boundaries per lymph node station (LNS) during minimally invasive esophagectomy (MIE) for esophageal cancer remain a topic of debate. This study investigated the opinion of Dutch esophageal cancer surgeons on their routine LND extent and anatomic boundaries per LNS during MIE. METHODS: In April 2023, an English web-based cross-sectional survey was conducted. In each of the 15 Dutch hospitals performing MIE, two MIE surgeons were asked to participate. The routine LND extent (quantity, specific LNS) for distal esophageal adenocarcinoma, (dis)agreement with the TIGER definition, and anatomic boundaries for each LNS in six directions were queried. RESULTS: The survey was completed by 24 Dutch MIE surgeons (80% response rate). Consensus on the routine LND extent ( ≥ 85% of the participating surgeons) included the left and right paracardial, left gastric artery, celiac trunk, proximal splenic artery, common hepatic artery, subcarinal middle mediastinal paraoesophageal, lower mediastinal paraoesophageal, pulmonary ligament, and upper mediastinal paraoesophageal LNSs. Other LNSs were not widely considered routine. Although, certain anatomic boundaries were consistent among the surgeons, the majority varied, even when they agreed on the TIGER definition. CONCLUSION: Significant variations in surgical practice among Dutch esophageal surgeons regarding their routine extent of LND and anatomic boundaries of LNSs during MIE were demonstrated. Variation may have an impact on clinical outcomes, hampering uniform treatment strategies and hindering comparison of performance assessments. This study highlighted the need for an international follow-up study toward one uniform defined LND during MIE for esophageal cancer.

Quantification of fluorescence angiography for visceral perfusion assessment: measuring agreement between two software algorithms.

BACKGROUND: Indocyanine green fluorescence angiography (ICG-FA) may reduce perfusion-related complications of gastrointestinal anastomosis. Software implementations for quantifying ICG-FA are emerging to overcome a subjective interpretation of the technology. Comparison between quantification algorithms is needed to judge its external validity. This study aimed to measure the agreement for visceral perfusion assessment between two independently developed quantification software implementations. METHODS: This retrospective cohort analysis included standardized ICG-FA video recordings of patients who underwent esophagectomy with gastric conduit reconstruction between August 2020 until February 2022. Recordings were analyzed by two quantification software implementations: AMS and CPH. The quantitative parameter used to measure visceral perfusion was the normalized maximum slope derived from fluorescence time curves. The agreement between AMS and CPH was evaluated in a Bland-Altman analysis. The relation between the intraoperative measurement of perfusion and the incidence of anastomotic leakage was determined for both software implementations. RESULTS: Seventy pre-anastomosis ICG-FA recordings were included in the study. The Bland-Altman analysis indicated a mean relative difference of + 58.2% in the measurement of the normalized maximum slope when comparing the AMS software to CPH. The agreement between AMS and CPH deteriorated as the magnitude of the measured values increased, revealing a proportional (linear) bias (R2 = 0.512, p < 0.001). Neither the AMS nor the CPH measurements of the normalized maximum slope held a significant relationship with the occurrence of anastomotic leakage (median of 0.081 versus 0.074, p = 0.32 and 0.041 vs 0.042, p = 0.51, respectively). CONCLUSION: This is the first study to demonstrate technical differences in software implementations that can lead to discrepancies in ICG-FA quantification in human clinical cases. The possible variation among software-based quantification methods should be considered when interpreting studies that report quantitative ICG-FA parameters and derived thresholds, as there may be a limited external validity.

Micronutrient deficiencies and anemia in the follow-up after gastroesophageal cancer surgery.

