Advances in Diagnosis and Management of Cancer Os The Esophagus BMJ

STATE OF THE ART REVIEW
Advances in diagnosis and management of cancer
BMJ: first published as 10.1136/bmj-2023-074962 on 3 June 2024. Downloaded from http://www.bmj.com/ on 25 June 2024 by guest. Protected by copyright.
of the esophagus
Nathaniel Deboever,1 Christopher M Jones,2,3 Kohei Yamashita,4 Jaffer A Ajani,4 Wayne L Hofstetter1
A B S T RAC T
1
Department of Thoracic and
Esophageal cancer is the seventh most common malignancy worldwide, with
Cardiovascular Surgery, MD over 470 000 new cases diagnosed each year. Two distinct histological subtypes
Anderson Cancer Center,
Houston, TX, USA predominate, and should be considered biologically separate disease entities.1
These subtypes are esophageal adenocarcinoma (EAC) and esophageal squamous
2
Early Cancer Institute,
Department of Oncology,
University of Cambridge, cell carcinoma (ESCC). Outcomes remain poor regardless of subtype, with most
Cambridge, UK
3
Addenbrooke’s Hospital, patients presenting with late stage disease.2 Novel strategies to improve early
Cambridge University Hospitals
NHS Foundation Trust,
detection of the respective precursor lesions, squamous dysplasia, and Barrett’s
Cambridge, UK esophagus offer the potential to improve outcomes. The introduction of a limited
4
Department of Gastrointestinal
Medical Oncology, MD Anderson number of biologic agents, as well as immune checkpoint inhibitors, is resulting
Cancer Center, Houston, TX, USA in improvements in the systemic treatment of locally advanced and metastatic
Correspondence to: N Deboever,
[email protected], esophageal cancer. These developments, coupled with improvements in minimally
[email protected]
Cite this as: BMJ 2024;385:e074962
invasive surgical and endoscopic treatment approaches, as well as adaptive and
http://dx.doi.org/10.1136/ precision radiotherapy technologies, offer the potential to improve outcomes
bmj‑2023‑074962
still further. This review summarizes the latest advances in the diagnosis and
Series explanation: State of the
Art Reviews are commissioned management of esophageal cancer, and the developments in understanding of the
on the basis of their relevance
to academics and specialists biology of this disease.
in the US and internationally.
For this reason they are written
predominantly by US authors.
Introduction Epidemiology
Esophageal cancer is a significant global health Together, EAC and ESCC impose a considerable
challenge, being the seventh most common healthcare burden; accounting for the annual loss
malignancy worldwide with over 470 000 new of more than 400 000 lives and 9.8 million disease
cases each year. Esophageal cancer primarily adjusted life years.3 4 These figures reflect a 52%
manifests in two histological subtypes: esophageal increase in the total number of new cases and a 40%
adenocarcinoma (EAC) and esophageal squamous rise in the total number of deaths between 1990 and
cell carcinoma (ESCC), which are biologically 2017, even as the age standardized incidence and
distinct. Despite advancements, outcomes mortality fell by 22% and 29%, respectively.3
for esophageal cancer remain poor, primarily Around 90% of worldwide cases are ESCC, which
owing to late stage diagnosis in most patients. has particularly high incidence in South America
However, emerging strategies aimed at the early and the Asian esophageal cancer belt that extends
detection of precursor lesions such as squamous from East Africa and sub-Saharan Africa through
dysplasia and Barrett’s esophagus hold promise much of Central Asia.3 5 6 EAC is, by contrast, more
for improving these outcomes. The treatment prevalent in Europe and high income North America,
landscape for esophageal cancer is evolving, where its incidence has increased fourfold over the
with the introduction of biologic agents and past four decades.3 7
immune checkpoint inhibitors enhancing systemic These trends are reflected by the different epidemio-
treatment for locally advanced and metastatic logical associations of the two subtypes. ESCC is linked
cases. Additionally, advancements in minimally with alcohol, tobacco and opium use, environmental
invasive surgical and endoscopic techniques, along pollution, ingestion of high temperature beverages,
with precision radiotherapy technologies, further nutritional deficiencies, and other dietary factors such
contribute to improved patient prognosis. This as consumption of pickled foods and high nitrosamine
comprehensive review explores the current state- exposure.5 8 In rare cases, human papillomavirus has
of-the-art diagnostic and treatment approaches for also been linked to ESCC development, although data
esophageal cancer, highlighting recent progress remain uncertain.9 10 By contrast, EAC associates with
in understanding the disease’s biology and the obesity, the metabolic syndrome and gastro-esophageal
implications for clinical practice. reflux disease (GERD).11
the bmj | BMJ 2024;385:e074962 | doi: 10.1136/bmj‑2023-074962 1

Sources and selection criteria response to chronic exposure to injurious acidic

We searched PubMed in March and November 2023 gastroduodenal refluxate, which is rich in bile salts.
