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Oesophageal cancer

Abstract

Oesophageal cancer is the sixth most common cause of cancer-related death worldwide and is therefore a major global health challenge. The two major subtypes of oesophageal cancer are oesophageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma (OAC), which are epidemiologically and biologically distinct. OSCC accounts for 90% of all cases of oesophageal cancer globally and is highly prevalent in the East, East Africa and South America. OAC is more common in developed countries than in developing countries. Preneoplastic lesions are identifiable for both OSCC and OAC; these are frequently amenable to endoscopic ablative therapies. Most patients with oesophageal cancer require extensive treatment, including chemotherapy, chemoradiotherapy and/or surgical resection. Patients with advanced or metastatic oesophageal cancer are treated with palliative chemotherapy; those who are human epidermal growth factor receptor 2 (HER2)-positive may also benefit from trastuzumab treatment. Immuno-oncology therapies have also shown promising early results in OSCC and OAC. In this Primer, we review state-of-the-art knowledge on the biology and treatment of oesophageal cancer, including screening, endoscopic ablative therapies and emerging molecular targets, and we discuss best practices in chemotherapy, chemoradiotherapy, surgery and the maintenance of patient quality of life.

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Figure 1: The global annual incidence of OSCC and OAC.
Figure 2: The pathogenesis of OSCC and OAC.
Figure 3: An endoscopic image of early OSCC.
Figure 4: Tumour–node–metastasis categories.
Figure 5: An algorithm for the management of localized oesophageal cancer.
Figure 6: Minimally invasive oesophagectomy for oesophageal cancer.
Figure 7: Potential drug targets in oesophageal cancer.

References

  1. 1

    Lin, Y. et al. Epidemiology of esophageal cancer in Japan and China. J. Epidemiol. 23, 233–242 (2013).

    Google Scholar 

  2. 2

    Cook, M. B., Chow, W. H. & Devesa, S. S. Oesophageal cancer incidence in the United States by race, sex, and histologic type, 1977–2005. Br. J. Cancer 101, 855–859 (2009).

    CAS  Google Scholar 

  3. 3

    Arnold, M., Soerjomataram, I., Ferlay, J. & Forman, D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut 64, 381–387 (2015).

    Google Scholar 

  4. 4

    The Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature 541, 169–175 (2017). A comprehensive multiplatform analysis of the molecular biology of OSCC and OAC.

    Google Scholar 

  5. 5

    Fitzgerald, R. C. et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus. Gut 63, 7–42 (2014). Guidelines that discuss the endoscopic management of Barrett oesophagus.

    Google Scholar 

  6. 6

    Lordick, F., Mariette, C., Haustermans, K., Obermannova, R. & Arnold, D. Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 27, v50–v57 (2016).

    CAS  Google Scholar 

  7. 7

    National Comprehensive Cancer Network. NCCN guidelines for patients — esophageal cancer. NCCNhttps://www.nccn.org/patients/guidelines/esophageal/files/assets/common/downloads/files/esophageal.pdf (2016).

  8. 8

    Waddell, T. et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 14, 481–489 (2013).

    CAS  Google Scholar 

  9. 9

    Lordick, F. et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 14, 490–499 (2013).

    CAS  Google Scholar 

  10. 10

    Shah, M. A. et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncol. 3, 620–627 (2017).

    Google Scholar 

  11. 11

    Cunningham, D. et al. Phase III, randomized, double-blind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy in patients (pts) with advanced MET-positive (pos) gastric or gastroesophageal junction (G/GEJ) cancer: RILOMET-1 study. J. Clin. Oncol. 33, 4000 (2015).

    Google Scholar 

  12. 12

    Backemar, L., Wikman, A., Djarv, T., Johar, A. & Lagergren, P. Co-morbidity after oesophageal cancer surgery and recovery of health-related quality of life. Br. J. Surg. 103, 1665–1675 (2016).

    CAS  Google Scholar 

  13. 13

    Anandavadivelan, P. & Lagergren, P. Cachexia in patients with oesophageal cancer. Nat. Rev. Clin. Oncol. 13, 185–198 (2016). A comprehensive review of the nutritional problems observed in patients with oesophageal cancer.

    CAS  Google Scholar 

  14. 14

    Siegel, R., Ma, J., Zou, Z. & Jemal, A. Cancer statistics, 2014. CA Cancer J. Clin. 64, 9–29 (2014).

    Google Scholar 

  15. 15

    Cancer Research UK. Oesophageal cancer statistics. Cancer Research UKhttp://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/oesophageal-cancer (2017).

  16. 16

    Trivers, K. F., Sabatino, S. A. & Stewart, S. L. Trends in esophageal cancer incidence by histology, United States, 1998–2003. Int. J. Cancer 123, 1422–1428 (2008).

    CAS  Google Scholar 

  17. 17

    Zhao, J., He, Y. T., Zheng, R. S., Zhang, S. W. & Chen, W. Q. Analysis of esophageal cancer time trends in China, 1989–2008. Asian Pac. J. Cancer Prev. 13, 4613–4617 (2012).

    Google Scholar 

  18. 18

    He, Y. T. et al. Trends in incidence of esophageal and gastric cardia cancer in high-risk areas in China. Eur. J. Cancer Prev. 17, 71–76 (2008).

    Google Scholar 

  19. 19

    Wei, W. Q. et al. Long-term follow-up of a community assignment, one-time endoscopic screening study of esophageal cancer in China. J. Clin. Oncol. 33, 1951–1957 (2015).

    Google Scholar 

  20. 20

    Edgren, G., Adami, H.-O., Weiderpass Vainio, E. & Nyrén, O. A global assessment of the oesophageal adenocarcinoma epidemic. Gut 62, 1406–1414 (2013).

    Google Scholar 

  21. 21

    Freedman, N. D. et al. A prospective study of tobacco, alcohol, and the risk of esophageal and gastric cancer subtypes. Am. J. Epidemiol. 165, 1424–1433 (2007).

    Google Scholar 

  22. 22

    Tran, G. D. et al. Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China. Int. J. Cancer 113, 456–463 (2005).

    CAS  Google Scholar 

  23. 23

    Yang, C. X. et al. Esophageal cancer risk by ALDH2 and ADH2 polymorphisms and alcohol consumption: exploration of gene–environment and gene–gene interactions. Asian Pac. J. Cancer Prev. 6, 256–262 (2005).

    Google Scholar 

  24. 24

    Prabhu, A., Obi, K. O. & Rubenstein, J. H. The synergistic effects of alcohol and tobacco consumption on the risk of esophageal squamous cell carcinoma: a meta-analysis. Am. J. Gastroenterol. 109, 822–827 (2014).

    Google Scholar 

  25. 25

    Freedman, N. D. et al. Fruit and vegetable intake and esophageal cancer in a large prospective cohort study. Int. J. Cancer 121, 2753–2760 (2007).