Due to insufficient dietary intake and altered digestion and absorption of nutrients, patients after gastroesophageal cancer surgery are at risk of becoming malnourished and consequently develop micronutrient deficiencies. The aim of this study was to determine the prevalence of micronutrient deficiencies and anemia during follow-up after gastroesophageal cancer surgery. This single-center cross-sectional study included patients after resection for esophageal or gastric cancer visiting the outpatient clinic in 2016 and 2017. Only patients without signs of recurrent disease were included. All patients were guided by a dietician in the pre- and postoperative phase. Dietary supplements or enteral tube feeding was prescribed in case of inadequate dietary intake. Blood samples were examined for possible deficiencies or abnormalities in hemoglobin, prothrombin time, iron, ferritin, folic acid, calcium, zinc, vitamin A, vitamin B1, vitamin B6, vitamin B12, vitamin D and vitamin E. The percentage of patients with micronutrient deficiencies were scored. Of the 335 patients visiting the outpatient clinic, measurements were performed in 263 patients (221 after esophagectomy and 42 after gastrectomy), resulting in an inclusion rate of 79%. In the esophagectomy group, deficiencies in iron (36%), vitamin D (33%) and zinc (20%) were most prevalent. After gastric resection, deficiencies were most frequently observed in vitamin D (52%), iron (33%), zinc (28%) and ferritin (17%). Low levels of hemoglobin were found in 21% of patients after esophagectomy and 24% after gastrectomy. Despite active nutritional guidance, deficiencies in vitamin D, iron, zinc and ferritin, as well as low levels of hemoglobin, are frequently observed following gastroesophageal resection for cancer. These micronutrients should be periodically checked during follow-up and supplemented if needed.

Contemporary outcomes of left thoraco-abdominal esophagectomy due to cancer in the esophagus or gastroesophageal junction, a multicenter cohort study.

Surgery for cancer of the esophagus or gastro-esophageal junction can be performed with a variety of minimally invasive and open approaches. The left thoracoabdominal esophagectomy (LTE) is an open technique that gives an opportunity to operate in the chest and abdomen with excellent exposure of the gastro-esophageal junction through a single incision, and there is currently no equivalent minimally invasive technique available. The aim of this multi-institutional review was to study a large contemporary international study cohort of patients treated with LTE. An international multicenter cohort study was performed including all patients treated with LTE at six high-volume centers for gastro-esophageal cancer surgery between 2012 and 2022. Patient data were prospectively collected in each participating centers' institutional database. Information about patient, tumor, and treatment details were collected. The study cohort included a total of 793 patients treated with LTE during the study period. The most frequently observed complications were pneumonia in 185/727 (25.5%) patients and atrial fibrillation in 91/727 (12.5%). Anastomotic leak occurred in 35/727 (4.8%) patients; no patient suffered from conduit necrosis. Thirty-day mortality occurred in 15/785 (1.9%) patients and 90-day mortality in 39/785 (5.0%) patients. Factors with statistically significant association with survival were American Society for Anesthesiologists-score, tumor location, tumor stage, and tumor free resection margins. Neoadjuvant therapy was not associated with increased survival compared to surgery alone but neoadjuvant chemoradiotherapy compared to neoadjuvant chemotherapy showed statistically significant improved survival with hazard ratio 0.60 (95% confidence intervals:0.44-0.80, P = 0.001) in a multivariable adjusted model. This study demonstrates that LTE can be applied in selected patients with results that are comparable to other large studies of open and minimally invasive surgery for esophageal or gastro-esophageal cancer at high-volume centers.

Perfusion assessment by fluorescence time curves in esophagectomy with gastric conduit reconstruction: a prospective clinical study.