using keywords such as “(o)esophageal cancer”, However, around 90% of people with a diagnosis of
“early-stage (o)esophageal cancer” OR “advanced (o) EAC have no history of Barrett’s esophagus; and at the
esophageal cancer”, and “esophageal endoscopy”. time of diagnosis, no identifiable Barrett’s esophagus
We considered studies published in the English lesions are found in around half of EAC cases.24-26
language from January 2010 to November 2023. Despite this, population modeling and molecular
Selected publications were included before 2010 if analyses increasingly point to Barrett’s esophagus
they were relevant to the topic. We excluded articles as the sole precursor to adenocarcinoma.27-29 Each
published in non-peer reviewed journals, case Barrett’s esophagus lesion is characterized by the
reports, and case series. Additional relevant high metaplastic replacement of native normal squamous
quality references identified from articles in the epithelium with a multicellular mosaic of columnar-
original search were also reviewed and included. We like epithelium.30 The two predominant subtypes
also accessed the National Comprehensive Cancer are intestinal metaplasia and gastric metaplasia;
Network (NCCN) guidelines. the former characterized by the presence of goblet
cells, the latter by their absence. The nature of the
Pathophysiology and molecular genomics cellular milieu from which these neo-epithelial
Pathophysiology linings originate has been strongly contested.1 27 28 31-
33
Somatic mutant clones that incorporate driver Recent evidence drawn from chromatin and
gene mutations colonize the esophageal normal single cell transcriptomic profiling suggests that a
squamous epithelium from infancy and increase transcriptional program driven by c-MYC and HNF4A
in number and size with age.12 13 This remodeling causes the development of Barrett’s esophagus
can be catalyzed by exogenous exposures, such from cells within the gastric cardia, and highlights
as alcohol consumption and smoking, eventually intestinal metaplasia as a specific precursor for
reaching between 9000 and 15 000 clones per adenocarcinoma.27 28 Gastric metaplasia, which is
esophagus.13 ESCC originates from one such clone, characterized by a lower mutation burden, might
but its development, and the squamous dysplasia instead coincide with indolent atrophic gastritis.27
that precedes it, is rare in comparison with the Moreover, intestinal metaplasia associated
incidence of mutation. Evidence from murine studies with Barrett’s esophagus is phenotypically
suggests that most newly formed ESCC is eradicated indistinguishable from gastric intestinal metaplasia,
following competition with other mutant clones in the precursor to gastric adenocarcinoma.27 This lack
adjacent normal squamous epithelium.14 15 These of distinction suggests a parallel natural history
data suggest treatment opportunities for disease for EAC and stomach cancer, supporting existing
prevention, such as through the blockade of wild evidence for substantial molecular similarities
type NOTCH1, a gene that potentially increases the between these two malignancies.1 27 34
aggressivity of tumor clones.13 16 Once established, the initial non-dysplastic
The transformation of normal squamous epithelium Barrett’s esophagus (NDBE) lesion generally features
to basal cell hyperplasia, which later evolves through a relatively high number of point mutations, but
a sequence of low grade intraepithelial neoplasia with intact p53 and a diploid genome that, as with
and high grade intraepithelial neoplasia to invasive the lesion itself, remain stable in most patients.35 36
carcinoma, is a multidimensional and poorly By contrast, a minority of patients with Barrett’s
understood process. The risk of squamous dysplasia esophagus will progress to adenocarcinoma via
progression to carcinoma increases depending on the development of low grade dysplasia and then
the degree of dysplasia, although a majority will not high grade dysplasia. For those with NDBE, the
progress. For those that do progress, progression can annual risk of progression is between 0.1 and
take many years.17 18 Single cell analyses suggest 0.5%.37-39 A higher but less precisely defined risk of
that a slow cycling basal cell gives rise to high grade developing EAC exists following the development of
intraepithelial neoplasia.19 dysplasia.37 38 The rate at which dysplasia worsens is
Genome-wide association studies from patients highly variable, and individual Barrett’s esophagus
of Chinese, European, and Japanese descent have lesions can incorporate different histopathological
shown multiple susceptibility loci for progression states, although three broad patterns of progression
to ESCC.20 Some of these loci interact with alcohol have been observed.36 40 For some patients, a gradual
consumption, including genes encoding alcohol accumulation of mutations occurs over time, with
dehydrogenase family proteins.21 A rare familial the risk of dysplastic progression conferred by the
disorder, tylosis, is also associated with a high acquisition of specific deleterious mutations.41 42
risk of progression to ESCC of around 90% by age Others can have seemingly stable, low risk Barrett’s
70 because of an autosomal dominant RHBDF2 esophagus that deteriorates in response to a
germline mutation.22 Other hereditary syndromes specific catastrophic event such as chromothripsis
associated with ESCC include Bloom syndrome and or kataegis, whereas a third “born bad” group
Fanconi anemia.23 might have high risk Barrett’s esophagus that is
By contrast, the EAC precursor Barrett’s esophagus primed to progress from the outset even when non-
arises at the gastro-esophageal junction as an adaptive dysplastic41 42 (fig 1).
2 doi: 10.1136/bmj‑2023-074962 | BMJ 2024;385:e074962 | the bmj

Squamous cell carcinoma development
NOTCH1 mutation Progenitor Early detection and screening
TP53 mutation slow cycling
NOTCH2 mutation KRT15+
STMN-basal
ARID1A mutation
layer cells Exhaled volatile organic compounds
Patchwork of somatic mutant Squamous dysplasia derives DNA
clones develops in response from competitive KRT15+
to aging and environment STMN-basal layer cone methylation
Modified
Clonal change Dysplasia endoscopic
approaches
Artificial
Adenocarcinoma formation Capsule based intelligence
c-Myc and Gradual accumulation non-endoscopic
HNF4A of genetic change sponge
catalyse IM
development
and maturation Born bad ctDNA Protein
Proximal SCJ migration
markers
Catastrophic event
Metaplastic mosaic of Three broad patterns of
columnar like epithelium progression from NDBE to
replaces stratified NSE LGD and HGD recognised
Metaplasia Dysplasia
Fig 1 | An overview of the development and progression of the squamous cell carcinoma and adenocarcinoma precursor lesions, squamous
dysplasia, and adenocarcinoma, alongside proposed approaches for their early detection. ctDNA=circulating tumor DNA; HGD=high grade
dysplasia; IM=intestinal metaplasia; NDBE=non-dysplastic Barrett’s esophagus; NSE=neosquamous epithelium; LGD=low grade dysplasia;
SCJ=squamocolumnar junction.