    CAS  Google Scholar 

  26. 26

    Yang, C. S. et al. Vitamin A and other deficiencies in Linxian, a high esophageal cancer incidence area in northern China. J. Natl Cancer Inst. 73, 1449–1453 (1984).

    CAS  Google Scholar 

  27. 27

    Taylor, P. R. et al. Prospective study of serum vitamin E levels and esophageal and gastric cancers. J. Natl Cancer Inst. 95, 1414–1416 (2003).

    Google Scholar 

  28. 28

    Cooper, S. C. et al. The influence of deprivation and ethnicity on the incidence of esophageal cancer in England. Cancer Causes Control 20, 1459–1467 (2009).

    Google Scholar 

  29. 29

    Islami, F. et al. High-temperature beverages and foods and esophageal cancer risk — a systematic review. Int. J. Cancer 125, 491–524 (2009).

    CAS  Google Scholar 

  30. 30

    Ludmir, E. B., Stephens, S. J., Palta, M., Willett, C. G. & Czito, B. G. Human papillomavirus tumor infection in esophageal squamous cell carcinoma. J. Gastrointest. Oncol. 6, 287–295 (2015).

    Google Scholar 

  31. 31

    Blaydon, D. C. et al. RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am. J. Hum. Genet. 90, 340–346 (2012).

    CAS  Google Scholar 

  32. 32

    Wang, L. D. et al. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat. Genet. 42, 759–763 (2010).

    CAS  Google Scholar 

  33. 33

    Abnet, C. C. et al. A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat. Genet. 42, 764–767 (2010).

    CAS  Google Scholar 

  34. 34

    Wu, C. et al. Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations. Nat. Genet. 46, 1001–1006 (2014).

    CAS  Google Scholar 

  35. 35

    Cui, R. et al. Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology 137, 1768–1775 (2009).

    CAS  Google Scholar 

  36. 36

    Liu, X. et al. Genetic alterations in esophageal tissues from squamous dysplasia to carcinoma. Gastroenterology 153, 166–177 (2017).

    CAS  Google Scholar 

  37. 37

    Fagundes, R. B., Melo, C. R., Putten, A. C., Moreira, L. F. & de Barros, S. G. p53 immunoexpression: an aid to conventional methods in the screening of precursor lesions of squamous esophageal cancer in patients at high-risk? Cancer Detect. Prev. 29, 227–232 (2005).

    Google Scholar 

  38. 38

    Muller, L. B. et al. Stepwise expression of CDKN2A and RB1 proteins in esophageal mucosa from patients at high risk for squamous cell carcinoma. Appl. Immunohistochem. Mol. Morphol. 22, 669–673 (2014).

    Google Scholar 

  39. 39

    Couch, G. et al. The discovery and validation of biomarkers for the diagnosis of esophageal squamous dysplasia and squamous cell carcinoma. Cancer Prev. Res. (Phila.) 9, 558–566 (2016).

    CAS  Google Scholar 

  40. 40

    Song, Y. et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature 509, 91–95 (2014).

    CAS  Google Scholar 

  41. 41

    Gao, Y. B. et al. Genetic landscape of esophageal squamous cell carcinoma. Nat. Genet. 46, 1097–1102 (2014).

    CAS  Google Scholar 

  42. 42

    Lin, D. C. et al. Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat. Genet. 46, 467–473 (2014).

    CAS  Google Scholar 

  43. 43

    Anderson, L. A. et al. Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study. World J. Gastroenterol. 13, 1585–1594 (2007).

    Google Scholar 

  44. 44

    Cook, M. B. et al. Gastroesophageal reflux in relation to adenocarcinomas of the esophagus: a pooled analysis from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). PLoS ONE 9, e103508 (2014).

    Google Scholar 

  45. 45

    Stein, D. J., El-Serag, H. B., Kuczynski, J., Kramer, J. R. & Sampliner, R. E. The association of body mass index with Barrett's oesophagus. Aliment. Pharmacol. Ther. 22, 1005–1010 (2005).

    CAS  Google Scholar 

  46. 46

    Akiyama, T. et al. Visceral obesity and the risk of Barrett's esophagus in Japanese patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 9, 56 (2009).

    Google Scholar 

  47. 47

    Leggett, C. L. et al. Metabolic syndrome as a risk factor for Barrett esophagus: a population-based case–control study. Mayo Clin. Proc. 88, 157–165 (2013).

    Google Scholar 

  48. 48

    Cook, M. B. et al. Cigarette smoking and adenocarcinomas of the esophagus and esophagogastric junction: a pooled analysis from the international BEACON consortium. J. Natl Cancer Inst. 102, 1344–1353 (2010).

    CAS  Google Scholar 

  49. 49

    Thrift, A. P., Kramer, J. R., Richardson, P. A. & El-Serag, H. B. No significant effects of smoking or alcohol consumption on risk of Barrett's esophagus. Dig. Dis. Sci. 59, 108–116 (2014).

    CAS  Google Scholar 

  50. 50

    Jiao, L. et al. Dietary consumption of meat, fat, animal products and advanced glycation end-products and the risk of Barrett's oesophagus. Aliment. Pharmacol. Ther. 38, 817–824 (2013).

    CAS  Google Scholar 

  51. 51

    Kubo, A. et al. Dietary antioxidants, fruits, and vegetables and the risk of Barrett's esophagus. Am. J. Gastroenterol. 103, 1614–1623 (2008).

    CAS  Google Scholar 

  52. 52

    Thrift, A. P. et al. Helicobacter pylori infection and the risks of Barrett's oesophagus: a population-based case–control study. Int. J. Cancer 130, 2407–2416 (2012).

    CAS  Google Scholar 

  53. 53

    Islami, F. & Kamangar, F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prev. Res. (Phila.) 1, 329–338 (2008).

    CAS  Google Scholar 

  54. 54

    Verbeek, R. E. et al. Familial clustering of Barrett's esophagus and esophageal adenocarcinoma in a European cohort. Clin. Gastroenterol. Hepatol. 12, 1656–1663.e1 (2014).

    Google Scholar 

  55. 55

    Chak, A. et al. Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol. Biomarkers Prev. 15, 1668–1673 (2006).

    Google Scholar 

  56. 56

    Vaughan, T. L. & Fitzgerald, R. C. Precision prevention of oesophageal adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 12, 243–248 (2015).

    Google Scholar 

  57. 57

    Su, Z. et al. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus. Nat. Genet. 44, 1131–1136 (2012).

    CAS  Google Scholar 

  58. 58

    Gharahkhani, P. et al. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis. Lancet Oncol. 17, 1363–1373 (2016).

    Google Scholar 

  59. 59

    Buas, M. F. et al. Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma. Guthttp://dx.doi.org/10.1136/gutjnl-2016-311622 (2016).

