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SUMMARY: Recurrence following a resection for an adenocarcinoma of the gastroesophageal junction leads to reduced long-term survival. This study aims to identify risk factors associated with recurrence, recurrence localization, time to recurrence, and long-term survival. All patients undergoing curative intended resection for an adenocarcinoma of the gastroesophageal junction at Rigshospitalet between June 2003 and December 2011 were identified through a prospectively maintained nationwide database and enrolled in this study. Only histologically verified recurrence was considered eligible. Recurrence within six months, microscopically incomplete resection margins, and death within eight weeks were excluded. A total of 348 patients were included in this study. Biopsy-verified recurrence occurred in 120 patients (34.5%), with 32 local (9.2%), and 88 distant (25.3%) recurrences. Lymph node metastases was associated with an increased risk of recurrence (hazard ratio; [95% confidence interval]: HR = 2.7; [1.7–4.3], P < 0.001). Median time to local versus distant recurrence was 18 months (interquartile range (IQR): 9–37 months) versus 17 months (IQR: 11–27 months), P = 0.96, respectively. A trend toward local recurrence was identified if patients had anastomotic leakage (HR = 2.64; [0.89–7.86], P = 0.08). Survival was inversely associated with recurrence, but a survival comparison between local and distant recurrences showed no significant difference: median survival time was 28 months (IQR: 17–43 months) versus 24 months (IQR: 16–36 months), P = 0.45, respectively. A trend toward local recurrence was seen if the patient had an anastomotic leakage event. However, no factors were associated with site-specific recurrence (local vs. distant). [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on prognostic value of hypoxia-regulated gene expression in gasatroesophageal cancer.

Introduction: Older patients with gastroesophageal (GE) cancer are at increased risk of low treatment tolerability and poor outcome. Dose reduced chemotherapy has been shown to improve tolerability without compromising efficacy in advanced GE cancer. However, the impact of reduced dose preoperative chemotherapy in the curative setting of older patients is unknown. The primary aim of this study was to investigate if dose reduction during preoperative chemotherapy impacts survival in older patients aged≥70 years with resectable GE cancer., Materials and Methods: This cohort study included consecutive patients referred to perioperative chemotherapy treated from November 2016 until October 2021. The primary endpoint was overall survival (OS) estimated by Kaplan-Meier analysis. The log-rank test was used to compare survival rates. A multivariate analysis was made to control for potentially interacting covariates., Results: A total of 548 patients (age ≥ 70, 179; age < 70, 369) were included. Fewer older compared to younger patients had Eastern Cooperative Oncology Group Performance Status 0 at baseline (50 % vs 63 %, p = 0.007). Preoperative chemotherapy was more often initiated at reduced dose in older patients compared to younger (37 % vs 14 %, p < 0.001). Older patients who did not receive a reduce dose in the second or subsequent cycles of preoperative chemotherapy were less likely to complete preoperative chemotherapy when compared to the younger patients (75 % vs 85 %, p = 0.03). Dose reduction in the second or subsequent preoperative chemotherapy cycles was associated with significantly better OS for the older patient population (HR = 0.54, 95 % CI: 1.2-2.9, p = 0.006) but not for the younger (HR = 0.97, 95 % CI: 0.75-1.4, p = 0.83). Dose reduction in the second or subsequent preoperative chemotherapy cycles was associated with lower mortality risk in the multivariate analysis for the older patients (HR = 0.56, 95 % CI: 0.33-0.97, p = 0.04)., Discussion: Dose reduction in the second or subsequent preoperative chemotherapy cycles seems safe and feasible in older patients without compromising survival and may result in a benefit in OS. This finding should be validated in an independent