Microenvironment in esophageal cancer and its but its importance is yet to be fully delineated. At
precursors present, lower microbial richness is recognized with
Squamous dysplasia and squamous cell cancer the development of squamous dysplasia, and an
The importance of the microenvironment to increase in Fusobacterium and Streptococcus is seen
squamous cell cancer development is shown by in ESCC compared with benign esophagus tissue.49
enrichment of a C:G>A:T mutational signature that A pathogenic role for Porphyromonas gingivalis in
is associated with tobacco exposure, as well as a the formation of squamous cell cancer has also been
difference in mutational environment between upper postulated.50
and lower squamous cell cancers.1 43 44 Interestingly,
recent evidence suggests that squamous dysplasia Barrett’s esophagus and adenocarcinoma
remodels its environment by reducing annexin A1 The impact of the Barrett’s esophagus and EAC
expression, and therefore signaling, via the formyl microenvironment is reflected by the frequent
peptide receptor 2 on fibroblasts, which results in the presence of signature 17, which is characterized
formation of cancer associated fibroblasts.45 by CTT trinucleotide repeat A:T>C:G transversions
The immune microenvironment in squamous that are thought to reflect oxidative damage.36 40 51
cell cancer is inflamed and enriched with Cancer associated fibroblasts are another key
immunosuppressive T regulatory, tumor associated stromal contributor to poorer outcomes in EAC, and
macrophages, and exhausted or inactivated natural are linked to impaired immunosurveillance, as well
killer cells, CD8+ cells, and CD4+ T cells.19 46 Unlike as chemotherapy resistance, which is alleviated in
in adenocarcinoma, B cell infiltration is relatively low. vitro by phosphodiesterase type 5 inhibitors that
Overall, this cellular milieu contributes to disease target cancer associated fibroblasts.52 Activation of a
progression and inter-tumoral heterogeneity.46 47 similar population of cancer associated fibroblast has
Through collaboration between tumor associated recently been associated with dysplastic progression
macrophages and cancer associated fibroblasts, of Barrett’s esophagus.27
tumor promoting CCL2, matrix metalloproteinase 9, The immune microenvironment of Barrett’s
and interleukin 6 are secreted.48 Consequently, it has esophagus most closely resembles that of duodenal
been suggested that anti-tumor immunity could be tissue than normal squamous epithelium.53 Recent
restored by targeting T regulatory cell modulation of evidence suggests that epithelial metaplasia is
macrophage function for treatment.46 Relevant to the mirrored by metaplastic changes in the stroma
development of immunotherapies for squamous cell that are characterized by an immunosuppressive
cancer, immune infiltrates are heterogeneous across environment mediated by natural killer cells, and the
tumors, and exert selection pressure that results in appearance of fibroblasts with a cancer associated
neoantigen evasion.47 fibroblast phenotype.54 A stromal T helper type 2
The local microbiome is also linked to the immune infiltrate, elevated infiltration of T cells,
progression of squamous dysplasia and ESCC, and more dendritic cells producing retinoic acid

have also previously been described.55 56 Progression differentiation (ZNF750), and NOTCH signaling
towards adenocarcinoma from Barrett’s esophagus (NOTCH1/3).65-70 Structural rearrangements
is associated with an increase in T regulatory resulting from chromothripsis, kataegis, and
cells, T cell costimulatory pathway activity, and breakage-fusion-bridge cycles are also observed in
CD163+ tumor associated macrophages, as well as over half of all cases.70 These rearrangements can
chemokines such as interleukin 6, CXCL8, and the result in amplification of oncogenes such as EGFR,
CXCR1/2 chemokine receptors.57 58 Recent immune ERBB2, and MYC.70 This chromosomal instability
profiling suggests that adenocarcinomas reside drives intra-tumoral heterogeneity.47 As with other
within one of four immune clusters; hot, suppressed, ESCC, amplification of chromosome 3q, and in
moderate, or cold.59 60 Moreover, the importance of a particular the SOX2 locus, is frequently seen.1 Lastly,
favorable immune landscape to long term outcomes frequent genomic amplification of CCND1 and TP63
is increasingly recognised.59 is also observed in this cohort.1
As with squamous cell cancer, evidence increasingly The Cancer Genome Atlas summarized these
suggests changes in the diversity and function of the alterations as three subgroups of ESCC that appear
oral and esophagus microbiome in patients with to show geographic variation.1 Although these
Barrett’s esophagus and adenocarcinoma.61 62 These subgroups have yet to be exploited, they have
changes have a role in adenocarcinoma development potential clinical significance. The first subgroup,
and progression, and are likely to come under ESCC1, is characterized by alterations in the oxidative
increasing focus as potential biomarkers. stress response NRF2 pathway, which is associated
with radiation resistance.1 ESCC2 is typified by high
Genomic differences in esophageal cancer rates of NOTCH1 and ZNF750 mutation and shows
Squamous cell cancer high levels of leukocyte infiltration and cleaved
Squamous cell cancer develops in response to caspase 7, which could be of benefit to pro-immune
the long term accumulation of somatic mutations and pro-apoptotic treatments.1 Recent evidence
caused by DNA damage.12 15 Correspondingly, its has expanded on this possibility, suggesting that
genomic profile is similar to that of other ESCC not loss of NOTCH1, TP53, and CDKN2A promote an
related to human papillomavirus.1 Defective repair immunosuppressive niche enriched by exhausted T
processes are seen early in progression to ESCC, as cells and M2 macrophages via the CCL2/CCR2 axis.72
are mutations of TP53 and CDK2NA.63 Aberrance ESCC3 is characterized by activating mutations of the
of p53 increases with cumulative dysplasia, and PI3K pathway.1
