Total neoadjuvant therapy in oesophageal and gastro-oesophageal junctional adenocarcinoma.

Adenocarcinoma of the oesophagus and gastro-oesophageal junction represent a large burden of cancer death in the Western World with an increasing incidence. In the past two decades, the overall survival of patients on a potentially curative treatment pathway has more than doubled due to the addition of perioperative oncological therapies to surgery. However, patients often fail to respond to oncological treatment or struggle to complete their treatment after surgery. In this review, we discuss the current evidence for total neoadjuvant therapy and options for assessment of treatment response.

Female Sex but Not Oestrogen Receptor Expression Predicts Survival in Advanced Gastroesophageal Adenocarcinoma-A Post-hoc Analysis of the GO2 Trial.

Gastroesophageal adenocarcinoma is a disease of older adults that is associated with a very poor prognosis. It is less common and has better outcomes in females. The reason for this is unknown but may relate to signalling via the main oestrogen receptors (ER) α and ß. In this study, we sought to investigate this using the GO2 clinical trial patient cohort. GO2 recruited older and/or frail patients with advanced gastroesophageal cancer. Immunohistochemistry was performed on tumour samples from 194 patients. The median age of the population was 76 years (range 52-90), and 25.3% were female. Only one (0.5%) tumour sample was positive for ERα, compared to 70.6% for ERß expression. There was no survival impact according to ERß expression level. Female sex and younger age were associated with lower ERß expression. Female sex was also associated with improved overall survival. To our knowledge, this is the largest study worldwide of ER expression in a cohort of patients with advanced gastroesophageal adenocarcinoma. It is also unique, given the age of the population. We have demonstrated that female sex is associated with better survival outcomes with palliative chemotherapy but that this does not appear to be related to ER IHC expression. The differing ER expression according to age supports the concept of a different disease biology with age.

Diagnosis, treatment, and outcome of patients with oesophagogastric cancer during the COVID-19 pandemic: national study.

BACKGROUND: The national response to COVID-19 has had a significant impact on cancer services. This study investigated the effect of national lockdown on diagnosis, management, and outcomes of patients with oesophagogastric cancers in Scotland. METHODS: This retrospective cohort study included consecutive new patients presenting to regional oesophagogastric cancer multidisciplinary teams in National Health Service Scotland between October 2019 and September 2020. The study interval was divided into before and after lockdown, based on the first UK national lockdown. Electronic health records were reviewed and results compared. RESULTS: Some 958 patients with biopsy-proven oesophagogastric cancer in 3 cancer networks were included: 506 (52.8 per cent) before and 452 (47.2 per cent) after lockdown. Median age was 72 (range 25-95) years and 630 patients (65.7 per cent) were men. There were 693 oesophageal (72.3 per cent) and 265 gastric (27.7 per cent) cancers. Median time to gastroscopy was 15 (range 0-337) days before versus 19 (0-261) days after lockdown (P < 0.001). Patients were more likely to present as an emergency after lockdown (8.5 per cent before versus 12.4 per cent after lockdown; P = 0.005), had poorer Eastern Cooperative Oncology group performance status, were more symptomatic, and presented with a higher stage of disease (stage IV: 49.8 per cent before versus 58.8 per cent after lockdown; P = 0.04). There was a shift to treatment with non-curative intent (64.6 per cent before versus 77.4 per cent after lockdown; P < 0.001). Median overall survival was 9.9 (95 per cent c.i. 8.7 to 11.4) months before and 6.9 (5.9 to 8.3) months after lockdown (HR 1.26, 95 per cent c.i. 1.09 to 1.46; P = 0.002). CONCLUSION: This national study has highlighted the adverse impact of COVID-19 on oesophagogastric cancer outcomes in Scotland. Patients presented with more advanced disease and a shift towards treatment with non-curative intent was observed, with a subsequent negative impact on overall survival.

Gastroesophageal adenocarcinoma in older adults: A comprehensive narrative review of management by the Young International Society of Geriatric Oncology.