cohort or a randomized trial., Competing Interests: Declaration of Competing Interest Josephine Skjoldbirk Andersen: None. Kristian Egebjerg: None. Michael Patrick Achiam: None. Camilla Qvortrup: Grants from Servier, personal fees from Pierre Fabre. Lene Bæksgaard: None. Cecilia M. Lund: None. Morten Mau-Sørensen: Morten Mau-Sørensen has served on advisory boards for Astellas, MSD/Merck, AstraZeneca, and BMS., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Gastric and gastroesophageal junction (GEJ) cancer represents a significant global health challenge, with high recurrence rates and poor survival outcomes. This study investigates circulating tumor DNA (ctDNA) as a biomarker for assessing recurrence risk in patients with resectable gastric and GEJ adenocarcinomas (AC)., Methods: Patients with resectable gastric and GEJ AC, undergoing perioperative chemotherapy and surgery, were prospectively enrolled. Serial plasma samples were collected at baseline, after one cycle of chemotherapy, after preoperative chemotherapy, and after surgery. ctDNA was assessed by a ddPCR test (TriMeth), which targets the gastrointestinal cancer-specific methylation patterns of the genes C9orf50, KCNQ5, and CLIP4., Results: ctDNA analysis was performed on 229 plasma samples from 86 patients. At baseline, ctDNA was detected in 56% of patients, which decreased to 37% following one cycle of chemotherapy, 25% after preoperative chemotherapy and 15% after surgical resection. The presence of ctDNA after one cycle of chemotherapy was associated with reduced recurrence-free survival (RFS) (HR = 2.54, 95% confidence interval (CI) 1.33-4.85, p = 0.005) and overall survival (OS) (HR = 2.23, 95% CI 1.07-4.62, p = 0.032). Similarly, ctDNA after surgery was associated with significantly shorter RFS (HR = 6.22, 95% CI 2.39-16.2, p < 0.001) and OS (HR = 6.37, 95% CI 2.10-19.3, p = 0.001). Multivariable regression analysis confirmed ctDNA after surgery as an independent prognostic factor (p < 0.001)., Conclusion: ctDNA analysis has the potential to identify patients at elevated risk of recurrence, thus providing personalized treatment strategies for patients with resectable gastric and GEJ cancer. Further validation in larger cohorts and ctDNA-guided interventions are needed for future clinical use., (© 2024. The Author(s).)

Background and Purpose: Perioperative 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) is recommended in resectable esophagogastric adenocarcinoma based on randomised trials. However, the effectiveness of FLOT in routine clinical practice remains unknown as randomised trials are subject to selection bias limiting their generalisability. The aim of this study was to evaluate the implementation of FLOT in real-world patients., Methods: Retrospectively collected data were analysed in consecutive patients treated before or after the implementation of FLOT. The primary endpoint was complete pathological response (pCR) and secondary endpoints were margin-free resection (R0), overall survival (OS), relapse-free survival (RFS) tolerability of chemotherapy and surgical complications., Results: Mean follow-up time for patients treated with FLOT (n = 205) was 37.7 versus 47.0 months for epirubicin, cis- or oxaliplatin, and capecitabine (ECX/EOX, n = 186). Surgical resection was performed in 88.0% versus 92.0%; pCR were observed in 3.8% versus 2.4%; and R0 resections were achieved in 78.0% versus 86.0% (p = 0.03) in the ECX/EOX and FLOT cohorts, respectively. Survival analysis indicated no significant difference in RFS (p = 0.17) or OS (p = 0.37) between the cohorts with a trend towards increased OS in performance status 0 (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.50-1.04). More patients treated with ECX/EOX completed chemotherapy (39% vs. 28%, p = 0.02). Febrile neutropenia was more common in the FLOT cohort (3.8% vs. 11%, p = 0.0086). 90-days mortality (1.2% vs. 0%) and frequency of anastomotic leakage (8% vs. 6%) were equal and low., Interpretation: Patients receiving FLOT did not demonstrate improved pCR, RFS or OS. However, R0 rate was improved and patients in good PS trended towards improved OS.