  60. 60

    Dai, J. Y. et al. A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett's esophagus. Cancer Epidemiol. Biomarkers Prev. 24, 1739–1747 (2015).

    CAS  Google Scholar 

  61. 61

    Dvorak, K. et al. Molecular mechanisms of Barrett's esophagus and adenocarcinoma. Ann. NY Acad. Sci. 1232, 381–391 (2011).

    CAS  Google Scholar 

  62. 62

    Vaninetti, N. M. et al. Inducible nitric oxide synthase, nitrotyrosine and p53 mutations in the molecular pathogenesis of Barrett's esophagus and esophageal adenocarcinoma. Mol. Carcinog. 47, 275–285 (2008).

    CAS  Google Scholar 

  63. 63

    Dulak, A. M. et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat. Genet. 45, 478–486 (2013).

    CAS  Google Scholar 

  64. 64

    Quante, M. et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 21, 36–51 (2012).

    CAS  Google Scholar 

  65. 65

    Wang, X. et al. Residual embryonic cells as precursors of a Barrett's-like metaplasia. Cell 145, 1023–1035 (2011).

    CAS  Google Scholar 

  66. 66

    di Pietro, M., Alzoubaidi, D. & Fitzgerald, R. C. Barrett's esophagus and cancer risk: how research advances can impact clinical practice. Gut Liver 8, 356–370 (2014).

    Google Scholar 

  67. 67

    Bansal, A. & Fitzgerald, R. C. Biomarkers in Barrett's esophagus: role in diagnosis, risk stratification, and prediction of response to therapy. Gastroenterol. Clin. North Am. 44, 373–390 (2015).

    Google Scholar 

  68. 68

    Duits, L. C. et al. Barrett's oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel. Gut 64, 700–706 (2015).

    Google Scholar 

  69. 69

    Weaver, J. M. J. et al. Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis. Nat. Genet. 46, 837–843 (2014).

    CAS  Google Scholar 

  70. 70

    Stachler, M. D. et al. Paired exome analysis of Barrett's esophagus and adenocarcinoma. Nat. Genet. 47, 1047–1055 (2015).

    CAS  Google Scholar 

  71. 71

    Reid, B. J. et al. Predictors of progression in Barrett's esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression. Am. J. Gastroenterol. 96, 2839–2848 (2001).

    CAS  Google Scholar 

  72. 72

    Galipeau, P. C., Prevo, L. J., Sanchez, C. A., Longton, G. M. & Reid, B. J. Clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in premalignant esophageal (Barrett's) tissue. J. Natl Cancer Inst. 91, 2087–2095 (1999).

    CAS  Google Scholar 

  73. 73

    Ross-Innes, C. S. et al. Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma. Nat. Genet. 47, 1038–1046 (2015).

    CAS  Google Scholar 

  74. 74

    Maley, C. C. et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat. Genet. 38, 468–473 (2006).

    CAS  Google Scholar 

  75. 75

    Martinez, P. et al. Dynamic clonal equilibrium and predetermined cancer risk in Barrett's oesophagus. Nat. Commun. 7, 12158 (2016).

    CAS  Google Scholar 

  76. 76

    Ross-Innes, C. S. et al. Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study. Lancet Gastroenterol. Hepatol. 2, 23–31 (2017).

    Google Scholar 

  77. 77

    Xu, E. et al. Genome-wide methylation analysis shows similar patterns in Barrett's esophagus and esophageal adenocarcinoma. Carcinogenesis 34, 2750–2756 (2013).

    CAS  Google Scholar 

  78. 78

    Wong, D. J., Barrett, M. T., Stoger, R., Emond, M. J. & Reid, B. J. p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas. Cancer Res. 57, 2619–2622 (1997).

    CAS  Google Scholar 

  79. 79

    Klump, B., Hsieh, C. J., Holzmann, K., Gregor, M. & Porschen, R. Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett's esophagus. Gastroenterology 115, 1381–1386 (1998).

    CAS  Google Scholar 

  80. 80

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  Google Scholar 

  81. 81

    Agrawal, N. et al. Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. Cancer Discov. 2, 899–905 (2012).

    CAS  Google Scholar 

  82. 82

    Dulak, A. M. et al. Gastrointestinal adenocarcinomas of the esophagus, stomach and colon exhibit distinct patterns of genome instability and oncogenesis. Cancer Res. 72, 4383–4393 (2012).

    CAS  Google Scholar 

  83. 83

    Deng, N. et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61, 673–684 (2012).

    CAS  Google Scholar 

  84. 84

    Secrier, M. et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat. Genet. 48, 1131–1141 (2016). A study that defines clinically relevant subgroups of OAC using whole-genome sequencing.

    CAS  Google Scholar 

  85. 85

    Kwak, E. L. et al. Clinical activity of AMG 337, an oral MET kinase inhibitor, in adult patients (pts) with MET-amplified gastroesophageal junction (GEJ), gastric (G), or esophageal (E) cancer. J. Clin. Oncol. 33, 1 (2015).

    Google Scholar 

  86. 86

    Paterson, A. L. et al. Characterization of the timing and prevalence of receptor tyrosine kinase expression changes in oesophageal carcinogenesis. J. Pathol. 230, 118–128 (2013).

    CAS  Google Scholar 

  87. 87

    Morita, F. H. et al. Narrow band imaging versus lugol chromoendoscopy to diagnose squamous cell carcinoma of the esophagus: a systematic review and meta-analysis. BMC Cancer 17, 54 (2017).

    Google Scholar 

  88. 88

    Graham, D. Y., Schwartz, J. T., Cain, G. D. & Gyorkey, F. Prospective evaluation of biopsy number in the diagnosis of esophageal and gastric carcinoma. Gastroenterology 82, 228–231 (1982).

    CAS  Google Scholar 

  89. 89

    Bosman, F. T., Carneiro, F., Hruban, R. H. & Theise, N. D. (eds) WHO Classification of Tumours of the Digestive System (IARC, 2010).

    Google Scholar 

  90. 90

    Wong, H. H. & Chu, P. Immunohistochemical features of the gastrointestinal tract tumors. J. Gastrointest. Oncol. 3, 262–284 (2012).

    Google Scholar 

  91. 91

    Amin, M. B. et al. (eds) AJCC Cancer Staging Manual 8th edn (Springer International Publishing, 2017).

    Google Scholar 

  92. 92

    Puli, S.-R. et al. Staging accuracy of esophageal cancer by endoscopic ultrasound: a meta-analysis and systematic review. World J. Gastroenterol. 14, 1479–1490 (2008).

    Google Scholar 

  93. 93

    Seevaratnam, R. et al. How useful is preoperative imaging for tumor, node, metastasis (TNM) staging of gastric cancer? A meta-analysis. Gastric Cancer 15 (Suppl. 1), S3–S18 (2012).

