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Background: Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an anti-PD-L1 IgG1, in previously treated patients with advanced non-small-cell lung cancer (NSCLC), gastric/gastro-oesophageal junction adenocarcinoma (gastric/GEJ), or hepatocellular carcinoma (HCC)., Patients and Methods: A 25-centre, phase Ia/b single-arm, non-randomised, multi-cohort study was undertaken in patients with advanced/metastatic disease, Eastern Cooperative Oncology Group performance status, 0-1, progression on prior therapy, no prior ramucirumab or immunotherapy and any PD-L1 status. Patients received ramucirumab (10 mg/kg) plus durvalumab (1125 mg) intravenously Q3W (NSCLC), or ramucirumab (8 mg/kg) plus durvalumab (750 mg) Q2W (gastric/GEJ, HCC)., Results: Phase Ia treatment was found safe for phase Ib expansion; final enrolment was NSCLC (n = 28), gastric/GEJ (n = 29), HCC (n = 28). Grade ≥3 treatment-related adverse events occurred in 32.1%, 37.9% and 42.9% of patients, respectively. The most common were fatigue (35.7%), hypertension (34.5%) and diarrhoea (28.6%), respectively. Two patients died owing to an adverse event; one was treatment-related (hepatitis acute, HCC cohort). Objective response rate was 11% for NSCLC and HCC and 21% for gastric/GEJ. Median progression-free survival and overall survival were, respectively, 2.7 and 11 months in NSCLC; 2.6 and 12.4 months in gastric/GEJ; 4.4 and 10.7 months in HCC, with more prolonged survival in patients with high PD-L1 expression., Conclusion: Ramucirumab/durvalumab exhibited manageable safety. The combination showed antitumour activity in all cohorts, particularly in patients with high PD-L1 expression., (Copyright © 2020 Eli Lilly and Company. Published by Elsevier Ltd.. All rights reserved.)

Half of patients newly diagnosed with esophageal squamous cell cancer (ESCC) have metastatic disease (mESCC) and therefore a poor prognosis. Furthermore, half of patients with initial loco-regional disease present disease recurrence after surgery and/or chemoradiation. In mESCC, the recommended first-line treatment combines 5-fluorouracil and cisplatin, although this has not been validated by a phase III trial. Patients with disease progression or recurrence after platinum-based chemotherapy and good performance status probably benefit from second-line chemotherapy. Several molecules have been evaluated in phase I/II trials or retrospective studies (docetaxel, paclitaxel and irinotecan) but no randomised studies are available. OESIRI is a multicentre, randomised, open-label phase II trial designed to evaluate efficacy and safety of liposomal irinotecan (nal-IRI) plus 5-FU versus paclitaxel as second-line therapy in patients with mESCC. The main inclusion criteria are histologically proven mESCC in progression after first-line platinum-based chemotherapy. Patients with initial resectable disease can be included if recurrence occurred within 6 months. The primary objective is to evaluate the percentage of patients alive 9 months after randomisation. Secondary endpoints are progression-free survival, overall survival, response rate, safety and quality of life. In addition, circulating tumour DNA will be monitored to assess its prognostic value., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathways, which promote tumour growth and proliferation, are often deregulated in advanced gastroesophageal adenocarcinomas. We assessed whether adding panitumumab (an EGFR inhibitor) or rilotumumab (a HGF inhibitor) to first-line fluoropyrimidine-based and platinum-based chemotherapy (modified oxaliplatin, leucovorin and fluorouracil [mFOLFOX6]) benefits to patients with advanced gastroesophageal adenocarcinoma., Patients and Methods: This phase II, open-label, randomised, three-arm study enrolled patients ≥18 years, with advanced gastroesophageal adenocarcinoma, Eastern Cooperative Oncology Group performance status 0-1 and no known HER2 overexpression. Patients were randomly assigned (1:1:1) mFOLFOX6 (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , 5-fluorouracil 400 mg/m 2 bolus then 2400 mg/m 2 over 46 h) alone or combined with panitumumab (6 mg/kg) or rilotumumab (10 mg/kg) every 2 weeks until limiting toxicity, patient's refusal or disease progression. The primary end-point was the 4-month progression-free survival (PFS) rate. Secondary end-points included overall survival (OS) and tolerance., Results: The study enrolled 162 patients in 29 French centres. The median follow-up was 23.6 months (interquartile range = 16.4-29.0). The 4-month PFS rate was 71% (95% confidence interval [CI] = 57-82) with chemotherapy alone, 57% (95% CI = 42-71) combined with panitumumab and 61% (95% CI = 47-74) combined with rilotumumab. Median OS was 13.1 months (95% CI = 8.7-16.9) with chemotherapy alone, 8.3 months (95% CI = 6.2-13.2) combined with panitumumab and 11.5 months (95% CI = 7.9-17.1) combined with rilotumumab. Adverse events grade ≥III occurred less frequently with chemotherapy alone (62%) than with panitumumab (83%) and rilotumumab (89%)., Conclusions: We found no benefit in adding panitumumab or rilotumumab to mFOLFOX6 first-line chemotherapy to treat advanced gastroesophageal adenocarcinoma patients., Trial Registration: European Clinical Trials Database, number 2009-012797-12., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial., Methods/design: PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio., Discussion: This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors., Trial Registration: NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).