Background: The optimum curative approach to adenocarcinoma of the oesophagus and oesophagogastric junction is unknown. We aimed to compare trimodality therapy (preoperative radiotherapy with carboplatin plus paclitaxel [CROSS regimen]) with optimum contemporaneous perioperative chemotherapy regimens (epirubicin plus cisplatin or oxaliplatin plus fluorouracil or capecitabine [a modified MAGIC regimen] before 2018 and fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT] subsequently)., Methods: Neo-AEGIS (CTRIAL-IE 10-14) was an open-label, randomised, phase 3 trial done at 24 centres in Europe. Patients aged 18 years or older with clinical tumour stage T2-3, nodal stage N0-3, and M0 adenocarcinoma of the oesophagus and oesophagogastric junction were randomly assigned to perioperative chemotherapy (three preoperative and three postoperative 3-week cycles of intravenous 50 mg/m 2 epirubicin on day 1 plus intravenous 60 mg/m 2 cisplatin or intravenous 130 mg/m 2 oxaliplatin on day 1 plus continuous infusion of 200 mg/m 2 fluorouracil daily or oral 625 mg/m 2 capecitabine twice daily up to 2018, with four preoperative and four postoperative 2-week cycles of 2600 mg/m 2 fluorouracil, 85 mg/m 2 oxaliplatin, 200 mg/m 2 leucovorin, and 50 mg/m 2 docetaxel intravenously on day 1 as an option from 2018) or trimodality therapy (41·4 Gy in 23 fractions on days 1-5, 8-12, 15-19, 22-26, and 29-31 with intravenous area under the curve 2 mg/mL per min carboplatin plus intravenous 50 mg/m 2 paclitaxel on days 1, 8, 15, 22, and 29). The primary endpoint was overall survival, assessed in all randomly assigned patients who received at least one dose of study drug, regardless of which study drug they received, by intention to treat. Secondary endpoints were disease-free survival, site of treatment failure, operative complications, toxicity, pathological response (complete [ypT0N0] and major [tumour regression grade 1 and 2]), margin-free resection (R0), and health-related quality of life. Toxicity and safety data were analysed in the safety population, defined as patients who took at least one dose of study drug, according to treatment actually received. The initial power calculation was based on superiority of trimodality therapy (n=366 patients); it was adjusted after FLOT became an option to a non-inferiority design with a margin of 5% for perioperative chemotherapy (n=540). This study is registered with ClinicalTrials.gov, NCT01726452., Findings: Between Jan 24, 2013, and Dec 23, 2020, 377 patients were randomly assigned, of whom 362 were included in the intention-to treat population (327 [90%] male and 360 [99%] White): 184 in the perioperative chemotherapy group and 178 in the trimodality therapy group. The trial closed prematurely in December, 2020, after the second interim futility analysis (143 deaths), on the basis of similar survival metrics and the impact of the COVID-19 pandemic. At a median follow-up of 38·8 months (IQR 16·3-55·1), median overall survival was 48·0 months (95% CI 33·6-64·8) in the perioperative chemotherapy group and 49·2 months (34·8-74·4) in the trimodality therapy group (3-year overall survival 55% [95% CI 47-62] vs 57% [49-64]; hazard ratio 1·03 [95% CI 0·77-1·38]; log-rank p=0·82). Median disease-free survival was 32·4 months (95% CI 22·8-64·8) in the perioperative chemotherapy group and 24·0 months (18·0-40·8) in the trimodality therapy group [hazard ratio 0·89 [95% CI 0·68-1·17]; log-rank p=0·41). The pattern of recurrence, locoregional or systemic, was not significantly different (odds ratio 1·35 [95% CI 0·63-2·91], p=0·44). Pathological complete response (odds ratio 0·33 [95% CI 0·14-0·81], p=0·012), major pathological response (0·21 [0·12-0·38], p<0·0001), and R0 rates (0·21 [0·08-0·53], p=0·0003) favoured trimodality therapy. The most common grade 3-4 adverse event was neutropenia (49 [27%] of 183 patients in the perioperative chemotherapy group vs 11 [6%] of 178 patients in the trimodality therapy group), followed by diarrhoea (20 [11%] vs none), and pulmonary embolism (ten [5%] vs nine [5%]). One (1%) patient in the perioperative chemotherapy group and three (2%) patients in the trimodality therapy group died from serious adverse events, two (one in each group) of which were possibly related to treatment. No differences were seen in operative mortality (five [3%] deaths in the perioperative chemotherapy group vs four [2%] in the trimodality therapy group), major morbidity, or in global health status at 1 and 3 years., Interpretation: Although underpowered and incomplete, Neo-AEGIS provides the largest comprehensive randomised dataset for patients with adenocarcinoma of the oesophagus and oesophagogastric junction treated with perioperative chemotherapy (predominantly the modified MAGIC regimen), and CROSS trimodality therapy, and reports similar 3-year survival and no major differences in operative and health-related quality of life outcomes. We suggest that these data support continued clinical equipoise., Funding: Health Research Board, Cancer Research UK, Irish Cancer Society, Oesophageal Cancer Fund, and French National Cancer Institute., Competing Interests: Declaration of interests SRP reports support for the present manuscript from Cancer Research UK; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Jabar Al Ahmed Hospital, Kuwait City, Kuwait; support for attending meetings or travel from the Ministry of Health Kuwait. MAL reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from AstraZeneca; participation on a data safety monitoring board or advisory board for Servier and Agios; other financial or non-financial interests (educational grant to institution from Roche and being principal investigator on clinical trials for MSD, Basilea, Exilexis, Astellas, Daichii Sancho, and Zymeworks). SC reports support for attending meetings or travel from MSD, Pfizer, and Roche. GOG reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AstraZeneca and AbbVie. IP reports support for the present manuscript from Health Research Board, Irish Cancer Society, and Oesophageal Cancer Fund to Cancer Trials Ireland. RR reports consulting