    Google Scholar 

  94. 94

    Findlay, J. M. et al. Pragmatic staging of oesophageal cancer using decision theory involving selective endoscopic ultrasonography, PET and laparoscopy. Br. J. Surg. 102, 1488–1499 (2015).

    CAS  Google Scholar 

  95. 95

    Smyth, E. et al. A prospective evaluation of the utility of 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography and computed tomography in staging locally advanced gastric cancer. Cancer 118, 5481–5488 (2012).

    Google Scholar 

  96. 96

    de Graaf, G. W., Ayantunde, A. A., Parsons, S. L., Duffy, J. P. & Welch, N. T. The role of staging laparoscopy in oesophagogastric cancers. Eur. J. Surg. Oncol. 33, 988–992 (2007).

    CAS  Google Scholar 

  97. 97

    Weber, W. A. et al. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J. Clin. Oncol. 19, 3058–3065 (2001).

    CAS  Google Scholar 

  98. 98

    Ott, K. et al. Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction. J. Clin. Oncol. 24, 4692–4698 (2006).

    Google Scholar 

  99. 99

    Lordick, F. et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol. 8, 797–805 (2007).

    Google Scholar 

  100. 100

    zum Büschenfelde, C. M. et al. 18F-FDG PET-guided salvage neoadjuvant radiochemotherapy of adenocarcinoma of the esophagogastric junction: the MUNICON II trial. J. Nucl. Med. 52, 1189–1196 (2011).

    Google Scholar 

  101. 101

    Goodman, K., Niedzwiecki, D. & Hall, N. Initial results of CALGB 80803 (Alliance): a randomized phase II trial of PET scan-directed combined modality therapy for esophageal cancer. J. Clin Oncol. 35, 1 (2017).

    Google Scholar 

  102. 102

    Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).

    Google Scholar 

  103. 103

    Shaheen, N. J., Falk, G. W., Iyer, P. G. & Gerson, L. B. ACG clinical guideline: diagnosis and management of Barrett's esophagus. Am. J. Gastroenterol. 111, 30–50 (2016).

    CAS  Google Scholar 

  104. 104

    Shariff, M. K. et al. Randomized crossover study comparing efficacy of transnasal endoscopy with that of standard endoscopy to detect Barrett's esophagus. Gastrointest. Endosc. 75, 954–961 (2012).

    Google Scholar 

  105. 105

    Alashkar, B. et al. Development of a program to train physician extenders to perform transnasal esophagoscopy and screen for Barrett's esophagus. Clin. Gastroenterol. Hepatol. 12, 785–792 (2014).

    Google Scholar 

  106. 106

    Bhardwaj, A., Hollenbeak, C. S., Pooran, N. & Mathew, A. A meta-analysis of the diagnostic accuracy of esophageal capsule endoscopy for Barrett's esophagus in patients with gastroesophageal reflux disease. Am. J. Gastroenterol. 104, 1533–1539 (2009).

    Google Scholar 

  107. 107

    Kadri, S. R. et al. Acceptability and accuracy of a non-endoscopic screening test for Barrett's oesophagus in primary care: cohort study. BMJ 341, c4372 (2010).

    Google Scholar 

  108. 108

    Ross-Innes, C. S. et al. Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case–control study. PLoS Med. 12, e1001780 (2015). A study that screened patients for Barrett oesophagus using the minimally invasive Cytosponge and biomarker stratification.

    Google Scholar 

  109. 109

    ISRCTN registry. BEST3 — a trial of a new GP-based test for patients with heartburn symptoms. ISRCTNhttp://www.isrctn.com/ISRCTN68382401 (2017).

  110. 110

    Desai, T. K. et al. The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis. Gut 61, 970–976 (2012).

    Google Scholar 

  111. 111

    Singh, S. et al. Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta-analysis. Gastrointest. Endosc. 79, 897–909.e4 (2014).

    Google Scholar 

  112. 112

    Rastogi, A. et al. Incidence of esophageal adenocarcinoma in patients with Barrett's esophagus and high-grade dysplasia: a meta-analysis. Gastrointestinal Endosc. 67, 394–398 (2008).

    Google Scholar 

  113. 113

    Hvid-Jensen, F., Pedersen, L., Drewes, A. M., Sorensen, H. T. & Funch-Jensen, P. Incidence of adenocarcinoma among patients with Barrett's esophagus. N. Engl. J. Med. 365, 1375–1383 (2011).

    CAS  Google Scholar 

  114. 114

    Kastelein, F. et al. Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with Barrett's oesophagus. Gut 62, 1676–1683 (2013).

    CAS  Google Scholar 

  115. 115

    Sikkema, M. et al. Aneuploidy and overexpression of Ki67 and p53 as markers for neoplastic progression in Barrett's esophagus: a case–control study. Am. J. Gastroenterol. 104, 2673–2680 (2009).

    CAS  Google Scholar 

  116. 116

    Maret-Ouda, J., Konings, P., Lagergren, J. & Brusselaers, N. Antireflux surgery and risk of esophageal adenocarcinoma: a systematic review and meta-analysis. Ann. Surg. 263, 251–257 (2016).

    Google Scholar 

  117. 117

    Kastelein, F. et al. Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett's esophagus. Clin. Gastroenterol. Hepatol. 11, 382–388 (2013).

    CAS  Google Scholar 

  118. 118

    Nguyen, D. M. et al. Medication usage and the risk of neoplasia in patients with Barrett's esophagus. Clin. Gastroenterol. Hepatol. 7, 1299–1304 (2009).

    Google Scholar 

  119. 119

    Hillman, L. C., Chiragakis, L., Shadbolt, B., Kaye, G. L. & Clarke, A. C. Proton-pump inhibitor therapy and the development of dysplasia in patients with Barrett's oesophagus. Med. J. Aust. 180, 387–391 (2004).

    Google Scholar 

  120. 120

    Brasky, T. M. et al. Non-steroidal anti-inflammatory drugs and cancer risk in women: results from the Women's Health Initiative. Int. J. Cancer 135, 1869–1883 (2014).

    CAS  Google Scholar 

  121. 121

    Cao, Y. et al. Population-wide impact of long-term use of aspirin and the risk for cancer. JAMA Oncol. 2, 762–769 (2016).

    Google Scholar 

  122. 122

    Corley, D. A., Kerlikowske, K., Verma, R. & Buffler, P. Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 124, 47–56 (2003).

    CAS  Google Scholar 

  123. 123

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT00357682 (2016).

  124. 124

    Shaheen, N. J. et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N. Engl. J. Med. 360, 2277–2288 (2009).

    CAS  Google Scholar 

  125. 125

    Prasad, G. A. et al. Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in Barrett's esophagus. Gastroenterology 132, 1226–1233 (2007).