BACKGROUND: Intraoperative perfusion assessment with indocyanine green fluorescence angiography (ICG-FA) may reduce postoperative anastomotic leakage rates after esophagectomy with gastric conduit reconstruction. This study evaluated quantitative parameters derived from fluorescence time curves to determine a threshold for adequate perfusion and predict postoperative anastomotic complications. METHODS: This prospective cohort study included consecutive patients who underwent FA-guided esophagectomy with gastric conduit reconstruction between August 2020 and February 2022. After intravenous bolus injection of 0.05-mg/kg ICG, fluorescence intensity was registered over time by PINPOINT camera (Stryker, USA). Fluorescent angiograms were quantitatively analyzed at a region of interest of 1 cm diameter at the anastomotic site on the conduit using tailor-made software. Extracted fluorescence parameters were both inflow (T0, Tmax, Fmax, slope, Time-to-peak) as outflow parameters (T90% and T80%). Anastomotic complications including anastomotic leakage (AL) and strictures were documented. Fluorescence parameters in patients with AL were compared to those without AL. RESULTS: One hundred and three patients (81 male, 65.7 ± 9.9 years) were included, the majority of whom (88%) underwent an Ivor Lewis procedure. AL occurred in 19% of patients (n = 20/103). Both time to peak as Tmax were significantly longer for the AL group in comparison to the non-AL group (39 s vs. 26 s, p = 0.04 and 65 vs. 51 s, p = 0.03, respectively). Slope was 1.0 (IQR 0.3-2.5) and 1.7 (IQR 1.0-3.0) for the AL and non-AL group (p = 0.11). Outflow was longer in the AL group, although not significantly, T90% 30 versus 15 s, respectively, p = 0.20). Univariate analysis indicated that Tmax might be predictive for AL, although not reaching significance (p = 0.10, area under the curve 0.71) and a cut-off value of 97 s was derived, with a specificity of 92%. CONCLUSION: This study demonstrated quantitative parameters and identified a fluorescent threshold which could be used for intraoperative decision-making and to identify high-risk patients for anastomotic leakage during esophagectomy with gastric conduit reconstruction. A significant predictive value remains to be determined in future studies.

The role of fluorescence angiography in colonic interposition after esophagectomy.

Colonic interposition is an alternative for gastric conduit reconstruction after esophagectomy. Anastomotic leakage (AL) occurs in 15-25% of patients and may be attributed to reduced blood supply after vascular ligation. Indocyanine green fluorescence angiography (ICG-FA) can visualize tissue perfusion. We aimed to give an overview of the first experiences of ICG-FA and AL rate in colonic interposition. This study included all consecutive patients who underwent a colonic interposition between January 2015 and December 2021 at a tertiary referral center. Surgery was performed for the following indications: inability to use the stomach because of previous surgery or extensive tumour involvement, cancer recurrence in the gastric conduit, or because of complications after initial esophagectomy. Since 2018 ICG-FA was performed before anastomotic reconstruction by administration of ICG injection (0.1 mg/kg/bolus), using the Spy-phi (Stryker, Kalamazoo, MI). Twenty-eight patients (9 female, mean age 62.8), underwent colonic interposition of whom 15 (54%) underwent ICG-FA-guided surgery. Within the ICG-FA group, three (20%) AL occurred, whereas in the non-ICG-FA group, three AL and one graft necrosis (31%) occurred (P=0.67). There was a change of management due to the FA assessment in three patients in the FA group (20%) which led to the choice of a different bowel segment for the anastomosis. Mean operative times in the ICG-FA and non-ICG-FA groups were 372±99 and 399±113 minutes, respectively (P=0.85). ICG-FA is a safe, easy and feasible technique to assess perfusion of colonic interpositions. ICG-FA is of added value leading to a change in management in a considerable percentage of patients. Its role in prevention of AL remains to be elucidated.

Health-related quality of life following neoadjuvant chemoradiotherapy versus perioperative chemotherapy and esophagectomy for esophageal cancer: a European multicenter study.

Curative treatment for locally advanced esophageal cancer consists of (neo)adjuvant treatment followed by esophagectomy. Both neoadjuvant chemoradiotherapy and perioperative chemotherapy improve the 5-year overall survival rate compared with surgery alone. However, it is unknown whether these treatment strategies are associated with differences in long-term health-related quality of life (HRQL). The aim of this study is to compare long-term HRQL in patients after esophagectomy treated with neoadjuvant chemoradiotherapy or perioperative chemotherapy. Disease-free cancer patients having undergone esophagectomy and (neo)adjuvant treatment in one of the participating lasting symptoms after esophageal resection (LASER) study centers between 2010 and 2016, were identified from the LASER study dataset. Included patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), EORTC QLQ-OG25, and LASER questionnaires at least 1 year after the completion of treatment. Long-term HRQL was compared between patients treated with neoadjuvant chemoradiotherapy or perioperative chemotherapy, using univariable and multivariable regression and presented as differences in mean score. Among the 565 included patients, 349 (61.8%) received neoadjuvant chemoradiotherapy, and 216 (38.2%) perioperative chemotherapy. Patients treated with perioperative chemotherapy reported more symptomatology for diarrhea (difference in means 5.93), reflux (difference in means 7.40), and odynophagia (difference in means 4.66). The differences did not exceed the 10 points to be of clinical relevance. No significant differences for the LASER key symptoms were observed. The observed differences in long-term HRQL are in favor of patients treated with neoadjuvant chemoradiotherapy compared with patients treated with perioperative chemotherapy; however, the differences were small. Patients need to be informed about long-term HRQL when considering allocation of (neo)adjuvant treatment.