fees from Servier; payment or honoraria for educational events from Bristol-Myers Squibb and Servier; support for attending meetings from Servier Laboratories; and advisory board fees from Servier Laboratories. SF reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Servier. GP reports support for the present manuscript from the French National Cancer Institute; grants or contracts from the French National Cancer Institute; consulting fees from Bristol-Myers Squibb, Astellas, and Nestle; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from the European Society for Medical Oncology; and support for attending meetings or travel from Metronic. DO'T reports honoraria for lectures and speaker bureaus from Ipsen, Novartis, Wyeth Ledrele, and AstraZeneca; support for attending meetings or travel from Ipsen, Novartis, and AstraZeneca; and unpaid leadership roles in other board, society, committee or advocacy groups (European Neuroendocrine Tumour Society Board). RM reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Bayer, Sanofi, Janssen, MSD, Pfizer, Novartis, Clovis, Astellas, Ipsen, and Bristol-Myers Squibb, and support for attending meetings from Pfizer, Janssen, Roche, and Ipsen. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: In this study, we aim to investigate gene expression changes in tumor samples obtained from patients with esophageal cancer treated with calcium electroporation. Previously, local treatment with calcium electroporation has been shown to induce gene expression alterations, potentially contributing to a more tumor-hostile microenvironment., Methods: In this sub-study of a phase I clinical trial, we included five patients with esophageal cancer treated with calcium electroporation. We compared cancer-associated gene expression patterns in tumor samples before and after treatment. Furthermore, we used linear support vector regression to predict the cellular composition of tumor samples., Results: Using differential expression analysis, we identified the downregulation of CXCL14 and upregulation of CCL21, ANGPTL4, and CRABP2 genes. We also found a decreased predicted proportion of dendritic cells while the proportion of neutrophils was increased., Conclusion: This study provides evidence that calcium electroporation for esophageal cancer induces local transcriptional changes and possibly alters the cellular composition of the tumor microenvironment. The results are explorative, larger studies are needed to confirm and further correlate our findings with clinical outcomes., (© 2023. The Author(s).)

Purpose: A majority of the patients with esophageal cancer (EC) suffer from dysphagia. Several endoscopic treatment options are available such as stent placement, argon plasma coagulation, and esophageal dilatation. This study aimed to map the use of endoscopic dysphagia relieving interventions and secondly investigate possible impact on survival., Methods: Data was collected at the Dept. of Surgery & Transplantation, Rigshospitalet, Denmark. Patients with non-curable EC referred from 2016 to 2019 were included. Type of dysphagia treatment, complications and the need for repeated treatments, and survival were registered., Results: In the study, 601 patients were included. Forty-five percent were treated with an endoscopic procedure due to dysphagia (82% had a stent placed). The median time from diagnosis to intervention was 24 days. The overall complication rate was 35% (38% in the stent group and 20% in the non-stent group, p = 0.03) and 13% of the patients were readmitted due to a complication. After 26% of the procedures, a repeated treatment was required. Patients having an endoscopic intervention had a worsened survival prognosis compared with the patients in the non-intervention group (HR: 2.17, 95% CI: 1.80-2.61, p < 0.001). In the sub analysis where only patients who had an intervention was included, a survival difference in favor of the non-stent group was found (HR: 0.61, 95% CI: 0.43-0.86, p = 0.005)., Conclusion: In this cohort, the incidence of endoscopic procedures was high, complication rates were considerable, and many the patients required a second treatment. A survival difference was seen, where the patients who had a stent placed seemed to have the worst survival outcomes. However, the causal relationship is yet to be determined why the results must be interpreted carefully. New interventions and tailored approaches that may positively affect functional and long-term oncological outcomes are highly warranted and this should preferably be investigated in randomized clinical trials., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Calcium electroporation (CaEP) is a novel cancer therapy wherein high intracellular calcium levels, facilitated by reversible electroporation, trigger tumor necrosis. This study aimed to establish safety with CaEP within esophageal cancer. Patients with non-curable esophageal cancer were included at Copenhagen University Hospital Rigshospitalet in 2021 and 2022. In an outpatient setting, calcium gluconate was injected intratumorally followed by reversible electroporation applied with an endoscopic electrode. The primary endpoint was the prevalence of adverse events, followed by palliation of dysphagia. All patients were evaluated with CT and upper endoscopies up to two months after treatment. The trial was registered at ClinicalTrials.gov (NCT04958044). Eight patients were treated. One serious adverse event (anemia, requiring a single blood transfusion) and three adverse events (mild retrosternal pain (two) and oral thrush (one)) were registered. Initially, six patients suffered from dysphagia: two reported dysphagia relief and four reported no change. From the imaging evaluation, one patient had a partial response, three patients had no response, and four patients had progression. Six months after treatment, the patient who responded well was still in good condition and without the need for further oncological treatment. CaEP was conducted in eight patients with only a few side effects. This study opens the way for larger studies evaluating tumor regression and symptom palliation.