Background: To determine efficacy and toxicity of radiation therapy combined with oxaliplatin, 5-fluorouracil, and folinic acid (FOLFOX) and cetuximab in patients with locally advanced oesophageal cancer., Patients and Methods: Patients with stage III oesophageal or gastro-oesophageal junction cancer were enrolled in a Simon's two-stage phase II study. Patients received FOLFOX and weekly cetuximab on week 1-10 with concurrent radiotherapy (50.4 Gy in 30 fractions) on week 5-10. Primary end-point was clinical overall response rate (ORR). An ORR rate of more than 50% was expected., Results: Among the 79 included patients, clinical ORR was 77% with 40% complete responses. Median overall survival and progression-free survival were 21.6 and 11.3 months, respectively. The most common grade III-IV toxicities observed during experimental chemoimmunotherapy followed by chemoradiation included neutropenia (28%), oesophagitis (12%), rash (11%), and allergy (9%). There was one treatment-related death due to oesophagitis with gastrointestinal bleeding., Conclusions: Cetuximab-FOLFOX regimen combined with radiotherapy demonstrated its efficacy and was well tolerated. Unfortunately, these results were not confirmed in two recent phase III studies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: This study aimed to identify predictors of tumor control (TC) in metastatic esophageal squamous cell carcinoma patients receiving first-line chemotherapy., Methods: A development cohort of 68 patients from a prospective multicenter trial (NCT01248299) was used to identify predictors of TC at first radiological tumor assessment and to generate a predictive score for TC. That score was applied in an independent retrospective single-center validation cohort of 60 consecutive patients., Results: Multivariate analysis identified three predictors of TC: body mass index ≥18.5 (OR 4.5, 95% CI 0.91-22.5), absence of bone metastasis (OR 4.6, 95% CI 0.91-23.2) and albumin ≥35 g/l (OR 3.5, 95% CI 1.0-12.1). Based on the presence or absence of these three independent prognosticators, we built a predictive model using a score from 0 to 3. In the development cohort, the TC rates were 14.3 and 78.0% and in the validation cohort 12.5 and 44.2%, for scores of 0-1 and 2-3, respectively. With negative predictive values of 85 and 88% in the development and validation cohorts, respectively, we were able to identify patients with a very low probability of TC., Conclusion: We have developed and validated a score that can be easily determined at the bedside to predict TC in metastatic esophageal squamous cell carcinoma patients., (© 2016 S. Karger AG, Basel.)

Objective: The study objectives were to analyze the impact of the number of lymph nodes (LNs) reported as resected (NLNr) and the number of LNs invaded (NLNi) on the prognosis of esophageal cancer (EC) after neoadjuvant chemoradiotherapy., Background: Pathological LN status is a major disease prognostic factor and marker of surgical quality. The impact of neoadjuvant chemoradiation (nCRT) on LN status remains poorly studied in EC., Methods: Post hoc analysis from a phase III randomized controlled trial comparing nCRT and surgery (group nCRT) to surgery alone (group S) in stage I and II EC (NCT00047112). Only patients who underwent surgical resection were considered (n = 170)., Results: nCRT resulted in tumoral downstaging (pT0, 40.7% vs 1.1%, P < 0.001), LN downstaging (pN0, 69.1% vs 47.2%, P = 0.016), and reduction in the median NLNr [16.0 (range, 0-47.0) vs 22.0 (range, 3.0-58.0), P = 0.001] and NLNi [0 (range, 0-25) vs 1.0 (range, 0-25), P = 0.001]. A good histological response (TRG1/2) in the resected esophageal specimen correlated with reduced median NLNi [0 (range, 0-10) vs 1.0 (range, 0-4), P = 0.007]. After adjustment by treatment, NLNi [hazards ratio (HR) (1-3 vs 0) 3.5, 95% confidence interval (CI): 2.3-5.5, and HR (>3 vs 0) 3.5, 95% CI: 2.0-6.2, P < 0.001] correlated with prognosis, whereas NLNr [HR (<15 vs ≥15) 0.95, 95% CI: 0.6-1.4, P = 0.807 and HR (<23 vs ≥23) 1.4, 95% CI: 0.9-2.0, P = 0.131] did not. In Poisson regression analysis, nCRT was an independent predictive variable for reduced NLNr [exp(coefficient) 0.80, 95% CI: 0.66-0.96, P = 0.018]., Conclusions: nCRT is not only responsible for disease downstaging but also predicts fewer LNs being identified after surgical resection for EC. This has implications for the current quality criteria for surgical resection.

