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A plateau in treatment effect can be seen for the current 'one-size-fits-all' approach to oesophageal adenocarcinoma (OAC) management using neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT). In OAC, the tumour microenvironment (TME) is largely immunosuppressed, however a subgroup of patients with an immune-inflamed TME exist and show improved outcomes. We aimed to understand the overall immune-based mechanisms underlying treatment responses and patient outcomes in OAC, and in relation to neoadjuvant therapy modality. This study included 107 patients; 68 patients were enrolled in the Australian Gastro-Intestinal Trials Group sponsored DOCTOR Trial, and 38 patients were included from the Cancer Evolution Biobank. Matched pre-treatment and post-treatment tumour biopsies were used to perform multi-modality analysis of the OAC TME including NanoString mRNA expression analysis, multiplex and single colour immunohistochemistry (IHC), and peripheral blood mononuclear cell analysis of tumour-antigen specific T cell responses. Patients with the best clinicopathological outcomes and survival had an immune-inflamed TME enriched with anti-tumour immune cells and pathways. Those with the worst survival showed a myeloid T regulatory cell enriched TME, with decreased CD8 + cell infiltration and increased pro-tumour immune cells. Multiplex IHC analysis identified that high intra-tumoural infiltration of CD8 + cells, and low infiltration with CD163 + cells was associated with improved survival. High tumour core CD8 + T cell infiltration, and a low tumour margin infiltration of CD163 + cells was also associated with improved survival. nCRT showed improved survival compared with nCT for patients with low CD8 + , or high CD163 + cell infiltration. Poly-functional T cell responses were seen with tumour-antigen specific T cells. Overall, our study supports the development of personalised therapeutic approaches based on the immune microenvironment in OAC. Patients with an immune-inflamed TME show favourable outcomes regardless of treatment modality. However, in those with an immunosuppressed TME with CD163 + cell infiltration, treatment with nCRT can improve outcomes. Our findings support previous studies into the TME of OAC and with more research, immune based biomarker selection of treatment modality may lead in improved outcomes in this deadly disease., Competing Interests: NW is a founder of genomiQa Pty Ltd and members of its Board. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lonie, Brosda, Bonazzi, Aoude, Patel, Brown, Sharma, Lampe, Addala, Koufariotis, Wood, Waddell, Dolcetti and Barbour.)

Background: Little is known about the association between signet ring cell (SRC) differentiation and response to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal and junctional adenocarcinoma (EAC). We aimed to assess if SRC differentiation is associated with survival and response to nCT or nCRT in patients with EAC., Methods: Patients who underwent nCT and nCRT followed by surgery for EAC from 2000 until 2016 were identified from two institutional prospectively maintained databases. The pretreatment biopsy report or surgical resection specimen was used to differentiate patients into an SRC or non-SRC group., Results: Overall, 129 (19%) of 689 patients included had SRCs (nCT: n = 64; nCRT: n = 65). The SRC group had a more advanced ypT stage (p = 0.003), a higher number of positive lymph nodes in the resection specimen {median (interquartile range [IQR]) 2 [0-5] vs. 1 [0-3]; p = 0.002} and a higher rate of R1/R2 resections (19.4% vs. 12%; p = 0.026). SRC differentiation was not an independent prognostic factor for overall survival (OS) or disease-free survival (DFS). Following nCT, the SRC group had significantly shorter DFS (median [IQR] 12 [5-50] vs. 23 [8-164]; p = 0.013), but not OS, compared with the non-SRC group. In contrast, no differences according to SRC status for OS or DFS were found in patients who underwent nCRT., Conclusions: SRC differentiation was not independently associated with worse OS in patients with EAC who underwent neoadjuvant therapy and surgery. However, nCRT was associated with greater tumor downstaging and better DFS.

Background: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC., Methods: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared., Results: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found., Conclusion: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities., (© 2018 Wiley Periodicals, Inc.)

