Current status and perspectives of esophageal cancer: a comprehensive review

Abstract

Esophageal cancer (EC) continues to be a significant global health concern, with two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Prevention and changes in etiology, improvements in early detection, and refinements in the treatment have led to remarkable progress in the outcomes of EC patients in the past two decades. This seminar provides an in-depth analysis of advances in the epidemiology, disease biology, screening, diagnosis, and treatment landscape of esophageal cancer, focusing on the ongoing debate surrounding multimodality therapy. Despite significant advancements, EC remains a deadly disease, underscoring the need for continued research into early detection methods, understanding the molecular mechanisms, and developing effective treatments.

Keywords: Comprehensive review; Esophageal cancer; Pathological characteristics; Prevention and Screening; Treatment advancements.

FIGURE 1

Histopathological progression of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC and EAC possess distinct carcinogenic and pathologic characteristics. From the early stages of dysplasia, both have exhibited a relatively stable state with high‐frequency clones and mutations. The differences lie in: during the progression of ESCC, CNAs and TP53 mutations occur in the early precancerous stage, while CNAs and APOBEC mutagenesis substantially increase in the late stage. EAC evolution is characterized by accumulating mutations (such as ARID1A and SMARCA4) in the early stage; TP53 mutations, genomic instability, high clonal diversity, frequent CNAs, and complex large‐scale structural rearrangements dominate the late stage. The genetic alterations associated with ESCC and EAC are described in the box at the bottom center of the figure. The histology of cells represented by various colours and shapes is shown in the box at the bottom right. Abbreviations: APOBEC, Apolipoprotein B mRNA editing enzyme catalytic polypeptide‐like; ARID1A, AT rich interaction domain 1A; CCND1, Cyclin D1; CDKN2A, Cyclin‐dependent kinase inhibitor 2A; c‐MYC, Cancer‐myelocytomatosis viral oncogene homolog; CNAs, Copy number alterations; ERBB2 (HER2), human epidermal growth factor receptor 2; GATA4, GATA binding protein 4; HNF4A, Hepatocyte nuclear factor 4, Alpha; NFE2L2, Nuclear factor erythroid 2‐related factor 2; SMARCA4, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4; SOX‐2, SRY‐box 2; TP53, Tumor protein 53; TP63, Tumor protein 63; VEGFA, vascular endothelial growth factor A.

FIGURE 2

Projected trends in esophageal cancer incidence and mortality by sex from 2022 to 2050 globally. Source: GLOBOCAN 2022, available at: https://gco.iarc.who.int/tomorrow/en/dataviz/trends?multiple_populations = 1&cancers = 6.

FIGURE 3

Bar chart of the region‐specific age‐standardized incidence and mortality rates of esophageal cancer by sex. Source: GLOBOCAN 2022, available at: https://gco.iarc.fr/today/en/dataviz/bars?mode = population&group_populations = 0&key = total&types = 0_1&sort_by = value1&populations = 905_906_910_911_912_913_914_915_916_920_921_922_923_924_925_926_927_928_931_954_957&cancers = 6&group_cancers = 1&multiple_cancers = 1&values_position = out

FIGURE 4

Age‐standardized incidence trend chart of esophageal cancer in countries with a recent upward trend. The incidence in Europe, especially in Northern Europe, has shown a significant upward trend after 2000. Ireland's males and both genders in Poland show a slight rise after 2014. Japan has seen a slow rise since the 1990s. After a decline, China and Israel are now experiencing a resurgence, and the decline in Australian females also appears to be reversing after 2014.

FIGURE 5

Ongoing phase III studies on the integration of immunotherapy and novel targeted agents in the perioperative treatment of esophageal cancer. The name of the trial is bolded in the second column. Meaning of box symbols: Blue ■: esophageal squamous cell carcinoma (ESCC); Green ■: esophageal adenocarcinoma (EAC); Grey ■: previous treatment before inclusion. The arrow indicates the treatment flow: Blue ►: Sequent treatment in the ESCC studies; Green ►: Sequent treatment in the EAC studies; Grey ►: Treatment flow in previous treatment before inclusion; Orange ►: Sequent treatment for both the study and control arms in the trial. Abbreviations: aIO, adjuvant immunotherapy; CRT, chemoradiotherapy; CT, chemotherapy; HER2, human epidermal growth factor receptor 2; IO, immunotherapy; nCRT, neoadjuvant chemoradiotherapy; nCT, neoadjuvant chemotherapy; nICRT: neoadjuvant immunotherapy plus chemoradiotherapy; nICT, neoadjuvant immunochemotherapy; pCR, pathological complete response; S, surgery.

FIGURE 6

Ongoing phase III studies on the organ preservation strategy for locally advanced esophageal cancer. The name of the trial is bolded in the second column. Meaning of box symbols: Blue ■: esophageal squamous cell carcinoma (ESCC); Green ■: esophageal adenocarcinoma (EAC); Grey ■: previous treatment before inclusion. The arrow indicates the treatment flow: Green ► Sequent treatment in the EAC trials; Grey ►: Treatment flow in previous treatment before inclusion. Abbreviations: AS, active surveillance; cCR, clinical complete response; CRE, clinical response evaluation; CRT, chemoradiotherapy; CT, chemotherapy; dCRT, definitive chemoradiotherapy; IO, immunotherapy; nCRT, neoadjuvant chemoradiotherapy; RT, radiotherapy; S, surgery; SS, Salvage surgery.

FIGURE 7

Ongoing phase III studies on the combination of immunotherapy with definitive chemoradiotherapy in unresectable locally advanced esophageal cancer. The name of the trial is bolded in the second column. Meaning of box symbols: Blue ■: esophageal squamous cell carcinoma (ESCC); Green ■: esophageal adenocarcinoma (EAC); Grey ■: previous treatment before inclusion. The arrow indicates the treatment flow: Blue ►: Sequent treatment in the ESCC studies; Green ►: Sequent treatment in the EAC trials; Grey ►: Treatment flow in previous treatment before inclusion. Abbreviations: Atezo, Atezolizumab; CRT, chemoradiotherapy; dCRT, definitive chemoradiotherapy; IO, immunotherapy; PD, progressive disease; Tirago, Tiragolumab.

FIGURE 8

Ongoing phase III studies of novel targeted agents in advanced esophageal cancer. The name of the trial is bolded in the second column. Meaning of box symbols: Blue ■: esophageal squamous cell carcinoma (ESCC); Green ■: esophageal adenocarcinoma (EAC); Grey ■: previous treatment before inclusion. The arrow indicates the treatment flow: Blue ►: Sequent treatment in the ESCC studies; Green ►: Sequent treatment in the EAC trials; Grey ►: Treatment flow in previous treatment before inclusion. Abbreviations: 1L, 1‐line; 2L, 2‐line; ADC, Antibody‐drug conjugate; CD47, cluster of differentiation 47; CT, chemotherapy; FGFR2b, Fibroblast growth factor receptor 2b; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; IO, immunotherapy; TKI, tyrosine kinase inhibitors; PD, progressive disease; VEGF, vascular endothelial growth factor.