its complete inactivation is considered critical for
the development of squamous cell cancer.64 While Barrett’s esophagus and adenocarcinoma
these changes underline the similar mutations At the genomic level, progression of Barrett’s esophagus
and markers of genetic instability seen between is associated at baseline with high clonal diversity
squamous dysplasia and squamous cell cancer, that reflects varying levels of multigenerational
squamous dysplasia is nevertheless polyclonal, and chromosomal instability.73 74 This association could
heterogeneity is seen between squamous dysplasia predict EAC before malignant transformation, and
and neighboring ESCC.63 64 is characterized by early copy number changes as
Once formed, the genomic features of ESCC well as aneuploidy and tetraploidy, which have been
are characterized by a high frequency of somatic linked to mitotic slippage.35 36 41 73 Accordingly, high
mutations and copy number alterations.1 65-70 levels of sensitivity and specificity for malignant
This mutational spectrum has been shown to vary transformation have been achieved through the
spatially, with a moderate overall mutational load measurement of genomic instability, primarily
characterized by a burden of around 5.8 single through assessment of copy number changes,
nucleotide variants per megabase (SNVs/Mb).44 65 71 including the use of flow cytometric DNA analysis,
Geographic variation in the genomic characteristics shallow whole genome arrays, and single nucleotide
of squamous cell cancers has been observed.64 71 polymorphism arrays.41 75 A complication of the
Enrichment of apolipoprotein B mRNA editing need to evaluate clonal diversity is the requirement
enzyme, catalytic polypeptide (APOBEC) signatures for a wide sampling field, which, given the potential
is a frequent feature of ESCC, and contributes to its complications of multiple biopsies, might favor the
mutational burden, the prognostic significance of use of pan-esophagus non-endoscopic sampling
which is uncertain.1 44 Around a quarter of patients modalities such as capsule delivered sponges.36
have mutations in DNA repair pathway genes, which By contrast, gene mutation panels are yet to
appear to interact with APOBEC processes that lead yield effective biomarkers, owing to high levels of
to a higher mutational burden.1 67 69 Age related heterogeneity.76 In Barrett’s esophagus, the burden
changes in mutational spectra are also observed, of mutations is reported at 5.6-6.8 SNVs/Mb, but
including an increased frequency of NOTCH1 whether this rate differs between dysplastic and
mutation.44 Commonly mutated genes that are non-dysplastic cases is uncertain.36 40 Nevertheless,
relevant to treatment include those involved in cell a predilection for early CDK2NA and somewhat later
cycle regulation (TP53, CDKN2A), the PI3K/AKT TP53 point mutations is recognized in Barrett’s
pathway (PIK3CA, PTEN), cell adhesion (AJUBA), esophagus.76 77 Aberrance of p53 detected by
chromatin remodeling (MLL2, KDM6A), epidermal immunohistochemistry correlates with progression

to high grade dysplasia and EAC, and its use as targetable receptor tyrosine kinases, several of which
an adjunct for histopathological assessment of are known to be expressed more during dysplastic
Barrett’s esophagus tissue is recommended by UK progression of Barrett’s esophagus.1 81 Over half of all
guidance.76 78 Reflecting the importance of p53 cases of EAC also contain sensitizing events for CDK4
in the pathogenesis of EAC, evidence is emerging and CDK6 inhibitors, the potential efficacy of which
for an association between p53 loss and the rapid has been shown in vitro.82
accumulation of copy number heterogeneity.74
Recent data also suggest that extrachromosomal Impact of gene regulatory mechanisms on
DNA (ecDNA) arises almost exclusively in the context development of esophageal cancer
of TP53 alteration in regions of high grade dysplasia, Squamous cell cancer
and amplifies a diversity of immunomodulatory A progressive increase in promoter hypermethylation
genes and oncogenes.79 Interestingly, a recent meta- with squamous dysplasia progression has been
analysis suggested a higher genetic correlation observed, including most reproducibly for CDKN2A.84
between GERD and Barrett’s esophagus than between Measurement of this increase has been exploited for
GERD and EAC.80 the development of novel early detection tools.85 86
Once developed, EAC is considered a Genome-wide hypomethylation is also associated
heterogeneous, structurally unstable, C type with squamous dysplasia progression, and correlates
malignancy that is characterized by frequent with chromosomal instability.87 88 In ESCC, abnormal
copy number changes and complex, large scale methylation is centered on genes involved in DNA
structural rearrangements.36 51 81 These structural damage repair, cell cycle regulation, and cellular
rearrangements have also been seen in high grade proliferation.89 Many of these genes are prognostic or
dysplasia, and include breakage-fusion-breakage predictive of response to anticancer treatments.90 91
cycles, fragile site deletions, somatic mobile element Similarly, close to 100 microRNAs (miRNAs) are now
insertions, and chromothripsis.51 EAC has a high considered to be dysregulated in ESCC, several of
mutational burden ranging from 7.1-25.2, with an which are considered to affect chemosensitivity.92 93
average of 9.9 SNVs/Mb.77 Reflecting early clonal
diversity, relatively little overlap is observed between Adenocarcinoma
the mutational patterns of EAC and adjacent Barrett’s The breakdown of gene regulation is of additional
esophagus. Over 60 mutational driver genes are now interest to EAC development. Marked changes in
recognized in EAC, with a median of five (interquartile chromatin accessibility are seen during progression
range 3-7) driver gene events per tumor.82 These of Barrett’s esophagus, and correlate with a
driver genes can be promoted and exacerbated by a transcription factor network that is centered on
plethora of patient specific helper genes.83 Among HNF4A and GATA6.94 Redistribution of KLF5 to