Neoadjuvant therapy (NAT) for oesophageal cancer may reduce cardiopulmonary function, assessed by cardiopulmonary exercise testing (CPEX). Impaired cardiopulmonary function is associated with mortality following esophagectomy. We sought to assess the impact of NAT on cardiopulmonary function using CPEX and assessing the clinical relevance of any change in particular if changes were associated with post-operative morbidity. This was a prospective, cohort study of 40 patients in whom CPEX was performed before and after NAT. Thirty-eight patients underwent surgery and follow-up with perioperative outcomes measured. The primary variables derived from CPEX were the anaerobic threshold (AT) and peak oxygen uptake (V˙O 2 peak). There were significant reductions in the AT (pre-NAT: 12.4 ± 3.0 vs. post-NAT 10.6 ± 2.0 mL kg -1 .min -1 ; p = 0.001). This reduction was also evident for V˙O 2 peak (pre-NAT: 16.6 ± 3.6 vs. post-NAT 14.9 ± 3.7 mL kg -1 .min -1 ; p = 0.004). The relative reduction in V˙O 2 peak was greater in chemotherapy patients who developed any peri-operative morbidity (p = 0.04). For patients who underwent chemoradiotherapy, there was a significantly greater relative reduction in AT (p = 0.03) for those who encountered a respiratory complication. Cardiopulmonary function significantly declined as a result of NAT prior to oesophagectomy. The reduction in AT and V˙O 2 peak was similar in both the chemotherapy and chemoradiotherapy groups., (Copyright © 2018 IJS Publishing Group Ltd. All rights reserved.)

Objective: Accurate staging is vital for esophageal cancer management. The utility of the American Joint Committee on Cancer (AJCC) staging system 6th edition for esophageal cancer has been questioned for resected patients who receive neoadjuvant chemoradiotherapy (CRT). This study was undertaken to assess the AJCC staging system for patients with esophageal cancer that have received neoadjuvant CRT and to identify clinicopathological variables that predict survival., Methods: Review of a prospective esophageal cancer database was undertaken for patients that received neoadjuvant CRT and resection. Primary tumor response was defined as major (10% residual tumor cells). Cox regression and concordance analyses were used to determine prognostic factors. Median follow-up was 61 months., Results: Of 131 patients with invasive cancer, there were 40/131 (31%) with squamous cell carcinoma (SCC) and 88/131 (65%) with adenocarcinoma. The procedure-related mortality rate was 3.8%. Median survival was 33 months. A major response was demonstrated by 79/131 (60%) patients. Survival analyses found that the AJCC 6th edition was unable to discriminate between stages 0, I, and IIa or stages IIb and III. Multivariate survival analyses found age, pretreatment tumor length >6 cm, positive lymph nodes, and a major tumor response were independent prognostic factors. These data were used to derive a new staging system that had improved discrimination of stage groups over the current AJCC system., Conclusion: The current AJCC staging system for esophageal cancer is inadequate for patients that receive neoadjuvant CRT. Refinement of the AJCC staging system should include primary tumor response for patients receiving neoadjuvant CRT.

Abstract: Introduction: Preoperative chemotherapy (CT) and preoperative chemoradiation therapy (CRT) for resectable oesophageal cancer have been shown to improve overall survival in meta-analyses. There are limited data comparing these preoperative therapies. We report the outcomes of a randomised phase II trial comparing preoperative CT and CRT for resectable adenocarcinoma of the oesophagus and gastro-oesophageal junction. Methods: Patients were randomised to receive preoperative CT with cisplatin (80mg/m2) and infusional 5 fluorouracil (1000mg/m2/d) on days 1 and 21, or preoperative CRT with the same drugs accompanied by concurrent radiation therapy commencing on day 21 of chemotherapy and the 5 fluorouracil reduced to 800mg/m2/d. The radiation dose was 35Gy in 15 fractions over 3weeks. The endpoints were toxicity, response rates, resection (R) status, progression-free survival (PFS), overall survival (OS) and quality of life. Results: Seventy-five patients were enroled on the study: 36 received preoperative CT and 39 preoperative CRT. Toxicity was similar for CT and CRT. Eight patients (11%) did not proceed to resection. The histopathological response rate (CRT 31% versus CT 8%, p =0.01) and R1 resection rate (CRT 0% versus CT 11%, p =0.04) favoured those receiving CRT. The median PFS was 14 and 26 months for CT and CRT respectively (p =0.37). The median OS was 29 months for CT compared with 32 months for CRT (p =0.83). Conclusions: Despite no difference in survival, the improvement from preoperative CRT with respect to margin involvement makes this treatment a reasonable option for bulky, locally advanced resectable adenocarcinoma of the oesophagus. [Copyright &y& Elsevier]