Background: No preferred first-line chemotherapy regimen exists for advanced esophagogastric adenocarcinoma. Addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has been shown to improve survival but is associated with increased toxicity. In this randomized, non-comparative phase 2 trial, we tested carboplatin, docetaxel, and capecitabine (CTX), a potentially useful modification of DCF (NCT02177552)., Patients and Methods: Patients with advanced HER2-negative esophagogastric adenocarcinoma not previously treated in the first-line setting were randomized to intravenous docetaxel 60 mg/m 2 and carboplatin AUC5 plus oral capecitabine 1000 mg/m 2 bd days 1-14, q4w (CTX) or intravenous epirubicin 50 mg/m 2 and oxaliplatin 130 mg/m 2 on day 1 plus oral capecitabine 625 mg/m 2 bd days 1-21, q3w (epirubicin, oxaliplatin and capecitabine [EOX]). Treatment continued until progression, intolerance or for a maximum of nine cycles. The primary endpoint was 1-year survival for patients treated with CTX., Results: Between June 2014 and January 2019, a total of 98 eligible patients were randomized. The 1-year survival rate was 34.7% (95% CI 21.8 - 47.9) with CTX and 36.7% (95% CI 23.6 - 50.0) with EOX. Progression-free survival and overall survival were 6.1 months (95% CI 5.5 - 7.1) and 9.8 months (95% CI 8.2 - 11.0) with CTX and 5.1 months (95% CI 4.3 - 7.0) and 10.2 months (95% CI 8.0 - 11.9) with EOX, respectively. Related grade 3 or 4 treatment-emergent adverse events (AEs) occurred in 86% of patients on CTX and 69% on EOX. Febrile neutropenia occurred in 31.4% of patients on CTX and 13.7% on EOX., Conclusions: First-line CTX showed insufficient efficacy and caused a high rate of febrile neutropenia. CTX could not, therefore, be recommended for further study. This trial adds to current knowledge of docetaxel combined with platinum and 5-FU: that the combination is associated with increased toxicity and its use should be limited to fit patients in need of a response.

Accurate data on HER2 positivity in esophageal squamous cell carcinoma patients (ESCC) is lacking. We conducted a systematic review and meta-analysis (Single Incidence Rates; metarate package, R) to examine the prevalence of HER2 in ESCC. Data on in situ hybridization (ISH) and immunohistochemistry (IHC) were extracted to derive pooled prevalence estimates, characteristics of the studies were extracted for subgroup analysis. Eighteen studies with 1505 patients were identified. HER2 gene amplification by ISH were prevalent in 10 % (95 % CI 6.9 %-15 %). Prevalence of HER2 overexpression (IHC3+) and borderline HER2 expression (IHC2+) were 6 % (95 % CI: 3.5 %-8.7 %) and 10 % (95 % CI: 6.0 %-17 %), respectively. An estimated 8.6 % (95 % CI: 5.5 %-13 %) of ESCC were HER2 positive using initial IHC followed by reflex ISH confirmation of borderline HER2 expression. In conclusion: Estimated prevalence of HER 2 positivity in ESCC were 10 % assessed by ISH and 8.6 % assessed by initial IHC followed by ISH., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Fish-oil, rich in Omega-3 long chain polyunsaturated fatty acids (n-3 LC PUFAs), may in high doses inhibit the development or progression of cancer cachexia. However, poor compliance to oral nutritional supplements is a well-known problem. We aimed to investigate acceptability and compliance to a nutritional drink with fish-oil compared to an equivalent dose of fish-oil administered as capsules in patients receiving chemotherapy for GI tract cancers. Moreover, we aimed to investigate, if there was a difference between a nutritional drink or capsules with respect to nutritional status and side effects. Finally, we aimed to examine, if n-3 LC PUFAs affect leukocyte and platelet counts, and markers of dose-limiting toxicities of chemotherapy., Methods: We consecutively included 41 patients with advanced cancer in the controlled study. Patients were allocated (not randomized) to ingest either 10 capsules/day for four weeks or 400 mL/day of a nutritional drink with same dose of n-3 LC PUFA dose. Compliance was assessed by daily self-registration and n-3 LC PUFAs in whole blood. Side effects were assessed by 10 cm visual analog scales., Results: Compliance and daily consumption of n-3 LC PUFAs were 96.4% (94.1-99.3) and 4.8 (4.7-4.9) g/day in the capsule group and 80.8 (55.4-93.6) % and 4.0 (2.8-4.7) g/day in the group, respectively (p ≤ 0.02). We found no differences between the groups with respect to changes in whole