Purpose: Although often investigated in locally advanced esophageal cancer (EC), the impact of neoadjuvant chemoradiotherapy (NCRT) in early stages is unknown. The aim of this multicenter randomized phase III trial was to assess whether NCRT improves outcomes for patients with stage I or II EC., Methods: The primary end point was overall survival. Secondary end points were disease-free survival, postoperative morbidity, in-hospital mortality, R0 resection rate, and prognostic factor identification. From June 2000 to June 2009, 195 patients in 30 centers were randomly assigned to surgery alone (group S; n = 97) or NCRT followed by surgery (group CRT; n = 98). CRT protocol was 45 Gy in 25 fractions over 5 weeks with two courses of concomitant chemotherapy composed of fluorouracil 800 mg/m(2) and cisplatin 75 mg/m(2). We report the long-term results of the final analysis, after a median follow-up of 93.6 months., Results: Pretreatment disease was stage I in 19.0%, IIA in 53.3%, and IIB in 27.7% of patients. For group CRT compared with group S, R0 resection rate was 93.8% versus 92.1% (P = .749), with 3-year overall survival rate of 47.5% versus 53.0% (hazard ratio [HR], 0.99; 95% CI, 0.69 to 1.40; P = .94) and postoperative mortality rate of 11.1% versus 3.4% (P = .049), respectively. Because interim analysis of the primary end point revealed an improbability of demonstrating the superiority of either treatment arm (HR, 1.09; 95% CI, 0.75 to 1.59; P = .66), the trial was stopped for anticipated futility., Conclusion: Compared with surgery alone, NCRT with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II EC., (© 2014 by American Society of Clinical Oncology.)

Objectives: The 7th edition of American Joint Committee on Cancer (AJCC) staging system of oesophageal cancer and gastro-oesophageal junction has re-staged positive nodes into N1-3 according to the number of invaded lymph nodes (LNs). However, this new classification does not consider the potential negative impact of the extracapsular breakthrough on survival. This study aims at assessing prognosis according to whether LN involvement is intracapsular (ICLNI) or extracapsular (ECLNI) on disease-free survival (DFS) among the three sub-groups of LN-positive patients., Methods: Four hundred and sixteen consecutive R0 patients who underwent transthoracic oesophagectomy for cancer between 1996 and 2011 were retrospectively re-classified using the latest AJCC TNM classification. Among them, 230 (55%) patients have received a neoadjuvant chemoradiotherapy. Prognostic impact of ICLNI and ECLNI on DFS was assessed according to their new LN status. Multivariate analysis was drawn to determine factors affecting DFS., Results: Among the 416 patients, there were 138 (33%) patients with positive LN: 79 (57%) with ICLNI and 59 (43%) with ECLNI. The proportion of ECLNI was 21 of 73 (28%), 21 of 41 (51%) and 17 of 24 (70%) in N1, N2 and N3 patients, respectively. In N1 patients, median DFS was 48 months in ICLNI and 13 months in ECLNI (P = 0.068). In N2 patients, median DFS was 19 months in ICLNI and 9 months in ECLNI (P = 0.07). In N3 patients, median DFS was not reached in ICLNI and was 6 months in ECLNI (P = 0.002). On multivariate analysis, the ECLNI (P < 0.001, hazard ratio, HR: 2.51) and the post-T stage (P = 0.03, HR: 1.62) were the two independent factors affecting DFS., Conclusions: Based on our limited study population, the existence of an ECLNI seems to have an additive negative impact on DFS, regardless of the pN stage. This suggests that extracapsular breakthrough status should be added to the new TNM staging system. This information has to be validated by further investigations.

