A global perspective on oesophageal cancer: two diseases in one
Authors: Andrew L K Ho, Elizabeth C Smyth
Journal: The Lancet. Gastroenterology & hepatology (2020)

Oesophageal cancer represents the sixth most common cause of cancer mortality worldwide.1Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (50311) Google Scholar Underlying this cancer type are two distinct diseases characterised by different histologies: oesophageal adenocarcinoma and oesophageal squamous cell carcinoma. Oesophageal adenocarcinoma predominately arises from Barrett's oesophagus, with histological progression from metaplasia through to invasive carcinoma, and is typically localised to the distal oesophagus. The main risk factors are gastro-oesophageal reflux and obesity; high intake of red meat and low intake of fruits and vegetables are also associated with development of oesophageal adenocarcinoma. Oesophageal squamous cell carcinoma develops from squamous epithelial cells and is typically localised to the upper two-thirds of the oesophagus. Tobacco consumption and alcohol intake are the most notable risk factors, although their relative risk varies by region. The GBD 2017 Oesophageal Cancer Collaborators used data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 dataset to provide a global overview of the distribution of oesophageal cancer and the morbidity, mortality, and key risk factors associated with the disease.2GBD 2017 Oesophageal Cancer CollaboratorsThe global, regional, and national burden of oesophageal cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet Gastroenterol Hepatol. 2020; (published online April 1.)https://doi.org/10.1016/S2468-1253(20)30007-8Google Scholar They describe national trends in incidence between 1990 and 2017 as well as the impact of risk factors on a regional level. Between 1990 and 2017, age-standardised incidence rates declined overall by 22·0% (95% uncertainty interval 18·6–25·2). This decline in age-standardised incidence was observed in all regions except for high-income North America (where oesophageal adenocarcinoma is predominant) and western sub-Saharan Africa. At the country level, there was an association between a higher proportion of squamous cell carcinoma (out of all oesophageal cancer cases) and lower socioeconomic development. The global variation to a large extent recapitulates that seen from an analysis of data from the Global Cancer Observatory (GLOBOCAN) and Cancer Incidence in Five Continents, Volume X (CI5X).3Malhotra GK Yanala U Ravipati A Follet M Vijayakumar M Are C Global trends in esophageal cancer.J Surg Oncol. 2017; 115: 564-579Crossref PubMed Scopus (198) Google Scholar A major limitation of this analysis of GBD 2017 data, acknowledged by the authors, is the inability to clearly demarcate between oesophageal adenocarcinoma and oesophageal squamous cell carcinoma. Summary data on oesophageal cancer as a whole should not mask the differing global distribution, risk factors, and temporal changes occurring between the two diseases. Their distinct biology is reflected in their management approaches. Although endoscopic management is appropriate for early-stage oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, treatment patterns frequently diverge for later stages. For more locally advanced oesophageal cancer, survival outcomes with surgery alone are poor and a multimodal approach is recommended for patients who are deemed fit to undergo surgery. Oesophageal squamous cell carcinoma is more sensitive than oesophageal adenocarcinoma to radiotherapy, therefore definitive chemoradiotherapy is an option for patients with oesophageal squamous cell carcinoma, with equivalent survival outcomes but higher rates of local relapse necessitating salvage oesophagectomy. Alternatively, both oesophageal adenocarcinoma and oesophageal squamous cell carcinoma can be treated by either perioperative chemotherapy or neoadjuvant chemoradiotherapy followed by surgery, with treatment preferences varying globally depending on the region. Given the reduced sensitivity of oesophageal adenocarcinoma to radiotherapy, patients with oesophageal adenocarcinoma should proceed to surgery even after showing good response to neoadjuvant chemoradiotherapy. For patients with oesophageal cancer of any histology with unresectable or metastatic disease, endoscopic treatments and palliative radiotherapy might provide symptomatic benefit. Palliative chemotherapy can be offered to selected patients; historically, metastatic squamous oesophageal cancer has been neglected in clinical trials, with regimens extrapolated from clinical trials of gastric and oesophageal adenocarcinoma. However, with the clarification of oesophageal squamous cell carcinoma as a biologically distinct disease entity, trials specific to oesophageal squamous cell carcinoma are beginning to emerge.4Moehler M Maderer A Thuss-Patience PC et al.Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER).Ann Oncol. 2020; 31: 228-235Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar In particular, there is growing evidence that oesophageal squamous cell carcinoma responds better to immunotherapy than oesophageal adenocarcinoma. For example, a clear benefit in terms of overall survival was observed in patients with oesophageal squamous cell carcinoma expressing high levels of high PD-L1 who were treated with pembrolizumab in KEYNOTE-181 (with no such benefit observed for similar patients with oesophageal adenocarcinoma in the same trial), and the ATTRACTION-3 trial showed a survival benefit for nivolumab in patients with oesophageal adenocarcinoma in the second-line setting, whereas similar trials showed no such benefit in patients with gastroesophageal adenocarcinoma.5Kojima T Muro K Francois E et al.Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phase III KEYNOTE-181 study.J Clin Oncol. 2019; (published online Jan 29.)DOI:10.1200/JCO.2019.37.4_suppl.2Crossref Google Scholar, 6Kato K Cho BC Takahashi M et al.Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 1506-1517Summary Full Text Full Text PDF PubMed Scopus (493) Google Scholar, 7Shitara K Özgüroğlu M Bang YJ et al.Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.Lancet. 2018; 392: 123-133Summary Full Text Full Text PDF PubMed Scopus (749) Google Scholar In the GBD analysis, the GBD 2017 Oesophageal Cancer Collaborators show the impact of modifiable risk factors on the global burden of oesophageal cancer, which present clear public health issues to be addressed. The global variation in the incidence of oesophageal adenocarcinoma and oesophageal squamous cell carcinoma (eg, the high incidence of oesophageal squamous cell carcinoma in the Asian oesophageal cancer belt) allows policy makers to tailor interventions. However, risk factors are only part of the story: early detection of disease via screening is equally important. Endoscopy is the traditional gold standard for detecting oesophageal cancer, but less invasive screening methods are being developed. For example, Cytosponge is a cell collection device that is swallowed and retrieved with a string, followed by analysis of cells for trefoil factor 3 protein. This method aims to identify patients who warrant an endoscopy for suspected Barrett's oesophagus and is being investigated in the BEST3 trial in the primary-care setting in England.8Offman J Muldrew B O'Donovan M et al.Barrett's oESophagus trial 3 (BEST3): study protocol for a randomised controlled trial comparing the Cytosponge-TFF3 test with usual care to facilitate the diagnosis of oesophageal pre-cancer in primary care patients with chronic acid reflux.BMC Cancer. 2018; 18: 784Crossref PubMed Scopus (32) Google Scholar In China, where oesophageal squamous cell carcinoma is predominant, screening of patients aged 40–69 years in high-incidence areas by use of endoscopy with Lugol's iodine reduced mortality from oesophageal squamous cell carcinoma. A randomised controlled trial is ongoing to ascertain the efficacy and cost-effectiveness of this strategy.9Wei W-Q Chen Z-F He Y-T et al.Long-term follow-up of a community assignment, one-time endoscopic screening study of esophageal cancer in China.J Clin Oncol. 2015; 33: 1951-1957Crossref PubMed Scopus (198) Google Scholar, 10He Z Liu Z Liu M et al.Efficacy of endoscopic screening for esophageal cancer in China (ESECC): design and preliminary results of a population-based randomised controlled trial.Gut. 2019; 68: 198-206Crossref PubMed Scopus (68) Google Scholar The data presented by the GBD 2017 Oesophageal Cancer Collaborators on patterns of oesophageal cancer provide a global perspective of the scale of disease, and an insight into how socioeconomic transitions can shape the burden of oesophageal adenocarcinoma and oesophageal squamous cell carcinoma. Effective screening tools, good access to diagnostics, and affordable treatments are needed to alter the future of oesophageal cancer. ECS declares honoraria from Astellas, AstraZeneca, Bristol-Myers Squibb, Celgene, Gritstone Therapeutics, Merck, and Servier. ALKH declares no competing interests. The global, regional, and national burden of oesophageal cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017Despite reductions in age-standardised incidence and mortality rates, oesophageal cancer remains a major cause of cancer mortality and burden across the world. Oesophageal cancer is a highly fatal disease, requiring increased primary prevention efforts and, possibly, screening in some high-risk areas. Substantial variation exists in age-standardised incidence rates across regions and countries, for reasons that are unclear. Full-Text PDF Open Access