blood n-3 LC PUFAs, weight, nutritional status, acceptability or side effects. However, in the capsule group the whole blood n-3 LC PUFAs correlated negatively with the increase in nausea (r s  = -0.39, p = 0.05), but not in the nutritional drink group. Nausea, reduced appetite and loose stools were of greatest importance for the deviations from recommended doses. The number of capsules had a negative impact on acceptability and compliance, whereas this was mainly related to taste and texture in the nutritional drink group. No changes in median thrombocyte or leukocyte blood counts were observed., Conclusions: Fish oil in capsules appeared to result in better compliance compared to a nutritional drink with an equivalent dose of n-3 LC PUFAs. However, capsules and the drink did not differ with respect to the effect on nutritional status or side effects. TRIAL REGISTRATION CLINICALTRIALS., Gov Identifier: NCT03751384., (Copyright © 2019 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Chemoradiotherapy is standard treatment for localized oesophageal cancer unsuitable for surgery. We aimed to evaluate the efficacy of cetuximab in combination with chemoradiotherapy., Methods: This non-randomised multicentre phase II trial recruited patients aged 18-75 with WHO performance status 0-2 having squamous cell carcinoma or adenocarcinoma in the oesophagus or gastro-oesophageal junction, T2-4, N0-3, M0 not suitable for surgery. Chemotherapy was three 21-day cycles of fluorouracil 750 mg/m2 D1-5 and oxaliplatin D1 (cycle 1:130mg/m 2, cycle 2-3:85 mg/m 2). Radiotherapy was 50Gy in 2Gy/fraction, 5 days a week, concurrent with cycle 2 and 3 and weekly cetuximab. The primary objective was loco-regional control at one year., Results: 52 patients were included. 51 were eligible for toxicity and survival analysis and 46 for recurrence analysis. Full radiotherapy dose was delivered to 80%, 75% received all three cycles of chemotherapy and 75% received four or more doses of cetuximab. The most common related grade III-IV adverse events were gastro-intestinal(16), hypersensitivity(6) and infection(5). There were two drug-related deaths. Within six months from the end of treatment, six patients died from complications from fistulas. The loco-regional control rate at one year was 47.3%(95%CI 30.9%-62.1%). Overall survival at three years was 29.1%(95% CI 17.4-41.9%)., Conclusions: Oxaliplatin and fluorouracil given concurrent with radiotherapy and cetuximab had an acceptable safety profile and showed a clinical response in patients with locoregionally advanced oesophageal cancer unsuitable for surgery. However, the primary end-point was not met, and the addition of cetuximab to definitive chemoradiotherapy cannot be recommended., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Study Design and Purpose: Positron emission tomography (PET)/magnetic resonance imaging (MRI) is a new modality that has showed promising results for various clinical indications. Currently, evaluation of neoadjuvant therapy (NT) among patients with adenocarcinoma of the esophagogastric junction has primarily been reserved for PET/computed tomography. Our aim was to evaluate if early response evaluation by PET/MRI is a feasible method to predict resectability., Methods and Materials: Patients with untreated adenocarcinoma of the esophagogastric junction (Siewert types I/II) and fit for NT with no contraindications for PET/MRI were considered eligible. A baseline scan was performed prior to NT induction and an evaluation scan 3 weeks later. For histopathological response evaluation, the Mandard tumor regression grade score was applied. Response on PET/MRI was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST 1.1), and change in ADC and SUV max values., Results: Twenty-eight patients were enrolled, and 22 completed both scans and proceeded to final analyses. Seventeen patients were found resectable versus five who were found unresectable. PET/MRI response evaluation had a sensitivity 94%, specificity 80%, and AUC = 0.95 when predicting resectability in patients with adenocarcinoma of the esophagogastric junction. No association with histopathological response (tumor regression grade) was found nor was RECIST correlated with resectability., Conclusion: Response evaluation using PET/MRI was a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction in this pilot study. However, larger studies are warranted to justify the use of the modality for this indication.