Early mobilization after esophageal cancer surgery: a retrospective cohort study.

A key component of the Enhanced Recovery After Surgery pathway for esophagectomy is early mobilization. Evidence on a specific protocol of early and structured mobilization is scarce, which explains variation in clinical practice. This study aims to describe and evaluate the early mobilization practice after esophagectomy for cancer in a tertiary referral center in the Netherlands. This retrospective cohort study included data from a prospectively maintained database of patients who underwent an esophagectomy between 1 January 2015 and 1 January 2020. Early mobilization entailed increase in activity with the first target of ambulating 100 meters. Primary outcomes were the number of postoperative days (PODs) until achieving this target and reasons for not achieving this target. Secondary outcomes were the relationship between preoperative factors (e.g. sex, BMI) and achieving the target on POD1, and the relationship between achieving the target on POD1 and postoperative outcomes (i.e. length of stay, readmissions). In total, 384 patients were included. The median POD of achieving the target was 2 (IQR 1-3), with 173 (45.1%) patients achieving this on POD1. Main reason for not achieving this target was due to hemodynamic instability (22.7%). Male sex was associated with achieving the target on POD1 (OR = 1.997, 95%CI 1.172-3.403, P = 0.011); achieving this target was not associated with postoperative outcomes. Ambulation up to 100 m on POD1 is achievable in patients after esophagectomy, with higher odds for men to achieve this target. ERAS pathways for post esophagectomy care are encouraged to incorporate 100 m ambulation on POD1 in their guideline as the first postoperative target.

Incidence and oncological implication of adrenal incidentalomas in esophageal cancer patients.

Adrenal incidentalomas are regularly encountered during imaging for esophageal cancer patients, but their oncological significance remains unknown. This study aimed to describe the incidence and etiology of adrenal incidentalomas observed throughout the diagnostic workup. This retrospective cohort study included all esophageal cancer patients referred to or diagnosed in the Amsterdam UMC between January 2012 and December 2016. Radiology and multidisciplinary team meeting reports were reviewed for adrenal incidentalomas. In case of adrenal incidentaloma, the 18FDG-PET/CT was reassessed by a radiologist blinded for the original report. In case of a metachronous incidentaloma during follow-up, visibility on previous imaging was reassessed. Primary outcome was the incidence, etiology and oncological consequence of synchronous adrenal incidentalomas. This study included 1,164 esophageal cancer patients, with a median age of 66 years. Patients were predominantly male (76.1%) and the majority had an adenocarcinoma (69.0%). Adrenal incidentalomas were documented in 138 patients (11.9%) during the diagnostic workup. At primary esophageal cancer workup, 22 incidentalomas proved malignant. However, follow-up showed that four incidentalomas were inaccurately diagnosed as benign and three malignant incidentalomas were visible on staging imaging but initially missed. Stage migration occurred in 15 of 22 (68.2%), but this would have been higher if none were missed or inaccurately diagnosed. The oncological impact of adrenal incidentalomas in patients with esophageal cancer is significant as a considerable part of incidentalomas changed treatment intent from curative to palliative. As stage migration is likely, pathological examination of a synchronous adrenal incidentaloma should be weighted in mind.

Survival after Ivor Lewis versus McKeown esophagectomy for cancer: propensity score matched analysis.