    Google Scholar 

  126. 126

    Phoa, K. N. et al. Radiofrequency ablation versus endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA 311, 1209–1217 (2014).

    CAS  Google Scholar 

  127. 127

    Pech, O. et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett's oesophagus. Gut 57, 1200–1206 (2008).

    CAS  Google Scholar 

  128. 128

    Manner, H. et al. Efficacy, safety, and long-term results of endoscopic treatment for early stage adenocarcinoma of the esophagus with low-risk sm1 invasion. Clin. Gastroenterol. Hepatol. 11, 630–635 (2013).

    Google Scholar 

  129. 129

    He, S. et al. Endoscopic radiofrequency ablation for early esophageal squamous cell neoplasia: report of safety and effectiveness from a large prospective trial. Endoscopy 47, 398–408 (2015).

    Google Scholar 

  130. 130

    Haidry, R. J. et al. Radiofrequency ablation for early oesophageal squamous neoplasia: outcomes form United Kingdom registry. World J. Gastroenterol. 19, 6011–6019 (2013).

    Google Scholar 

  131. 131

    Bergman, J. J. et al. Outcomes from a prospective trial of endoscopic radiofrequency ablation of early squamous cell neoplasia of the esophagus. Gastrointest. Endosc. 74, 1181–1190 (2011).

    Google Scholar 

  132. 132

    Blot, W. J. et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J. Natl Cancer Inst. 85, 1483–1492 (1993).

    CAS  Google Scholar 

  133. 133

    Sun, L. & Yu, S. Meta-analysis: non-steroidal anti-inflammatory drug use and the risk of esophageal squamous cell carcinoma. Dis. Esophagus 24, 544–549 (2011).

    Google Scholar 

  134. 134

    Rutegård, M. et al. Population-based esophageal cancer survival after resection without neoadjuvant therapy: an update. Surgery 152, 903–910 (2012).

    Google Scholar 

  135. 135

    Pech, O. et al. Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology 146, 652–660.e1 (2014).

    Google Scholar 

  136. 136

    Desai, M. et al. Efficacy and safety outcomes of multimodal endoscopic eradication therapy in Barrett's esophagus-related neoplasia: a systematic review and pooled analysis. Gastrointest. Endosc. 85, 482–495.e4 (2017).

    Google Scholar 

  137. 137

    Merkow, R. P. et al. Treatment trends, risk of lymph node metastasis, and outcomes for localized esophageal cancer. J. Natl Cancer Inst. 106, dju133 (2014).

    Google Scholar 

  138. 138

    Boys, J. A. et al. Can the risk of lymph node metastases be gauged in endoscopically resected submucosal esophageal adenocarcinomas? A multi-center study. J. Gastrointest. Surg. 20, 6–12 (2016).

    Google Scholar 

  139. 139

    Haverkamp, L., Ruurda, J. P., van Leeuwen, M. S., Siersema, P. D. & van Hillegersberg, R. Systematic review of the surgical strategies of adenocarcinomas of the gastroesophageal junction. Surg. Oncol. 23, 222–228 (2014).

    CAS  Google Scholar 

  140. 140

    Martin, J. T., Mahan, A., Zwischenberger, J. B., McGrath, P. C. & Tzeng, C. W. Should gastric cardia cancers be treated with esophagectomy or total gastrectomy? A comprehensive analysis of 4,996 NSQIP/SEER patients. J. Am. Coll. Surg. 220, 510–520 (2015).

    Google Scholar 

  141. 141

    Wei, M. T. et al. Transthoracic versus transhiatal surgery for cancer of the esophagogastric junction: a meta-analysis. World J. Gastroenterol. 20, 10183–10192 (2014).

    Google Scholar 

  142. 142

    Aurello, P. et al. Transthoracically or transabdominally: how to approach adenocarcinoma of the distal esophagus and cardia. A meta-analysis. Tumori 102, 352–360 (2016).

    Google Scholar 

  143. 143

    de Boer, A. G. et al. Quality of life after transhiatal compared with extended transthoracic resection for adenocarcinoma of the esophagus. J. Clin. Oncol. 22, 4202–4208 (2004).

    CAS  Google Scholar 

  144. 144

    Luketich, J. D. et al. Minimally invasive esophagectomy: results of a prospective phase II multicenter trial — the eastern cooperative oncology group (E2202) study. Ann. Surg. 261, 702–707 (2015).

    Google Scholar 

  145. 145

    Dantoc, M. M., Cox, M. R. & Eslick, G. D. Does minimally invasive esophagectomy (MIE) provide for comparable oncologic outcomes to open techniques? A systematic review. J. Gastrointest. Surg. 16, 486–494 (2012).

    Google Scholar 

  146. 146

    Biere, S. S. et al. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet 379, 1887–1892 (2012).

    Google Scholar 

  147. 147

    Maas, K. W. et al. Quality of life and late complications after minimally invasive compared to open esophagectomy: results of a randomized trial. World J. Surg. 39, 1986–1993 (2015).

    CAS  Google Scholar 

  148. 148

    Rizk, N. P. et al. Optimum lymphadenectomy for esophageal cancer. Ann. Surg. 251, 46–50 (2010).

    Google Scholar 

  149. 149

    Lagergren, J. et al. Extent of lymphadenectomy and prognosis after esophageal cancer surgery. JAMA Surg. 151, 32–39 (2016).

    Google Scholar 

  150. 150

    van der Schaaf, M., Johar, A., Wijnhoven, B., Lagergren, P. & Lagergren, J. Extent of lymph node removal during esophageal cancer surgery and survival. J. Natl Cancer Inst. 107, djv043 (2015).

    Google Scholar 

  151. 151

    Koen Talsma, A. et al. Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival. Ann. Surg. 260, 786–792; discussion 792–783 (2014).

    CAS  Google Scholar 

  152. 152

    Filip, B. et al. Minimally invasive surgery for esophageal cancer: a review on sentinel node concept. Surg. Endosc. 28, 1238–1249 (2014).

    Google Scholar 

  153. 153

    Derogar, M., Sadr-Azodi, O., Johar, A., Lagergren, P. & Lagergren, J. Hospital and surgeon volume in relation to survival after esophageal cancer surgery in a population-based study. J. Clin. Oncol. 31, 551–557 (2013). A study that assesses surgeon and hospital volume in relation to long-term prognosis, and that is important because it adjusts for all relevant factors, including mutual adjustment for surgeon and hospital volume.

    Google Scholar 

  154. 154

    Brusselaers, N., Mattsson, F. & Lagergren, J. Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis. Gut 63, 1393–1400 (2014).

    Google Scholar 

  155. 155

    Mamidanna, R. et al. Surgeon volume and cancer esophagectomy, gastrectomy, and pancreatectomy: a population-based study in England. Ann. Surg. 263, 727–732 (2016).