Objective:: To evaluate the feasibility of a new liquid fiducial marker for use in image-guided radiotherapy for oesophageal cancer., Methods:: Liquid fiducial markers were implanted in patients with metastatic or inoperable locally advanced oesophageal or gastro-oesophageal junction cancer receiving radiotherapy. Markers were implanted using a conventional gastroscope equipped with a 22 G Wang needle. Marker visibility was evaluated on fluoroscopy, CT, MRI and cone beam CT scans., Results:: Liquid markers (n = 16) were injected in four patients. No Grade 2 or worse adverse events were observed in relation to the implantation procedure, during treatment or in the follow-up period. 12/16 (75%) markers were available at the planning CT-scan and throughout the treatment- and follow-up period. The implanted markers were adequately visible in CT and cone beam CT but were difficult to distinguish in fluoroscopy and MRI without information from the corresponding CT image., Conclusion:: Liquid fiducial marker placement in the oesophagus proved safe and clinically feasible., Advances in Knowledge:: This paper presents the first clinical use of a new liquid fiducial marker in patients with oesophageal cancer and demonstrates that marker implantation using standard gastroscopic equipment and subsequent use in three-dimensional image-guided radiation therapy is safe and clinically feasible.

Oncological treatment of colorectal cancer (CRC) has been available in Greenland since 2004. Treatment is provided by Queen Ingrid´s Hospital (QIH), under supervision from the Department of Oncology, Rigshospitalet, Denmark. The study describes patient characteristics, oncological treatment and survival for the first 8 years of treatment. The study was a registry-based observational study of all patients in Greenland diagnosed with histologically verified CRC from August 2004 to August 2012. Analyses were stratified according to stage and discussed in relation to reported data from patients with CRC in Denmark. 180 patients were included. . Stage I, II, III, and IV comprised 15, 34, 23, and 23%, respectively. 5% presented with unknown stage. A total of 51% received oncological treatment. 79% of patients with Stage III disease received adjuvant chemotherapy, 61% of patients with metastatic CRC received palliative chemotherapy. Five-year survival was 48 and 53% for colon and rectum cancer, respectively. An insignificant trend towards higher survival in men than in women was seen; adjusted hazard ratio for death (women vs men) = 1.46 (95% CI = 0.97-2.19). In conclusion; Stage distribution, provision of oncological treatment and 5-year survival were comparable to patients diagnosed and treated in Denmark.

Background and Study Aims:  Esophageal cancer is on the rise in the western world and the disease has a poor 5-year survival prognosis below 20 %. Electrochemotherapy is a treatment where a chemotherapeutic drug is combined with locally applied electrical pulses, in order to increase the drug's cytotoxicity in malignant cells. This study presents the first results with electrochemotherapy treatment in esophageal cancer., Patients and Methods:  In this first-in-human trial, six patients with advanced esophageal cancer were treated with electrochemotherapy using intravenous bleomycin. All side effects and adverse events (AEs) were registered and the patients were later evaluated with gastroscopy and 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI)., Results:  Treatment were well tolerated, main AEs being nausea, vomiting, oral thrush, pneumonia, retrosternal pain, fever, and hoarseness. No serious complications were observed. Five patients had a visual tumor response confirmed by gastroscopy. In two cases, these findings were confirmed with 18F-FDG PET/MRI as it revealed a reduction of total tumor mass., Conclusion:  Electrochemotherapy in patients with advanced esophageal cancer was conducted without major safety concerns. This study paves the way for larger studies, which may further elucidate response rates for and side effects of this new treatment.