Gastroesophageal adenocarcinoma is a disease of older adults with very poor survival rates. Its incidence has risen dramatically across the world in recent decades. Current treatment approaches for older adults are based largely on extrapolated evidence from clinical trials conducted in younger and fitter participants than those more commonly encountered in clinical practice. Understanding how to apply available evidence to our patients in the clinic setting is essential given the high morbidity of both curative and palliative treatment. This review aims to use available data to inform the management of an older adult with gastroesophageal adenocarcinoma.

Cardiotoxicity and Chemotherapy-The Role of Precision Medicine.

Cancer and cardiovascular disease are the leading causes of death in the United Kingdom. Many systemic anticancer treatments are associated with short- and long-term cardiotoxicity. With improving cancer survival and an ageing population, identifying those patients at the greatest risk of cardiotoxicity from their cancer treatment is becoming a research priority and has led to a new subspecialty: cardio-oncology. In this concise review article, we discuss cardiotoxicity and systemic anticancer therapy, with a focus on chemotherapy. We also discuss the challenge of identifying those at risk and the role of precision medicine as we strive for a personalised approach to this clinical scenario.

Resistance to immune checkpoint inhibitors in advanced gastro-oesophageal cancers.

Immune checkpoint inhibitors (ICIs) have altered the treatment paradigm across a range of tumour types, including gastro-oesophageal cancers. For patients with any cancer type who respond, ICIs can confer long-term disease control and significantly improve survival and quality of life, but for patients with gastro-oesophageal cancer, ICIs can be transformative, as durable responses in advanced disease have hitherto been rare, especially in those patients who are resistant to first-line cytotoxic therapies. Results from trials in patients with advanced-stage gastro-oesophageal cancer have raised hopes that ICIs will be successful as adjuvant and neoadjuvant treatments in early-stage disease, when the majority of patients relapse after potential curative treatments, and several trials are ongoing. Unfortunately, however, ICI-responding patients appear to constitute a minority subgroup within gastro-oesophageal cancer, and resistance to ICI therapy (whether primary or acquired) is common. Understanding the biological mechanisms of ICI resistance is a current major research challenge and involves investigation of both tumour and patient-specific factors. In this review, we discuss the mechanisms underlying ICI resistance and their potential specific applications of this knowledge towards precision medicine strategies in the management of gastro-oesophageal cancers in clinical practice.

Best supportive care and prognosis: advanced gastroesophageal adenocarcinoma.

OBJECTIVES: Real-world data are lacking on survival in patients with advanced gastroesophageal adenocarcinoma (GOA) treated with best supportive care (BSC) alone. This knowledge is vital to personalise cancer treatment and obtain informed consent. This study aimed to define and compare survival in patients with advanced GOA treated with and without palliative chemotherapy (CTx), and to explore the factors that impact prognosis. METHODS: Patients in NHS Tayside, Scotland, diagnosed with advanced GOA (defined as non-resectable) over a 2-year period were identified retrospectively. Clinical data were obtained from electronic records. Kaplan-Meier and Cox regression analysis were performed to determine median overall survival (mOS) and investigate contributing factors. RESULTS: 127 eligible patients were identified. There was a significant difference in mOS between patients in the BSC and CTx groups (3.1 months vs 8.9 months, p=0.00089). This was maintained when those deemed not fit for CTx were removed. One-year survival was 16% versus 33%. Cox regression analysis in the BSC group identified stage (p<0.001) and Eastern Cooperative Oncology Group performance status (ECOG PS) (p=0.013) as having independent predictive value for survival. Age was not related to outcome. Palliative stents were inserted in 48 patients (37.8%). CONCLUSIONS: To our knowledge, this is the largest reported study in Europe of outcomes in patients with advanced GOA treated with BSC only. The mOS with BSC is approximately 3 months. Cancer stage and ECOG PS have a role in prognostication at diagnosis. Our findings support the benefit of palliative chemotherapy in this population, and real-world survival corresponds to published trial data.

Cancer Treatment Helpline: a retrospective study of the NHS Tayside experience.