    Google Scholar 

  156. 156

    Tapias, L. F. & Morse, C. R. Minimally invasive Ivor Lewis esophagectomy: description of a learning curve. J. Am. Coll. Surg. 218, 1130–1140 (2014).

    Google Scholar 

  157. 157

    Markar, S. R., Mackenzie, H., Lagergren, P., Hanna, G. B. & Lagergren, J. Surgical proficiency gain and survival after esophagectomy for cancer. J. Clin. Oncol. 34, 1528–1536 (2016). A study that reveals a long learning curve for surgeons performing oesophagectomies.

    Google Scholar 

  158. 158

    Markar, S. R., Mackenzie, H., Lagergren, P. & Lagergren, J. Surgeon age in relation to prognosis after esophageal cancer resection. Ann. Surg.http://dx.doi.org/10.1097/SLA.0000000000002260 (2017).

  159. 159

    Lagergren, J., Mattsson, F. & Lagergren, P. Weekday of esophageal cancer surgery and its relation to prognosis. Ann. Surg. 263, 1133–1137 (2016).

    Google Scholar 

  160. 160

    Nienhueser, H. et al. Surgery of gastric cancer and esophageal cancer: does age matter? J. Surg. Oncol. 112, 387–395 (2015).

    Google Scholar 

  161. 161

    Alibakhshi, A. et al. The effect of age on the outcome of esophageal cancer surgery. Ann. Thorac Med. 4, 71–74 (2009).

    Google Scholar 

  162. 162

    Paulus, E. et al. Esophagectomy for cancer in octogenarians: should we do it? Langenbecks Arch. Surg. 402, 539–545 (2017).

    Google Scholar 

  163. 163

    Liu, J. H. et al. Disparities in the utilization of high-volume hospitals for complex surgery. JAMA 296, 1973–1980 (2006).

    CAS  Google Scholar 

  164. 164

    Revels, S. L., Morris, A. M., Reddy, R. M., Akateh, C. & Wong, S. L. Racial disparities in esophageal cancer outcomes. Ann. Surg. Oncol. 20, 1136–1141 (2013).

    Google Scholar 

  165. 165

    Zhang, S. S. et al. The impact of body mass index on complication and survival in resected oesophageal cancer: a clinical-based cohort and meta-analysis. Br. J. Cancer 109, 2894–2903 (2013).

    CAS  Google Scholar 

  166. 166

    Kayani, B. et al. Does obesity affect outcomes in patients undergoing esophagectomy for cancer? A meta-analysis. World J. Surg. 36, 1785–1795 (2012).

    Google Scholar 

  167. 167

    Zheng, Y. et al. Smoking affects treatment outcome in patients with resected esophageal squamous cell carcinoma who received chemotherapy. PLoS ONE 10, e0123246 (2015).

    Google Scholar 

  168. 168

    Huang, Q. et al. Impact of alcohol consumption on survival in patients with esophageal carcinoma: a large cohort with long-term follow-up. Cancer Sci. 105, 1638–1646 (2014).

    CAS  Google Scholar 

  169. 169

    Brusselaers, N., Mattsson, F., Lindblad, M. & Lagergren, J. Association between education level and prognosis after esophageal cancer surgery: a Swedish population-based cohort study. PLoS ONE 10, e0121928 (2015).

    Google Scholar 

  170. 170

    Rice, T. W., Rusch, V. W., Ishwaran, H. & Blackstone, E. H. Cancer of the esophagus and esophagogastric junction: data-driven staging for the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer Cancer Staging Manuals. Cancer 116, 3763–3773 (2010).

    Google Scholar 

  171. 171

    Sunde, B. et al. Relief of dysphagia during neoadjuvant treatment for cancer of the esophagus or gastroesophageal junction. Dis. Esophagus 29, 442–447 (2016).

    CAS  Google Scholar 

  172. 172

    Stahl, M. et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J. Clin. Oncol. 23, 2310–2317 (2005).

    Google Scholar 

  173. 173

    Bedenne, L. et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J. Clin. Oncol. 25, 1160–1168 (2007).

    CAS  Google Scholar 

  174. 174

    Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 359, 1727–1733 (2002).

    Google Scholar 

  175. 175

    Allum, W. H., Stenning, S. P., Bancewicz, J., Clark, P. I. & Langley, R. E. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J. Clin. Oncol. 27, 5062–5067 (2009). A paper that reports the long-term results of a trial that defined neoadjuvant chemotherapy as a standard of care for resectable oesophageal cancer.

    Google Scholar 

  176. 176

    Alderson, D. et al. Neoadjuvant chemotherapy for resectable oesophageal and junctional adenocarcinoma: results from the UK Medical Research Council randomised OEO5 trial (ISRCTN 01852072). J. Clin. Oncol. 33, 4002 (2015).

    Google Scholar 

  177. 177

    Cunningham, D. et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N. Engl. J. Med. 355, 11–20 (2006).

    CAS  Google Scholar 

  178. 178

    Ychou, M. et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J. Clin. Oncol. 29, 1715–1721 (2011).

    CAS  Google Scholar 

  179. 179

    Al-Batran, S.-E. et al. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 17, 1697–1708 (2016).

    CAS  Google Scholar 

  180. 180

    Al-Batran, S., Homann, N., Schmalenberg, H. & Kopp, H. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial. J. Clin. Oncol. 35, 4004 (2017).

    Google Scholar 

  181. 181

    Sjoquist, K. M. et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 12, 681–692 (2011).

    Google Scholar 

  182. 182

    Mariette, C. et al. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J. Clin. Oncol. 32, 2416–2422 (2014).

    CAS  Google Scholar 

  183. 183

    van Hagen, P. et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N. Engl. J. Med. 366, 2074–2084 (2012). A randomized trial that defines neoadjuvant chemoradiotherapy as a standard of care for resectable oesophageal cancer.

    CAS  Google Scholar 

  184. 184

    Walsh, T. N. et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N. Engl. J. Med. 335, 462–467 (1996).

    CAS  Google Scholar 

  185. 185

    Shapiro, J. et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 16, 1090–1098 (2015).

    Google Scholar 

  186. 186

    Klevebro, F. et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann. Oncol. 27, 660–667 (2016).

    CAS  Google Scholar 

  187. 187

    Yoon, D. H. et al. Randomized phase 2 trial of S1 and oxaliplatin-based chemoradiotherapy with or without induction chemotherapy for esophageal cancer. Int. J. Radi. Oncol. Biol. Phys. 91, 489–496 (2015).

    CAS  Google Scholar 

  188. 188

    Ajani, J. A. et al. A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer. Ann. Oncol. 24, 2844–2849 (2013).