the known drivers, SMAD4 mutation or deletion, control cell cycle genes in EAC has also been reported,
present in around one third of EAC, is associated with and potentially contributes to its development from
a significantly poorer prognosis (hazard ratio 0.60, Barrett’s esophagus.95 Gene regulation in Barrett’s
95% confidence interval 0.42 to 0.84; p=0.003).82 esophagus and EAC is also known to be affected by
A similar trend is seen for GATA4 amplification CpG island methylation, for which a similar profile is
(0.54, 0.38-0.78; p<0.001), while activation of the seen in EAC, gastric cancer, and colon cancer.1 This
Wnt pathway appears to be associated with well has broader relevance to the chromosomal instability
differentiated tumors.82 Furthermore, a higher that dominates Barrett’s esophagus and EAC, given
proportion of APOBEC signatures is seen in later stage that commonly methylated genes include those
disease and is associated with worsened outcomes.59 involved in chromosomal segregation and spindle
Broadly, these mutational signatures can be formation.96
subdivided into three treatment relevant groups.81 Numerous methylation based subtypes of Barrett’s
Around one fifth of patients have a signature of DNA esophagus and EAC have been proposed, and have
damage repair impairment featuring defects in the potential prognostic and treatment relevance.96 97
homologous repair pathway, which could actually These subtypes include EAC cases in which high
provide susceptibility to treatment using irradiation levels of methylation are observed, which could be
or other DNA damaging agents combined with more sensitive to treatment with the topoisomerase I
poly ADP ribose polymerase (PARP) inhibition.81 inhibitor irinotecan, or in which susceptibility to the
A second group enriches for a C>A/T dominant alkylating agent temozolomide might be conferred by
mutational pattern associated with aging, while high levels of MGMT promoter methylation.97 Clearly
a third group of around half of all patients have a also, aberrant DNA methylation holds considerable
dominant T>G mutational pattern that associates promise for the development of biomarkers, some of
with a high mutational load.81 Evidently, such which have been evaluated using non-endoscopic
hypermutation associates with Wnt dysregulation capsule based sponge assays.98 99 These biomarkers
and the loss of immune signaling genes such as β2 include detection of methylated VIM and methylated
microglobulin, which could explain the relatively CCNA1 via the EsoCheck device.99 In a further study,
poor sensitivity of EAC to checkpoint inhibition.82 the use of a four gene digital droplet polymerase
The immune landscape is likely to be further shaped chain reaction and next generation sequencing based
by frequent amplification and co-amplification of four marker methylation panel shown sensitivity of

84.2%, 85.0%, and 90.8% for the detection of NDBE, Future approaches to early detection
high grade dysplasia, and EAC, respectively; albeit in Modeling of American data suggests that up
a mixed population of biopsy and surgical resection to half of all cases of EAC could be prevented
specimens.98 Similar to ESCC, nearly 100 miRNAs through the systematic screening of individuals
have been proposed as contributors to Barrett’s with symptoms of GERD who are not currently
esophagus progression; however, these miRNAs are referred for investigation.111 Unfortunately, current
supported by varying levels of evidence and often endoscopic approaches to diagnosis and screening
associated with conflicting data.100 Expression are impractical, and better understanding is required
changes in some of the pleiotropic group of long non- to effectively stratify patients for both screening and
coding RNAs (lncRNAs) are also associated with EAC ongoing surveillance of premalignant lesions, most
development and progression, but their significance importantly through further development of risk
is unclear.101 prediction models.112
Emerging technologies with the potential to
Advances in early diagnosis and prevention improve early detection of esophageal cancer and their
Current approaches to screening and monitoring of premalignant lesions include capsule endoscopy,
Barrett’s esophagus and squamous dysplasia the analysis of volatile organic compounds within
The early detection of both EAC and ESCC, or better exhaled breath, or the use of minimally invasive
still, their precursors Barrett’s esophagus and capsule delivered sponges.99 113 114 The latter
squamous dysplasia, holds considerable promise pairs cytological assessment with the detection
for reducing the burden imposed by these diseases. of biomarkers such as DNA methylation status,
At present, strategies for screening and surveillance miRNA assays, or cell surface proteins.99 113 This
of Barrett’s esophagus and squamous dysplasia includes the Cytosponge, which detects Barrett’s
vary worldwide, but mostly rely on white light esophagus intestinal metaplasia defining trefoil
endoscopy.78 102 factor 3 (TFF3). In a previous trial including patients
Most guidelines for Barrett’s esophagus emphasize presenting to primary care with reflux symptoms,
the importance of targeted screening at patients a 10.6-fold increase in detection of Barrett’s
with symptoms of GERD, with further stratification esophagus was seen for those within a cohort in
relating to age and other known risk factors for which the Cytosponge-TFF3 was offered compared
Barrett’s esophagus.78 102 Subsequent monitoring of with a cohort offered standard care alone.113 The
those with established Barrett’s esophagus usually integration of multiplatform data, such as cytological
proceeds at intervals of 3-5 years based on the and epidemiological data, could also be beneficial,
degree of dysplasia and length of the metaplastic with a recent prospective Chinese study showing
segment. Endoscopic protocols that use systematic favorable performance of a prediction tool that
four quadrant biopsies have been shown to improve employed machine learning to enhance diagnosis