BACKGROUND: Treatment-related toxicity and delays in the management of this toxicity can impact the outcomes of patient with cancer. In Scotland, a national cancer helpline was established to provide triage assessment for patients receiving systemic anticancer therapy (SACT) in an attempt to minimise delays in toxicity management. In this article, we describe the use and impact of the helpline in our region over the last 5 years. METHODS: Patients who contacted the NHS Tayside cancer helpline between 1 January 2016 and 31 December 2020 were retrospectively identified. Patient demographics as well as the reason and outcome of each call was recorded. A descriptive analysis was performed. RESULTS: 6562 individual patients received SACT and 8385 calls were recorded during the time period. Median age of callers was 63 years (range 17-98) and 59.2% were women. Use of the helpline increased by 83.6% between 2016 and 2020, driven by an increase in in-hours calls. 41% of calls required review by a healthcare professional only, 24% required review and admission and the remaining 35% telephone advice only. The majority of cases (85%) were either assessed or advised solely by oncology. The proportional use of general practitioner services has decreased. CONCLUSIONS: The helpline provides a way for patients to report symptoms directly to their clinical team and receive appropriate specialist advice at an early stage. We demonstrate that most of these calls can be managed solely by our oncology team. This system can reduce pressure on other parts of the local health system.

Real­world challenge for clinicians treating advanced gastroesophageal adenocarcinoma (Review).

Gastroesophageal adenocarcinoma (GOA) is a disease of older people. Incidence is rising in the developed world and the majority of patients present with advanced disease. Based on clinical trial data, systemic chemotherapy in the advanced setting is associated with improvements in quality of life and survival. However, there is a recognised mismatch between trial populations and the patients encountered in clinical practice in terms of age, comorbidity and fitness. Appropriate patient selection is essential to safely deliver effective treatment. In this narrative review, we discuss the challenges faced by clinicians when assessing real­world patients with advanced GOA for systemic therapy. We also highlight the importance of frailty screening and the current available evidence we can use to guide our management.

The impact of COVID-19 on systemic anticancer treatment delivery in Scotland.

Understanding the impact of the COVID-19 pandemic on systemic anticancer therapy delivery (SACT) is crucial to appreciate the short- and long-term consequences for cancer patients and plan future care. Here, we report real-time national SACT delivery data from NHS Scotland. We demonstrate an initial rapid reduction in patient attendance of 28.7% with subsequent rapid recovery following service redesign. The smallest decrease was seen in breast cancer (19.7%), which also had the most rapid recovery and the largest decrease seen in colorectal cancer (43.4%). Regional variation in the magnitude of impact on SACT delivery was observed, but nadirs occurred at the same time and the rate of recovery was similar across all regions. This recovery reflected a coordinated national approach and associated patient and clinician support structures, which facilitated the creation of COVID-19-protected areas for SACT delivery in Scottish cancer centres enabling rapid sharing of successful and innovative strategies. The data show that these actions have limited the disadvantage to cancer patients.

Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: why clinical trials might have failed and how they could succeed.

PURPOSE: Oesophageal squamous cell carcinoma (ESCC) has a poor prognosis. Advanced tumours are treated with fluoropyrimidine/platinum chemotherapy followed by irinotecan or taxane monotherapy, but resistance is common and new treatments are needed. Approximately 20% of ESCCs carry copy number gain (CNG) of the epidermal growth factor receptor (EGFR) gene. Previous trials show that while anti-EGFR monotherapy benefits biomarker-selected patients with EGFR CNG and/or high EGFR expression, combining anti-EGFR therapies with platinum fluoropyrimidine chemotherapies is not effective, and uncertainty remains regarding the optimal cytotoxic chemotherapy partner for anti-EGFR therapies in ESCC. METHODS: The effects of EGFR CNG on fluoropyrimidine/platinum chemotherapy sensitivity in a cohort of gastroesophageal cancer patients (n = 302) was evaluated. Drug combination studies using the EGFR inhibitor gefitinib with cytotoxic chemotherapies, docetaxel, cisplatin, oxaliplatin and irinotecan, on cell proliferation and cell death of EGFR CNG ESCC cell lines were assessed. RESULTS: EGFR CNG in gastroesophageal cancer patients was associated with improved overall survival following fluoropyrimidine/platinum chemotherapy. However, co-administration of gefitinib and oxaliplatin or cisplatin was frequently antagonistic in cell-based assays in EGFR CNG ESCC, whereas the combination of gefitinib with docetaxel or irinotecan was more efficacious. Co-administration of gefitinib/docetaxel and sequential administration of docetaxel before gefitinib showed synergy, but docetaxel given after gefitinib was antagonistic. CONCLUSION: Gefitinib/platinum co-administration demonstrated antagonism suggesting a possible explanation for the lack of benefit from addition of anti-EGFR therapies to fluoropyrimidine/platinum chemotherapy in trials. Gefitinib/docetaxel co-administration demonstrated synergy suggesting taxanes could be the most effective cytotoxic partner for anti-EGFR therapies in EGFR CNG-positive ESCC, but careful consideration of drug scheduling is required.