It is unknown whether Ivor Lewis (IL) or McKeown (McK) esophagectomy is preferred in patients with potentially curable esophageal or gastro-esophageal junction (GEJ) cancer. Patients with mid- and distal esophageal and GEJ cancer without distant metastases who underwent IL or McK esophagectomy in the Netherlands between 2015 and 2017, were selected from the Netherlands Cancer Registry. Patients were propensity score matched for sex, age, American Society of Anesthesiologist classification, comorbidity, tumor type, tumor location, clinical stage, neoadjuvant treatment and year of diagnosis. The primary outcome was a 3-year relative survival (RS). Secondary outcome parameters were number of lymph nodes examined, number of positive lymph nodes, radical resection rate, tumor regression grade, post-operative complications and mortality. A total of 1627 patients who underwent IL (n = 1094) or McK (n = 533) esophagectomy were included. Patient and tumor characteristics were balanced after propensity score matching, leaving 658 patients to be compared. The 3-year RS was 54% after IL and 50% after McK esophagectomy, P = 0.140. The median number of lymph nodes examined, median number of positive lymph nodes, radical resection rate and tumor regression grade were comparable between both groups. Recurrent laryngeal nerve palsy (2 vs. 5%, P = 0.006) occurred less frequently after IL esophagectomy. No differences were observed in post-operative anastomotic leakage rate, pulmonary complication rate and mortality rates. There was no statistically significant difference in the 3-year RS between IL and McK esophagectomy. Based on these results, both IL and McK esophagectomy can be performed in patients with mid to distal esophageal and GEJ cancer.

FOXO transcriptional activity is associated with response to chemoradiation in EAC.

In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.

Adjuvant chemotherapy is superior to chemoradiation after D2 surgery for gastric cancer in the per-protocol analysis of the randomized CRITICS trial.

BACKGROUND: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy (CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial. PATIENTS AND METHODS: The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib-Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival. RESULTS: Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios. CONCLUSION: After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).

Postoperative Complications and Long-Term Quality of Life After Multimodality Treatment for Esophageal Cancer: An Analysis of the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP).

BACKGROUND: Esophagectomy has major effects on health-related quality of life (HR-QoL). Postoperative complications might contribute to a decreased HR-QOL. This population-based study aimed to investigate the difference in HR-QoL between patients with and without complications after esophagectomy for cancer. METHODS: A prospective comparative cohort study was performed with data from the Netherlands Cancer Registry (NCR) and Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP). All patients with esophageal and gastroesophageal junction (GEJ) cancer after esophagectomy in the period 2015-2018 were enrolled. The study investigated HR-QoL at baseline, then 3, 6, 9, 12, 18, and 24 months postoperatively, comparing patients with and without complications as well as with and without anastomotic leakage. RESULTS: The 486 enrolled patients comprised 270 patients with complications and 216 patients without complications. Significantly more patients with complications had comorbidities (69.6% vs 57.3%; p = 0.001). No significant difference in HR-QoL was found over time between the patients with and without complications. In both groups, a significant decline in short-term HR-QoL was found in various HR-QoL domains, which were restored to the baseline level during the 12-month follow-up period. No significant difference was found in HR-QoL between the patients with and without anastomotic leakage. The patients with grades 2 and 3 anastomotic leakage reported significantly more "choking when swallowing" at 6 months (ß = 14.5; 95% confidence interval [CI], - 24.833 to - 4.202; p = 0.049), 9 months (ß = 22.4, 95% CI, - 34.259 to - 10.591; p = 0.007), and 24 months (ß = 24.6; 95% CI, - 39.494 to - 9.727; p = 0.007) than the patients with grade 1 or no anastomotic leakage. CONCLUSION: In general, postoperative complications were not associated with decreased short- or long-term HR-QoL for patients after esophagectomy for esophageal or GEJ cancer. The temporary decrease in HR-QoL likely is related to the nature of esophagectomy and reconstruction itself.

Supervised exercise after oesophageal cancer surgery: the PERFECT multicentre randomized clinical trial.