    CAS  Google Scholar 

  189. 189

    Minsky, B. D. et al. INT 0123 (Radiation Therapy Oncology Group 94–05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J. Clin. Oncol. 20, 1167–1174 (2002).

    CAS  Google Scholar 

  190. 190

    Markar, S. et al. Salvage surgery after chemoradiotherapy in the management of esophageal cancer: is it a viable therapeutic option? J. Clin. Oncol. 33, 3866–3873 (2015).

    CAS  Google Scholar 

  191. 191

    Marks, J. L. et al. Salvage esophagectomy after failed definitive chemoradiation for esophageal adenocarcinoma. Ann. Thorac. Surg. 94, 1126–1132; discussion 1132–1123 (2012).

    Google Scholar 

  192. 192

    Swisher, S. G., Marks, J. & Rice, D. Salvage esophagectomy for persistent or recurrent disease after definitive chemoradiation. Ann. Cardiothorac Surg. 6, 144–151 (2017).

    Google Scholar 

  193. 193

    Conroy, T. et al. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 15, 305–314 (2014).

    CAS  Google Scholar 

  194. 194

    Schmid, E. U. et al. The value of radiotherapy or chemotherapy after intubation for advanced esophageal carcinoma — a prospective randomized trial. Radiother. Oncol. 28, 27–30 (1993).

    CAS  Google Scholar 

  195. 195

    Levard, H. et al. 5-Fluorouracil and cisplatin as palliative treatment of advanced oesophageal squamous cell carcinoma. A multicentre randomised controlled trial. Eur. J. Surg. 164, 849–857 (1998).

    CAS  Google Scholar 

  196. 196

    Smyth, E. C. et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 27, v38–v49 (2016).

    CAS  Google Scholar 

  197. 197

    Guimbaud, R. et al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Cooperateur Multidisciplinaire en Oncologie) study. J. Clin. Oncol. 32, 3520–3526 (2014).

    CAS  Google Scholar 

  198. 198

    Dank, M. et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann. Oncol. 19, 1450–1457 (2008).

    CAS  Google Scholar 

  199. 199

    Cunningham, D. et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N. Engl. J. Med. 358, 36–46 (2008).

    CAS  Google Scholar 

  200. 200

    Koizumi, W. et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 9, 215–221 (2008).

    CAS  Google Scholar 

  201. 201

    Ajani, J. A. et al. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J. Clin. Oncol. 23, 6957–6965 (2005).

    CAS  Google Scholar 

  202. 202

    Thuss-Patience, P. C. et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer — a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur. J. Cancer 47, 2306–2314 (2011).

    CAS  Google Scholar 

  203. 203

    Kang, J. H. et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J. Clin. Oncol. 30, 1513–1518 (2012).

    CAS  Google Scholar 

  204. 204

    Ford, H. E. et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 15, 78–86 (2014).

    CAS  Google Scholar 

  205. 205

    Wagner, A. D. et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst. Rev. 3, CD004064 (2010).

    Google Scholar 

  206. 206

    Van Cutsem, E. et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group. J. Clin. Oncol. 24, 4991–4997 (2006).

    CAS  Google Scholar 

  207. 207

    Shah, M. A. et al. Randomized multicenter phase II study of modified docetaxel, cisplatin, and fluorouracil (DCF) versus DCF plus growth factor support in patients with metastatic gastric adenocarcinoma: a study of the US Gastric Cancer Consortium. J. Clin. Oncol. 33, 3874–3879 (2015).

    CAS  Google Scholar 

  208. 208

    Van Cutsem, E. et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18, 476–484 (2015).

    CAS  Google Scholar 

  209. 209

    Bang, Y. J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376, 687–697 (2010).

    CAS  Google Scholar 

  210. 210

    Fuchs, C. S. et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383, 31–39 (2014).

    CAS  Google Scholar 

  211. 211

    Wilke, H. et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 15, 1224–1235 (2014).

    CAS  Google Scholar 

  212. 212

    Lagergren, J. & Lagergren, P. Oesophageal cancer. BMJ 341, c6280 (2010).

    Google Scholar 

  213. 213

    Blazeby, J. M. et al. Core information set for oesophageal cancer surgery. Br. J. Surg. 102, 936–943 (2015).

    CAS  Google Scholar 

  214. 214

    McNair, A. G. et al. What surgeons tell patients and what patients want to know before major cancer surgery: a qualitative study. BMC Cancer 16, 258 (2016).

    Google Scholar 

  215. 215

    Le Roy, B. et al. Effect of prehabilitation in gastro-oesophageal adenocarcinoma: study protocol of a multicentric, randomised, control trial-the PREHAB study. BMJ Open 6, e012876 (2016). A paper that describes the protocol of an important trial that aimed to prepare patients before surgery to recover more quickly during their rehabilitation.

    Google Scholar 

  216. 216

    Correia, M. I. & Waitzberg, D. L. The impact of malnutrition on morbidity, mortality, length of hospital stay and costs evaluated through a multivariate model analysis. Clin. Nutr. 22, 235–239 (2003).

    Google Scholar 

  217. 217

    Baiocchi, G. L. et al. Follow-up after gastrectomy for cancer: the Charter Scaligero Consensus Conference. Gastric Cancer 19, 15–20 (2016).

    Google Scholar 

  218. 218

    Blazeby, J. M., Sanford, E., Falk, S. J., Alderson, D. & Donovan, J. L. Health-related quality of life during neoadjuvant treatment and surgery for localized esophageal carcinoma. Cancer 103, 1791–1799 (2005).

    Google Scholar 

  219. 219

    Rees, J. et al. Patient-reported outcomes during and after definitive chemoradiotherapy for oesophageal cancer. Br. J. Cancer 113, 603–610 (2015).

    CAS  Google Scholar 

  220. 220

    Rutegard, M. et al. Population-based study of surgical factors in relation to health-related quality of life after oesophageal cancer resection. Br. J. Surg. 95, 592–601 (2008).

    CAS  Google Scholar 

  221. 221

    Derogar, M., Orsini, N., Sadr-Azodi, O. & Lagergren, P. Influence of major postoperative complications on health-related quality of life among long-term survivors of esophageal cancer surgery. J. Clin. Oncol. 30, 1615–1619 (2012). A well-designed, population-based, prospective and nationwide study with short-term and long-term data on health-related QOL.

    Google Scholar 

  222. 222

    Wainwright, D., Donovan, J. L., Kavadas, V., Cramer, H. & Blazeby, J. M. Remapping the body: learning to eat again after surgery for esophageal cancer. Qual. Health Res. 17, 759–771 (2007).

    Google Scholar 

  223. 223

    Amdal, C. D., Jacobsen, A. B., Guren, M. G. & Bjordal, K. Patient-reported outcomes evaluating palliative radiotherapy and chemotherapy in patients with oesophageal cancer: a systematic review. Acta Oncol. 52, 679–690 (2013).