Combining precision medicine and prophylaxis in oesophageal squamous cell carcinoma.

A trial update confirms improved survival for prophylactic elective nodal irradiation and addition of erlotinib to definitive chemoradiotherapy in oesophageal squamous cell carcinoma (ESCC). High tumour EGFR protein expression shows promise to identify those who will benefit from erlotinib. This represents therapeutic progress, and has wider relevance for precision medicine strategies in ESCC.

Novel biomarkers for risk stratification of Barrett's oesophagus associated neoplastic progression-epithelial HMGB1 expression and stromal lymphocytic phenotype.

BACKGROUND: The incidence of oesophageal adenocarcinoma is increasing globally. Barrett's oesophagus (BO) is a pre-malignant condition with no biomarker to risk stratify those at highest risk of dysplasia and malignant transformation. METHODS: Subcellular epithelial protein (HMGB1, p53, RUNX3) expression, alongside expression of CD20, CD4, CD8 and Foxp3 to characterise stromal B lymphocyte, and helper, cytotoxic and regulatory T-lymphocyte cell infiltrate, respectively, was assessed by immunohistochemistry in 218 human tissue samples including normal oesophageal/gastric biopsies (n = 39), BO (non-dysplasia, dysplasia, non-dysplastic background from progressors to dysplasia or cancer, n = 121) and oesophageal adenocarcinoma (n = 58). RESULTS: There is a dynamic subcellular epithelial expression of HMGB1 (loss of nuclear, emergence of cytoplasmic), associated with epithelial p53 expression and differential immune cell phenotype in oesophageal neoplastic progression. We identify a protein signature and lymphocyte infiltrate in non-dysplastic BO when progressive disease (dysplasia or adenocarcinoma) is present but not histologically represented in the biopsied field. There is a dynamic stromal lymphocytic infiltrate in oesophageal neoplastic progression. CONCLUSIONS: This data reveals novel insights into the microenvironment of BO and progression towards cancer and identifies a novel high-risk biomarker of disease progression to aid surveillance strategies to identify early progression and impact future incidence of oesophageal cancer.

Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer.

Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma.

BACKGROUND: Clinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC. RESULTS: Dual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %). Two independent operator scores for FISH positivity were 100 % concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03). CONCLUSION: Our FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 %) of FISH positive patients. EGFR amplification, which is found in 6.3 %, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies.

Biomarkers and novel agents in esophago-gastric cancer: are we making progress?

Esophago-gastric cancer (EGC) provides a formidable healthcare challenge. Conventional chemotherapy provides modest survival benefit in patients with advanced disease especially in the second-line setting. The recent paradigm shift in the oncology community towards targeting growth factor pathways and the immune system using novel targeted agents has now demonstrated clinical utility in EGC, but recent trial results have highlighted the complexity of disease pathogenesis and significant challenges remain. Here, we describe the current role of targeted therapies in EGC, and their corresponding biomarkers. We aim to provide a comprehensive review of the current climate of novel agents and their biomarkers in advanced EGC.

Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial.

BACKGROUND: Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer. METHODS: For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0-2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. FINDINGS: Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23-4·50, for gefitinib vs 3·67 months, 95% CI 2·97-4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74-1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference -8·61, 95% CI -14·49 to -2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI -2·33 to 7·72, n=231, p=0·293), dysphagia (-3·18, 95% CI -8·36 to 2·00, n=231, p=0·228), and eating (-4·11, 95% CI -9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23-1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07-1·37 in the placebo group; HR 0·80, 95% CI 0·66-0·96, p=0·020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3-4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). INTERPRETATION: The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. FUNDING: Cancer Research UK.