BACKGROUND: This study investigated whether a supervised exercise programme improves quality of life (QoL), fatigue and cardiorespiratory fitness in patients in the first year after oesophagectomy. METHODS: The multicentre PERFECT trial randomly assigned patients to an exercise intervention (EX) or usual care (UC) group. EX patients participated in a 12-week moderate- to high-intensity aerobic and resistance exercise programme supervised by a physiotherapist. Primary (global QoL, QoL summary score) and secondary (QoL subscales, fatigue and cardiorespiratory fitness) outcomes were assessed at baseline, 12 and 24 weeks and analysed as between-group differences using either linear mixed effects models or ANCOVA. RESULTS: A total of 120 patients (mean(s.d.) age 64(8) years) were included and randomized to EX (61 patients) or UC (59 patients). Patients in the EX group participated in 96 per cent (i.q.r. 92-100 per cent) of the exercise sessions and the relative exercise dose intensity was high (92 per cent). At 12 weeks, beneficial EX effects were found for QoL summary score (3.5, 95 per cent c.i. 0.2 to 6.8) and QoL role functioning (9.4, 95 per cent c.i. 1.3 to 17.5). Global QoL was not statistically significant different between groups (3.0, 95 per cent c.i. -2.2 to 8.2). Physical fatigue was lower in the EX group (-1.2, 95 per cent c.i. -2.6 to 0.1), albeit not significantly. There was statistically significant improvement in cardiorespiratory fitness following EX compared with UC (peak oxygen uptake (1.8 ml/min/kg, 95 per cent c.i. 0.6 to 3.0)). After 24 weeks, all EX effects were attenuated. CONCLUSIONS: A supervised exercise programme improved cardiorespiratory fitness and aspects of QoL. TRIAL REGISTRATION: Dutch Trial Register NTR 5045 (www.trialregister.nl/trial/4942).

Patient-reported outcomes after oesophagectomy in the multicentre LASER study.

BACKGROUND: Data on the long-term symptom burden in patients surviving oesophageal cancer surgery are scarce. The aim of this study was to identify the most prevalent symptoms and their interactions with health-related quality of life. METHODS: This was a cross-sectional cohort study of patients who underwent oesophageal cancer surgery in 20 European centres between 2010 and 2016. Patients had to be disease-free for at least 1 year. They were asked to complete a 28-symptom questionnaire at a single time point, at least 1 year after surgery. Principal component analysis was used to assess for clustering and association of symptoms. Risk factors associated with the development of severe symptoms were identified by multivariable logistic regression models. RESULTS: Of 1081 invited patients, 876 (81.0 per cent) responded. Symptoms in the preceding 6 months associated with previous surgery were experienced by 586 patients (66.9 per cent). The most common severe symptoms included reduced energy or activity tolerance (30.7 per cent), feeling of early fullness after eating (30.0 per cent), tiredness (28.7 per cent), and heartburn/acid or bile regurgitation (19.6 per cent). Clustering analysis showed that symptoms clustered into six domains: lethargy, musculoskeletal pain, dumping, lower gastrointestinal symptoms, regurgitation/reflux, and swallowing/conduit problems; the latter two were the most closely associated. Surgical approach, neoadjuvant therapy, patient age, and sex were factors associated with severe symptoms. CONCLUSION: A long-term symptom burden is common after oesophageal cancer surgery.

Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus minimally invasive esophagectomy for resectable esophageal adenocarcinoma, a randomized controlled trial (ROBOT-2 trial).

BACKGROUND: For patients with esophageal adenocarcinoma or cancer of the gastroesophageal junction, radical esophagectomy with 2-field lymphadenectomy is the cornerstone of the multimodality treatment with curative intent. Both conventional minimally invasive esophagectomy (MIE) and robot assisted minimally invasive esophagectomy (RAMIE) were shown to be superior compared to open transthoracic esophagectomy considering postoperative complications. However, no randomized comparison exists between MIE and RAMIE in the Western World for patients with esophageal adenocarcinoma. METHODS: This is an investigator-initiated and investigator-driven multicenter randomized controlled parallel-group superiority trial. All adult patients (age ≥ 18 and ≤ 90 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 218) with resectable esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction are randomized to either RAMIE (n = 109) or MIE (n = 109). The primary outcome of this study is the total number of resected abdominal and mediastinal lymph nodes specified per lymph node station. CONCLUSION: This is the first randomized controlled trial designed to compare RAMIE to MIE as surgical treatment for resectable esophageal adenocarcinoma or adenocarcinoma of the gastroesophageal junction in the Western World. The hypothesis of the proposed study is that RAMIE will result in a higher abdominal and mediastinal lymph node yield specified per station compared to conventional MIE. Short-term results and the primary endpoint (total number of resected abdominal and mediastinal lymph nodes per lymph node station) will be analyzed and published after discharge of the last randomized patient within this trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04306458 . Registered 13th March 2020, https://clinicaltrials.gov/ct2/show/NCT04306458; Date of first enrolment 18.01.2021; Target sample size 218; Recruitment status: Recruiting; Protocol version 2; Issue date 10.03.2020; Rev. 02.02.2021; Authors ET, PCvdS, PPG.