dysplasia detection for Barrett’s esophagus, and of EAC and ESCC.114 The analysis of circulating
are widely recommended to guide esophageal cfDNA to enable liquid biopsies of early disease has
sampling.103 No data relate to the effect of screening been more disappointing, with reported sensitivity
for Barrett’s esophagus on mortality, and data of less than 20% using the Galleri and CancerSEEK
relating to the efficacy of surveillance are mixed.104 tests.115 116
By contrast, Lugol chromoendoscopy is used
for the identification of early ESCC, and has been Prevention of progression to invasive disease
shown to increase identification of squamous Interest has been shown in the use of proton pump
dysplasia.105 Evidence suggests that squamous cell inhibitors or non-steroidal anti-inflammatory
screening programs reduce mortality and are cost drugs to reduce dysplastic progression of Barrett’s
effective when targeting endemic and high risk esophagus, as was assessed in the phase 3
populations.25 104 A cluster randomized controlled multicenter AspECT trial.117 In this study, use of
trial evaluating efficacy in non-high incidence areas high dose proton pump inhibitor (esomeprazole 40
is under way.106 mg twice daily) (time ratio 1.27, 95% confidence
Several alternative and complementary strategies interval 1.01 to 1.58; p=0.038) and combined high
aimed at improving dysplasia detection for both dose proton pump inhibitor with aspirin (300-325
neoplastic subtypes are in development. Examples mg once daily) (1.59, 1.14 to 2.23; p=0.068) resulted
include the use of wide area transepithelial sampling, in prolonged time to a composite endpoint of all
fluorescence aided molecular endoscopy, and cause mortality, high grade dysplasia, or invasive
capsule delivered sponges for Barrett’s esophagus, disease, when compared with low dose proton pump
the use of high resolution microendoscopy and inhibitor (esomeprazole 20 mg once daily) alone.
confocal laser endomicroscopy for squamous Despite this result, no difference was seen between
dysplasia, and computer aided detection for both treatments in a secondary endpoint of the time to the
subtypes.107-109 Detection of loss of heterozygosity development of EAC or high grade dysplasia. As such,
in cell free DNA (cfDNA) has also been studied as the specificity of any advantage conferred by high
a method of monitoring dysplastic progression of dose proton pump inhibitor or aspirin is uncertain,
Barrett’s esophagus, though the sensitivity appears and further studies are required to define their role in
to be limited in early disease.110 the chemoprevention of dysplasia.

Once established, dysplastic Barrett’s esophagus study is evaluating whether endoscopic follow-up
should be eradicated using endoscopic eradication might be an acceptable alternative to esophagectomy
therapy. Current guidelines advocate for the for patients with T1b N0 EAC.125 Preliminary data
subsequent ablation of any residual Barrett’s indicate that this approach is feasible in patients
esophagus as well.78 102 In the context of low grade with high risk and low risk disease.125
dysplasia, a meta-analysis has shown a relative The risk of nodal metastasis is around 4% for
risk of progression with radiofrequency ablation pT1a ESCCs but higher than EAC for pT1b, at around
versus surveillance of 0.14 (95% confidence interval 30%.126 pT1a lesions can be managed endoscopically,
0.04 to 0.45; p=0.001).118 Alternative approaches though m3 lesions with additional risk factors will
include cryotherapy (via spray, carbon dioxide gas, generally be considered for additional treatment.127
or cryoballoon with nitrous oxide gas) and hybrid Endoscopic submucosal dissection delivers more
argon plasma coagulation, which have been studied favorable local outcomes than endoscopic mucosal
as primary treatments and for salvage after failed resection, and should be considered.128 ESCC pT1b
radiofrequency ablation.119 120 lesions can be managed with surgical resection or
adjuvant chemoradiotherapy, both of which are
Management of early disease associated with excellent long term outcomes.129
Intramuscosal (T1a) cancers are subclassified by
involvement of the epithelium (m1), lamina propria Management of locally advanced disease
(m2), or muscularis mucosae (m3). Submucosal Molecular testing is frequently used once a
lesions (T1b) are separated by a low (<500 µm; sm1), pathological diagnosis is made, particularly for
medium (500-1000 µm), or high (>1000 µm) depth microsatellite instability, but interest in HER2 and
of invasion. The Paris classification distinguishes programmed death ligand 1 (PDL1) status has been
lesions by endoscopic appearances into those that growing. Recent evidence points to an emerging role
are protruding (type I), flat and superficial (type for artificial intelligence in supporting pathological
0-II), or excavated (type 0-III).121 Tumor depth, size, assessment, including for accurately assessing HER2
lymphovascular invasion, and poor differentiation status.130 131 Esophageal cancer is generally staged
are known prognostic features.122 using positron emission tomography-computed
In EAC, the risk of nodal metastases rises from less tomography (PET-CT) and endoscopic ultrasound,
than 5% for intramucosal (pT1a) lesions to 26% for although the utility of this latter assessment has
disease invading the submucosa (pT1b).123 pT1a been questioned.132 Other staging modalities
lesions with no adverse features can be managed include diagnostic laparoscopy in selected cases to
definitively using either endoscopic mucosal assess for occult peritoneal metastatic disease, and
resection or endoscopic submucosal dissection, bronchoscopy where concern exists about airway
which deliver similar outcomes.124 pT1b lesions invasion.133-136 A multidisciplinary discussion is
might necessitate an esophagectomy, though an required to define treatment options once the stage is
endoscopic approach can be considered for sm1 known, and open dialogue with patients is essential
lesions with no adverse features and no residual to define an individualized treatment strategy.