Objectives: Recent studies have suggested that postoperative complications could have a potential negative effect on long-term outcome after oesophagectomy for cancer. Because respiratory failures represent the most frequent postoperative complication, we have investigated the prognostic impact of these complications on disease-free survival (DFS)., Methods: From a prospective single-institution database of 405 consecutive patients who underwent transthoracic oesophagectomy for cancer, we retrospectively analysed medical charts of all patients with microscopically complete resection (R0, n = 384 patients). Complications were graded according to the modified Clavien classification. Respiratory complications were defined as atelectasis, pneumonia or acute respiratory distress syndrome in the absence of early surgical complications. Patients with grade 5 (postoperative mortality, n = 43, 11%) were excluded from the analysis. The remaining 341 patients were analysed for estimation of DFS according to the Kaplan-Meier method. Logistic regression analysis was conducted to discriminate predictive factors affecting DFS., Results: According to the modified Clavien classification, postoperative complications rates were grade 0: 147 (44%), grade 1: 7 (2%), grade 2: 56 (16%), grade 3: 69 (20%) and grade 4: 62 (18%). Five-year DFS rates were not significantly different between grade 0 (no complication, 38%, n = 147) and other grades (grade 1, 2, 3 and 4 (64, 45, 56 and 48%, respectively)). Respiratory complications occurred in 107 patients (31%) and the 5-year DFS in this subgroup was 47% compared with 38% observed in grade 0 patients (P = 0.75). Clavien classification and respiratory complications did not come out in the univariate analysis of factors affecting DFS. On logistic regression, only two variables affected DFS: c-N stage and extracapular lymph node involvement., Conclusions: When postoperative mortality is excluded, postoperative complications do not affect DFS in patients with complete resection. This deserves substantial information regarding the prognosis of subgroup of patients in critical situations where incrementing intensive care is debated.

Objective: Malnutrition is common after oesophageal cancer surgery. This study aims to investigate body mass index (BMI) kinetics and the risk factors of malnutrition among 1-year disease-free survivors after radical transthoracic oesophagectomy for cancer., Methods: From a prospective single-institution database, 118 1-year disease-free survivors having undergone a R0 transthoracic oesophagectomy with gastric tubulization between 2000 and 2008 were identified retrospectively. BMI values were collected at the onset of the disease (pre-treatment BMI), at the time of surgery (preoperative BMI), at postoperative 6 months and 1 year after oesophagectomy (1-year BMI). Logistic regression was performed with adjustment for confounders to estimate odds ratios of the factors associated with a 1-year weight loss (WL) of at least 15% of the pre-treatment body weight (BW)., Results: At the onset of the disease, 5 patients (4%) were underweighted (BMI < 8.5 kg/m&sup2;), 65 (55%) were normal (BMI = 18.5-24.9 kg/m&sup2;), 36 (31%) were overweighted (BMI > 25 kg/m&sup2;) and 12 (10%) were obese (BMI > 30 kg/m&sup2;). Mean pre-treatment, preoperative, postoperative 6-month and 1-year BMI values were 24.64 ± 4 kg/m&sup2;, 23.55 ± 3.8 kg/m&sup2;, 21.7 ± 3 kg/m&sup2; and 21.97 ± 4 kg/m&sup2;, respectively. One-year WL ≥ 15% of the pre-treatment BW was present in 29 patients (25%): 18 among the 48 patients (37%) with a pre-treatment BMI ≥ 25 and 11 among the 70 patients (15%) with pre-treatment BMI < 25 (P = 0.006). On logistic regression, initial overweighting was the sole independent prognosticator of 1-year postoperative WL of at least 15% of the pre-treatment BW (P = 0.039; OR: 2.96, [1.06-8.32])., Conclusions: Postoperative malnutrition remains a severe problem after oesophageal cancer resection, even in long-term disease-free survivors. Overweight and obese patients are the segment population most exposed to this postoperative malnutrition, suggesting that such surgery could have substantial bariatric effect. A special vigilance programme on the nutritional status of this sub-group of patients should be the rule.

Target therapies and notably monoclonal antibodies are currently being considered for esophageal, gastric, and gastroesophageal junction cancers. EGFR was found to be overexpressed in 60-86% of gastric or gastroesophageal tumors and in 50-70% of esophageal cancers. Cetuximab was shown to be a radiosensitizing agent in the treatment of ENT neoplasia. These results led to several phase II encouraging therapeutic trials evaluating the combination of cetuximab with radiochemotherapy in locally advanced esophageal cancers. Numerous encouraging phase II trials evaluating cetuximab combined with chemotherapy in patients with gastric adenocarcinoma or gastroesophageal junction cancer were reported. These promising results are still to be confirmed by the ongoing phase III trials. Several studies reported HER2 overexpression in gastric cancer (7-34%), which appeared to be associated with poorer prognosis. Trastuzumab is a monoclonal antibody directed against the extracellular HER2 domain. The international phase III trial known as ToGA (Trastuzumab for Gastric Cancer) aimed to determine the clinical efficacy and acceptable toxicity profile of trastuzumab in combination with first-line chemotherapy in HER2-overexpressing gastric or gastroesophageal cancer. Angiogenesis is an essential step in the initial phase of tumorigenesis, and it is normally absent from healthy tissues except for particular physiological situations, such as wound healing. VEGF-A plays a role in endothelial growth and angiogenesis. Bevacizumab, a humanized monoclonal anti-VEGF-A antibody, is currently being studied for gastric cancer. The phase III AVAGAST study, evaluating bevacizumab in association with chemotherapy in advanced gastric adenocarcinoma, did not achieve its primary aim of improved OS in bevacizumab-treated patients.