Background/aim: The present study aimed to identify hypoxia-regulated microRNAs (HRMs) in vitro and investigate the clinical role of candidate HRMs in patients with gastroesophageal cancer (GEC)., Materials and Methods: microRNA expression changes induced by hypoxia in human GEC cell lines were measured with microarrays and validated by quantitative real-time polymerase chain reaction. Candidate HRMs were measured in pre-therapeutic tumor samples from 195 patients with GEC., Results: Expression of miR-210 was shown to be significantly induced in esophageal squamous cell carcinoma (9.26-fold, p<0.001) and adenocarcinoma cell lines (4.95-fold, p<0.001) and miR-27a-star was significantly up-regulated in adenocarcinoma cell lines (4.79-fold, p=0.04). A weak but significant correlation between miR-210 expression and a 15-gene hypoxia signature was observed (Pearson r correlation: r=0.38, p<0.001). No significant associations of HRMs and clinical outcome in patients with GEC were identified., Conclusion: This study supports the involvement of hypoxia on miRNAs in vitro and confirms the role of miR-210 as being a universal HRM., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Recent clinical trials have demonstrated the benefit and feasibility of perioperative chemotherapy for treatment of gastroesophageal adenocarcinoma (GEA). Despite convincing results, patients entering such trials usually represent only a fraction of those who are candidates for treatment. Confirmation of trial-reported effects and tolerability in unselected cohorts is therefore required. The aims of this study were to confirm the safety and efficacy of perioperative chemotherapy for resectable GEA and to delineate risks of treatment failure., Methods: We conducted a national retrospective cohort analysis of patients admitted for perioperative chemotherapy for resectable GEA. Regimens were epirubicin and capecitabine combined with oxaliplatin or cisplatin., Results: The intention-to-treat analysis included 271 patients. Eighty-seven percent of patients completed preoperative chemotherapy, and 63 % received radical resection. Age >70 years (odds ratio 2.58) and hypoalbuminemia (odds ratio 4.10) were independent predictors of not undergoing scheduled surgery (P = 0.033). Grade 3 or higher febrile neutropenia, fatigue, and diarrhea were common in the oxaliplatin group (n = 128), but hypomagnesaemia and tinnitus/hearing loss were more common in the cisplatin group (n = 135). The median overall survival was 26.4 months, and the 1- and 2-year survival rates were 76 and 53 %, respectively. Performance status >0 (hazard ratio 1.64) and elevated serum lactate dehydrogenase (hazard ratio 3.03) were independent predictors of poor prognosis (P ≤ 0.05)., Conclusions: Perioperative chemotherapy is feasible and well tolerated in patients with good performance status and low incidence of comorbidities.

Background: MicroRNAs (miRNAs) have been associated with prognosis in esophageal cancer, suggesting a role for miRNAs to help guide treatment decisions. Especially, miR-21 and miR-375 have been investigated as prognostic biomarkers. The aim of this study was to evaluate the prognostic potential of miR-21 and miR-375 in primary esophageal squamous cell carcinomas (ESCC) and esophagogastric adenocarcinomas (EAC)., Material and Methods: Pre-therapeutic tumor specimens from 195 patients with loco-regional esophageal cancer treated with neoadjuvant or definitive chemoradiotherapy or perioperative chemotherapy were analyzed. Expression levels of miR-21 and miR-375 were quantified using Affymetrix GeneChip miRNA 1.0 Array. The Cox proportional hazards model was used to assess the correlation of miR-21 and miR-375 with disease-specific survival (DSS) and overall survival (OS). Forest plots were performed to evaluate the prognostic impact of miR-21 and miR-375 in the present study and previously published reports., Results: In ESCC, patients with miR-21 expression levels above median showed a trend towards poorer DSS and OS. When dividing miR-21 expression by tertiles, high levels of miR-21 significantly correlated with shortened DSS [HR 1.76 (95% CI 1.05-2.97) but not OS. Similarly for EAC, a significant association between miR-21 expression above median and DSS was observed [HR 3.37 (95% CI 1.41-8.05)], in addition to a trend towards poorer OS for patients with miR-21 expression above median. Multivariate analyses identified miR-21 as an independent prognostic marker for DSS in EAC [HR 3.52 (95% CI 1.06-11.69)]. High miR-375 was not correlated with improved prognosis in either histology. However, Forest plots demonstrated that both miR-21 and miR-375 were of prognostic impact in ESCC., Conclusion: In this study, miR-21 was identified as an independent prognostic biomarker for DSS in patients with EAC whereas miR-21 failed to show independent prognostic significance in ESCC. High miR-375 was not associated with enhanced survival in either histology.