    CAS  Google Scholar 

  224. 224

    Verschuur, E. M. et al. Nurse-led follow-up of patients after oesophageal or gastric cardia cancer surgery: a randomised trial. Br. J. Cancer 100, 70–76 (2009).

    CAS  Google Scholar 

  225. 225

    Polinder, S., Verschuur, E. M., Siersema, P. D., Kuipers, E. J. & Steyerberg, E. W. Cost comparison study of two different follow-up protocols after surgery for oesophageal cancer. Eur. J. Cancer 45, 2110–2115 (2009).

    Google Scholar 

  226. 226

    Lewis, R. et al. Nurse-led versus conventional physician-led follow-up for patients with cancer: systematic review. J. Adv. Nurs. 65, 706–723 (2009).

    Google Scholar 

  227. 227

    Kumar, S. et al. Mass spectrometric analysis of exhaled breath for the identification of volatile organic compound biomarkers in esophageal and gastric adenocarcinoma. Ann. Surg. 262, 981–990 (2015).

    Google Scholar 

  228. 228

    Dutton, S. J. et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 15, 894–904 (2014).

    CAS  Google Scholar 

  229. 229

    Ohtsu, A. et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J. Clin. Oncol. 31, 3935–3943 (2013).

    CAS  Google Scholar 

  230. 230

    Ohtsu, A. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J. Clin. Oncol. 29, 3968–3976 (2011).

    CAS  Google Scholar 

  231. 231

    Bang, Y.-J. et al. A randomized, open-label phase II study of AZD4547 (AZD) versus paclitaxel (P) in previously treated patients with advanced gastric cancer (AGC) with fibroblast growth factor receptor 2 (FGFR2) polysomy or gene amplification (amp): SHINE study. J. Clin. Oncol. 33, 4014 (2015).

    Google Scholar 

  232. 232

    Ge, X. et al. Clinical significance of assessing Her2/neu expression in gastric cancer with dual tumor tissue paraffin blocks. Hum. Pathol. 46, 850–857 (2015).

    CAS  Google Scholar 

  233. 233

    Yoon, H. H. et al. Adverse prognostic impact of intratumor heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma. J. Clin. Oncol. 30, 3932–3938 (2012).

    Google Scholar 

  234. 234

    Gomez-Martin, C. et al. Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab. J. Clin. Oncol. 31, 4445–4452 (2013).

    CAS  Google Scholar 

  235. 235

    Petty, R. D. et al. Epidermal growth factor receptor copy number gain (EGFR CNG) and response to gefitinib in esophageal cancer (EC): results of a biomarker analysis of a phase III trial of gefitinib versus placebo (TRANS-COG). J. Clin. Oncol. 32, 4016 (2014).

    Google Scholar 

  236. 236

    Pearson, A. et al. High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial. Cancer Discov. 6, 838–851 (2016).

    CAS  Google Scholar 

  237. 237

    Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 375, 1738–1748 (2016).

    CAS  Google Scholar 

  238. 238

    Ismail, A. et al. Early G1 cyclin-dependent kinases as prognostic markers and potential therapeutic targets in esophageal adenocarcinoma. Clin. Cancer Res. 17, 4513–4522 (2011).

    CAS  Google Scholar 

  239. 239

    Bang, Y. et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy: phase III GOLD study. Ann. Oncol. 27, 1–36 (2016).

    Google Scholar 

  240. 240

    Cafferkey, C. et al. Genomic loss of heterozygosity (LOH) and survival in patients (pts) treated with epirubicin, oxaliplatin, capecitabine (EOC) ± panitumumab (P) in the REAL3 trial. Ann. Oncol. 27, 649P (2016).

    Google Scholar 

  241. 241

    Swisher, E. M. et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 18, 75–87 (2017).

    CAS  Google Scholar 

  242. 242

    Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).

    CAS  Google Scholar 

  243. 243

    Doi, T. et al. Updated results for the advanced esophageal carcinoma cohort of the phase 1b KEYNOTE-028 study of pembrolizumab. J. Clin. Oncol. 34, 4046 (2016).

    Google Scholar 

  244. 244

    Kudo, T. et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol. 18, 631–639 (2017).

    CAS  Google Scholar 

  245. 245

    Janjigian, Y. Y. et al. CheckMate-032: phase I/II, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J. Clin. Oncol. 34, 4010 (2016).

    Google Scholar 

  246. 246

    Kang, Y. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after 2nd or later line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): a double-blinded, randomized phase III trial. J. Clin. Oncol. 35, 2 (2017).

    Google Scholar 

  247. 247

    Rice, T. W., Ishwaran, H., Ferguson, M. K., Blackstone, E. H. & Goldstraw, P. Cancer of the esophagus and esophagogastric junction: an eighth edition staging primer. J. Thorac. Oncol. 12, 36–42 (2017).

    Google Scholar 

  248. 248

    Tepper, J. et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J. Clin. Oncol. 26, 1086–1092 (2008).

    CAS  Google Scholar 

  249. 249

    Herskovic, A. et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N. Engl. J. Med. 326, 1593–1598 (1992).

    CAS  Google Scholar 

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Acknowledgements

E.C.S. and D.C. acknowledge funding support from the Royal Marsden Institute of Cancer Research National Institute of Health Research Biomedical Research Centre, London, UK.

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Introduction (E.C.S. and D.C.); Epidemiology (E.C.S. and D.C.); Mechanisms/pathophysiology (R.C.F.); Diagnosis, screening and prevention (R.C.F.); Management (E.C.S., J.L., F.L. and M.A.S.); Quality of life (P.L.); Outlook (All); Overview of Primer (E.C.S. and D.C.).

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Correspondence to David Cunningham.

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Competing interests

E.C.S. declares honoraria for an advisory role from Five Prime Therapeutics and Bristol-Myers Squibb. D.C. declares institutional research funding from Amgen, AstraZeneca, Bayer, Celgene, MedImmune, Merck Serono, Merrimack and Sanofi. F.L. has received research support from GlaxoSmithKline and Fresenius Biotech; lecture and advisory honoraria from Amgen, Biontech, Bristol-Myers Squibb, Eli Lilly, Ganymed, Merck Serono, MSD, Nordic and Roche; and travel support from Amgen, Bayer, Roche and Taiho. M.A.S. declares institutional research funding from Genentech, Sanofi and Lilly. J.L., P.L. and R.C.F. are named on patents related to the Cytosponge and associated assays, which have been licensed by the Medical Research Council to Covidien (now Medtronic).

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Smyth, E., Lagergren, J., Fitzgerald, R. et al. Oesophageal cancer. Nat Rev Dis Primers 3, 17048 (2017). https://doi.org/10.1038/nrdp.2017.48

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