Introduction: To assess prognosis depending on whether lymph node involvement (LNI) is intracapsular or with extracapsular breakthrough in patients with a locally advanced esophageal cancer treated with neoadjuvant chemoradiation and surgery., Methods: Ninety-four consecutive patients with an esophageal cancer staged IIB (n = 17) and III (n = 77) received neoadjuvant chemoradiation followed by transthoracic esophagectomy with two-field lymphadenectomy. Histology was squamous cell carcinoma (n = 46) and adenocarcinoma (n = 48). Neoadjuvant therapy consisted of association of 5-fluorouracil/cisplatin concomitantly with a 45-Gy radiation therapy. Disease-free survival (DFS) excluding the in-hospital mortality was analyzed according to the nodal status and the invaded/resected lymph node ratio (LNR). Clinical factors affecting survival or predictors of extracapsular invasion were investigated by multivariate analysis., Results: Five-year DFS rates were 46, 36, and 11% in N0 patients (n = 56), intracapsular LNI patients (n = 18), and extracapsular LNI patients (n = 10), respectively (p = 0.002). Intracapsular LNI patients with an LNR <0.1 (n = 12) had a 5-year DFS rate similar to N0 patients (44 versus 46%, p = 0.95). Intracapsular LNI patients with an LNR > or =0.1 (n = 6) had a DFS rate similar to extracapsular LNI patients (18 versus 11%, p = 0.69). Multivariate analysis revealed that the sole independent factor affecting DFS was the extracapsular LNI (HR = 3.9, p = 0.026). The number of invaded LN seemed to be the sole significant predictive factor for the development of ECLNI (HR = 2.39, p = 0.008)., Conclusion: After neoadjuvant chemoradiotherapy, there was a significant difference on DFS depending on whether LNI was intracapsular or extracapsular. Extracapsular invasion seems to be an independent negative prognostic factor affecting survival, and its presence is related to the number of invaded LN.

Objective: Some patients with localised oesophageal cancer are treated with definitive chemoradiotherapy (CRT) rather than surgery. A subset of these patients experiences local failure, relapse or treatment-related complication without distant metastases, with no other curative treatment option but salvage oesophagectomy. The aim of this study was to assess the benefit/risk ratio of surgery in such context., Methods: Review of a single institution experience with 24 patients: 18 men and 6 women, with a mean age of 59 years (+/-9). Histology was squamous cell carcinoma in 18 cases and adenocarcinoma in 6. Initial stages were cIIA (n=5), cIIB (n=1) and cIII (n=18). CRT consisted of 2-6 sessions of the association 5-fluorouracil/cisplatin concomitantly with a 50-75 Gy radiation therapy. Salvage oesophagectomy was considered for the following reasons: relapse of the disease with conclusive (n=11) or inconclusive biopsies (n=7), intractable stenosis (n=3), and perforation or severe oesophagitis (n=3), at a mean delay of 74 days (14-240 days) following completion of CRT., Results: All patients underwent a transthoracic en-bloc oesophagectomy with 2-field lymphadenectomy. Thirty-day and 90-day mortality rates were 21% and 25%, respectively. Anastomotic leakage (p=0.05), cardiac failure (p=0.05), length of stay (p=0.03) and the number of packed red blood cells (p=0.02) were more frequent in patients who received more than 55 Gy, leading to a doubled in-hospital mortality when compared to that of patients having received lower doses. A R0 resection was achieved in 21 patients (87.5%). A complete pathological response (ypT0N0) was observed in 3 patients (12.5%). Overall and disease-free 5-year survival rates were 35% and 21%, respectively. There was no long-term survivor following R1-R2 resections. Functional results were good in more than 80% of the long-term survivors., Conclusion: Salvage surgery is a highly invasive and morbid operation after a volume dose of radiation exceeding 55 Gy. The indication must be carefully considered, with care taken to avoid incomplete resections. Given that long-term survival with a fair quality of life can be achieved, such high-risk surgery should be considered in selected patients at an experienced centre.