Anastomotic leakage after esophagectomy for esophageal cancer: definitions, diagnostics, and treatment.

Anastomotic leakage is one of the most severe complications after esophagectomy and is associated with increased postoperative morbidity and mortality. Several projects ranging from small retrospective studies to large collaborations have aimed to identify potential pre- and perioperative risk factors and to improve the diagnostic processes and management. Despite the increase in available literature, many aspects of anastomotic leakage are still debated, without the existence of widely accepted guidelines. The purpose of this review is to provide a cutting edge overview of the recent literature regarding the definition and classification of anastomotic leakage, risk factors, novel diagnostic modalities, and emerging therapeutic options for treatment and prevention of anastomotic leakage following esophagectomy.

A proposal for uniformity in classification of lymph node stations in esophageal cancer.

The 11th edition of the "Japanese Classification of Esophageal Cancer" by the Japan Esophageal Society (JES) and the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) "Cancer Staging Manual" are two separate classification systems both widely used for the clinical and pathological staging of esophageal cancer. Furthermore, the lymph node stations from these classification systems are combined for research purposes in the multinational TIGER study, which investigates the distribution pattern of lymph node metastases. The existing classification systems greatly differ with regard to number, location and anatomical boundaries of locoregional lymph node stations. The differences in these classifications cause significant heterogeneity in studies on lymph node metastases in esophageal cancer. This makes data interpretation difficult and comparison of studies challenging. In this article, we propose a match for these two commonly used classification systems and additionally for the TIGER study classification, in order to be able to compare results of studies and exchange knowledge and to make steps towards one global uniform classification system for all patients with esophageal cancer.

Quantitative fluorescence-guided perfusion assessment of the gastric conduit to predict anastomotic complications after esophagectomy.

BACKGROUND: Fluorescence angiography (FA) assesses anastomotic perfusion during esophagectomy with gastric conduit reconstruction, but its interpretation is subjective. This study evaluated time to fluorescent enhancement in the gastric conduit, with the aim to determine a threshold to predict postoperative anastomotic complications. METHODS: In a prospective cohort study, all consecutive patients undergoing esophagectomy with gastric conduit reconstruction from July 2018 to October 2019 were included. FA was performed before anastomotic reconstruction following injection of indocyanine green (ICG). During FA, the following time points were recorded: ICG injection, first fluorescent enhancement in the lung, at the base of the gastric conduit, at the planned anastomotic site, and at ICG watershed or in the tip of the gastric conduit. Anastomotic complications including anastomotic leakage and clinically relevant strictures were documented. RESULTS: Eighty-four patients were included, the majority (67 out of 84, 80%) of which underwent an Ivor Lewis procedure. After a median follow-up of 297 days, anastomotic leakage was observed in 12 out of 84 (14.3%) and anastomotic stricture in 12 out of 82 (14.6%). Time between ICG injection and enhancement in the tip was predictive for anastomotic leakage (P = 0.174, area under the curve = 0.731), and a cut-off value of 98 seconds was derived (specificity: 98%). All times to enhancement at the planned anastomotic site and ICG watershed were significantly predictive for the occurrence of a stricture, however area under the curves were <0.7. CONCLUSIONS: The identified fluorescent threshold can be used for intraoperative decision making or to identify potentially high-risk patients for anastomotic leakage after esophagectomy with gastric conduit reconstruction.