tumor at the deep margin.122 Eradication of Treatment approaches have nuances specific to
remaining Barrett’s esophagus via radiofrequency regions and centers, although the focus is on
ablation is mandated following endoscopic ensuring that patients are treated at dedicated high
treatment, as is close surveillance. The ongoing volume centers, with access to highly experienced
international multicenter PREFER (NCT03222635) teams (table 1).137-142 144-153
Table 1 | The landmark clinical trials on localized treatments in esophageal and gastro-esophageal junction cancers
Overall survival PFS/DFS
Trial identifier Treatment Hazard ratio (95% CI), Hazard ratio (95% CI), P pCR, R0,
Trial (phase) setting Tumor type Treatment arm (N) P value value % %
MAGIC137 ISRCTN93793971 pCT EAC, GEJAC, GAC Perioperative ECF (250) 5 year OS 36% v 23% Median PFS NA 31 79
(3) 0.75 (0.60 to 0.93), 0.009 0.66 (0.53 to 0.81), 0.001
Surgery alone (253) - 70
FLOT138 NCT01216644 pCT GEJAC, GAC Perioperative FLOT (356) Median OS 50 v 35 months, 5 Median DFS 30 v 18 months 16 85
(2/3) year OS 45% v 36% 0.75 (0.62 to 0.91), 0.0036
0.77 (0.63 to 0.94), 0.012
Perioperative ECF/ECX (360) 6 78
FNCLCC NCT00002883 pCT EAC, GEJAC, GAC Perioperative CF (113) 5 year OS 38% v 24% 5 year DFS 34 v 19% - 84
ACCORD07139 (3) 0.69 (0.50 to 0.95), 0.02 0.65 (0.48 to 0.89), 0.003
CROSS140 NTR487 nCRT ESCC, EAC, GEJ nCRT with PC (178) Median OS 49 v 24 months, 5 Median DFS NR v 24 months 29 92
(3) cancer year OS 47% v 44% 0.498 (0.357 to 0.693),
0.68 (0.53 to 0.88), 0.003 0.001
(Continued)

Table 1 | Continued
Overall survival PFS/DFS
Trial identifier Treatment Hazard ratio (95% CI), Hazard ratio (95% CI), pCR, R0,
Trial (phase) setting Tumor type Treatment arm (N) P value P value % %
NeoCRTEC5010141 NCT01216527 nCRT OSCC nCRT with VC (224) Median OS 100 v 67 months Median DFS 100 v 42 43 98
(3) 0.71 (0.53 to 0.96), 0.025 months
0.58 (0.43 to 0.78), 0.001
NEO-AEGIS142 NCT01726452 pCT, nCRT EAC, GEJAC CROSS regimen (178) 3 year OS 57% v 55% Ongoing 16 95
(3) 1.03 (0.77 to 1.38), NS
mMAGIC/FLOT regimen (184) 5 82
ESOPEC143 NCT02509286 pCT, nCRT EAC, GEJAC CROSS regimen Ongoing Ongoing
(3)
FLOT regimen
OEO2144 145 UK MRC OE02 nCT ESCC, EAC nCT with CF (400) Median OS 17 v 13 months, 5 Median DFS NA - 60
(3) year OS 23% v 17% 0.82 (0.71 to 0.95), 0.003
0.84 (0.72 to 0.98), 0.03
RTOG 8911/ SWOG-9013/ nCT ESCC, EAC nCT with CF (213) Median OS 15 v 16 months - - 62
INT-113146 RTOG 8911 (3) 1.07 (0.87 to 1.32), NS
NeoRes147 NCT01362127 nCT, nCRT ESCC, EAC, GEJ nCRT with CF (90) 3 year OS 47% vs 49% 3 year PFS 44% v 44% 28 87
(2) cancer 1.09 (0.73 to 1.64), 0.77 1.0 (0.68 to 1.47), NS
nCT with CF (91) 9 74
JCOG 1109/ UMIN000009482 nCT, nCRT OSCC nCRT with CF (200) Median OS 6.0 v NR v 4.6 years, Median PFS 2.7 v NR v 5.3 39 88
NExT148 (3) 3 year OS 68% v 72% v 63% years
nCRT with CF; 0.84 (0.63 to 3 year PFS 48% v 62% v
1.12), 0.12 59%
nCT with DCF; 0.68 (0.50 to NA
0.92), 0.006
nCT with DCF (202) 20 86
nCT with CF (199) 2 84
RTOG 85-01149 150 RTOG 85-01 dCRT ESCC, EAC dCRT with CF (134) Median OS 14 v 9 months, 5 - - -
(3) year OS 26% v 0%
NA, NA
RT alone (62) - -
PRODIGE5/ NCT00861094 dCRT ESCC, EAC dCRT with FOLFOX (134) Median OS 20 v 18 months Median PFS 9.7 v 9.4 months 44* -
ACCORD17151 (2/3) 0.94 (0.68 to 1.29), 0.70 0.93 (0.70 to 1.24), 0.64
dCRT with FP (133) 43* -
FFCD9102152 NCT00416858 dCRT, nCRT OSCC nCRT with FP (129) Median OS 18 v 19 months, 2 - - -
(3) year OS 34% v 40%
0.90 (NA), 0.44
dCRT with FP (130) - -
CheckMate 577153 NCT02743494 aIO ESCC, EAC, GEJ Adjuvant nivolumab (532) Ongoing Median DFS 24 v 11 months - -
(3) cancer 0.69 (0.56 to 0.86), 0.001
Adjuvant placebo (262) - -
aIO=adjuvant immunotherapy; CF=cisplatin, fluorouracil; CI=confidence interval; DCF=docetaxel, cisplatin, fluorouracil; dCRT=definitive chemoradiation therapy; DFS=disease free survival;
ECF=epirubicin, cisplatin, fluorouracil; ECX=epirubicin, cisplatin, capecitabine; FOLFOX=fluorouracil, leucovorin, oxaliplatin; FLOT=fluorouracil, leucovorin, oxaliplatin, docetaxel; FP=fluoropyrimidine,
