Immune checkpoint blockade (ICB) has revolutionised the treatment of solid tumours, yet most patients do not derive a clinical benefit. Resistance to ICB is often contingent on the tumour microenvironment (TME) and modulating aspects of this immunosuppressive milieu is a goal of combination treatment approaches. Radiation has been used for over a century in the management of cancer with more than half of all cancer patients receiving radiotherapy. Here, we outline the rationale behind combining radiotherapy with ICB, a potential synergy through mutually beneficial remodelling of the TME. We discuss the pleiotropic effects radiation has on the TME including immunogenic cell death, activation of cytosolic DNA sensors, remodelling the stroma and vasculature, and paradoxical infiltration of both anti-tumour and suppressive immune cell populations. These events depend on the radiation dose and fractionation and optimising these parameters will be key to develop safe and effective combination regimens. Finally, we highlight ongoing efforts that combine radiation, immunotherapy and inhibitors of DNA damage response, which can help achieve a favourable equilibrium between the immunogenic and tolerogenic effects of radiation on the immune microenvironment.

Summary: Background: Chyle leakage is an uncommon but potentially life-threatening complication following esophageal resections. The optimal management strategy is not clear, with a limited evidence base. Methods: Searches were conducted up to 31 December 2020 on MEDLINE, Embase, and Web of Science for randomized trials or retrospective studies that evaluated the management of chyle leakage following esophageal resection. Two authors independently screened studies, extracted data, and assessed for bias. The protocol was prospectively registered on PROSPERO (CRD: 42021224895) and reported in accordance with preferred reporting items for systematic reviews and meta-analyses guidelines. Results: A total of 530 citations were reviewed. Twenty-five studies, totaling 1016 patients met the inclusion criteria, including two low-quality clinical trials and 23 retrospective case series. Heterogeneity of study design and outcomes prevented meta-analysis. The overall incidence of chyle leak/fistula was 3.2%. Eighteen studies describe management of chyle leaks conservatively, 17 by surgical ligation of the thoracic duct, 5 by pleurodesis, and 6 described percutaneous lymphangiography with thoracic duct embolization or disruption. Conclusions: The evidence base for optimal management of chyle leakage postesophagectomy is lacking, which may be related to its low incidence. There is a paucity of high-quality prospective studies directly comparing treatment modalities, but there is some low-certainty evidence that percutaneous approaches have reduced morbidity but lower efficacy compared with surgery. Further high-quality, prospective studies that compare interventions at different levels of severity are needed to determine the optimal approach to treatment.

Background and Aims: The FLOT4-AIO trial established the FLOT regimen as a compelling option for gastric, junctional and esophageal adenocarcinoma. Data on FLOT with en-bloc transthoracic esophagectomy (TTE) are limited. This study explored operative complications, tolerance, toxicity, physiological impact, and oncologic outcomes. Study design: An observational cohort study on consecutive patients at 3 tertiary centers undergoing FLOT and TTE. Toxicity, operative complications (per ECCG definitions), tumor regression grade (TRG), recurrences and survival were documented, as well as pre and post FLOT assessment of sarcopenia and pulmonary physiology. Results: 175 patients (cT2-4a, N_any) commenced treatment, 84% male, median age 65, 94% cT3/T4a, 73% cN+. 89% completed 4 preoperative cycles, and 35% all cycles. Grade 3/4 toxicities included neutropenia (12%), diarrhoea (13%), and infection (15%). Sarcopenia increased from 18% to 37% (P = 0.020), and diffusion capacity (DLCO) decreased by 8% (-34% + 25%; P < 0.010). On pathology, ypT3/4 was 59%, and ypN+54%, with 10% TRG 1, 14% TRG 2, and 76% TRG3-5, and R0 95%. 161 underwent TTE, with an in-hospital mortality of 0.6%, 24%-pneumonia, 11%-anastomotic leak, and Clavien Dindo ≥III in 27%. At a median follow up of 12 months (1-85), 33 relapsed, 8 (5%) locally, and 3yr survival was 60%. Conclusion: FLOT and en bloc TTE was safe, with no discernible impact on operative complications, with 24% having a major pathologic response. Caveats include a limited pathologic response in the majority, and negative impact on muscle mass and lung physiology, and low use of adjuvant cycles. These data may provide a real-world benchmark for this complex care pathway.

Immunotherapy has achieved long-term disease control in a proportion of cancer patients, but determinants of clinical benefit remain unclear. A greater understanding of antitumor immunity on an individual basis is needed to facilitate a precision oncology approach. A conceptual framework called the “cancer-immune set point” has been proposed to describe the equilibrium between factors that promote or suppress anticancer immunity and can serve as a basis to understand the variability in clinical response to immune checkpoint blockade. Oesophageal cancer has a high mutational burden, develops from pre-existing chronic inflammatory lesions and is therefore anticipated to be sensitive to immune checkpoint inhibition. However, both tumour- and patient-specific factors including the immune microenvironment, the microbiome, obesity, and host genetics contribute to an immune set point that confers a lower-than-expected response to checkpoint blockade. Immunotherapy is therefore currently confined to latter lines of treatment of advanced disease, with no reliable predictive biomarker of response. In this review, we examine oesophageal cancer in the context of the cancer-immune set point, discuss factors that contribute to response to immunotherapeutic intervention, and propose areas requiring further investigation to improve treatment response.

Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis and incidence is increasing rapidly in the Western world. Multi-modal treatment has improved survival outcomes but only for a minority of patients. Currently no markers have been identified to predict treatment response. This study investigated the association between clinical outcomes and pre-treatment levels of 54 serum proteins in n = 80 patients with EAC. Low tumor regression grade (TRG), corresponding to a favorable treatment response, was linked to prolonged overall survival (OS). CCL4 was higher in patients with a favorable treatment response, while Tie2 and CRP were higher in poor responders. Elevated CCL22 and CCL26 was associated with improved OS, while elevated IL-10 showed a negative association. CCL3, CCL4, IL-1α and IL-12/IL23p40 were highest in individuals with no adverse features of tumor biology, whereas levels of Tie2 and VEGF were lowest in this cohort. CCL4 was also elevated in patients with high tumor lymphocyte infiltration. Comparison of matched pre- and post-treatment serum (n = 28) showed a large reduction in VEGFC, and a concomitant increase in other cytokines, including CCL4. These data link several serum markers with clinical outcomes, highlighting an important role for immune cell trafficking in the EAC antitumor immune response.