platinum; GAC=gastric adenocarcinoma; GEJ=gastro-esophageal junction; GEJAC=gastro-esophageal junction adenocarcinoma; NA=not available; nCRT=neoadjuvant chemoradiation therapy;
nCT=neoadjuvant chemotherapy; NR=not reached; NS=not significant; EAC=esophageal adenocarcinoma; ESCC=esophageal squamous cell carcinoma; OS=overall survival; PC=paclitaxel,
carboplatin; pCR=pathologic complete response; pCT=perioperative chemotherapy; PFS=progression free survival; R0=R0 resection rate; RT= radiotherapy; VC=vinorelbine, cisplatin.
*Clinical complete response rate.
Surgery is the definitive treatment of choice for neoadjuvant chemoradiotherapy appeared to be

locally advanced EAC and ESCC, but evidence beneficial for patients with squamous cell cancers,
indicates that neoadjuvant treatment improves patients with EAC had similar outcomes at a follow-
outcomes.137 141 145 154 No one approach, however, up of 10 years. Additionally, patients in the CROSS
is the gold standard, and the use of bimodality or trials were managed predominantly with transhiatal
trimodality treatment is subject to considerable esophagectomy, which might suggest that these
geographic variation. patients required radiation to augment regional
The seminal CROSS trial of 366 patients with control. A similar advantage for neoadjuvant
EAC (75%) and ESCC established the superiority chemoradiotherapy versus surgery alone in ESCC
of neoadjuvant chemoradiotherapy (41.4 Gy in 23 was identified by the NEOCRTEC5010 trial, in which
fractions with concurrent carboplatin/paclitaxel) median overall survival improved from 66.5 to 100.1
over surgery alone.140 At 10 years, overall survival months (hazard ratio 0.71, 95% confidence interval
with neoadjuvant chemoradiotherapy was greater 0.53 to 0.96; p=0.25).141
for ESCCs (46%, 95% confidence interval 33 to Neoadjuvant or perioperative chemotherapy is
64) than EAC (36%, 29 to 45).154 However, while an alternative standard of care for both subtypes.

For ESCCs, the JCOG1109 NExT study is comparing Personalized treatment

doublet cisplatin/fluorouracil, triplet docetaxel, Current neoadjuvant treatment approaches remain
cisplatin, fluorouracil (DCF) and concurrent largely empiric and an opportunity is open to
chemoradiotherapy (41.4 Gy in 23 fractions with define imaging, molecular, and immune tumor
cisplatin/fluorouracil).148 155 Interim results have characteristics that associate with, and therefore
been presented, with respective three year survival of allow selection of, specific treatments. The use of
62.6%, 72.1%, and 68.3% respectively. This result PET-CT to assess early metabolic response and guide
underlines previous data indicating impressive ongoing treatment has been explored in the MUNICON
responses with DCF.156 I and II, AGITG DOCTOR, MEMORI, SCOPE-2, and
For EAC, the UK MAGIC (epirubicin, cisplatin, CALGB80803 trials.160-165 Broadly, PET-CT appears
fluorouracil (ECF)) and French ACCORD (cisplatin, prognostic for outcome in EAC, but as yet no benefit
fluorouracil (CF)) trials provided initial evidence for of adapting perioperative chemotherapy or switching
the superiority of perioperative chemotherapy over to chemoradiotherapy in patients with a poor early
surgery alone.137 145 154 Recently, the German FLOT-AIO metabolic response has been reported. However, the
trial showed a substantial overall survival advantage CALGB80803 study suggests that a PET-CT directed
with a perioperative regimen of fluorouracil, switch in systemic treatment based on response to
leucovorin, oxaliplatin, docetaxel (FLOT) compared induction treatment can improve outcomes from
with the MAGIC ECF regimen (median overall survival chemoradiotherapy in patients with EAC.161 Early
50 v 35 months, hazard ratio 0.77, 95% confidence metabolic response appears not to be prognostic for
interval 0.63 to 0.94; p=0.012).138 As a caveat to overall survival in ESCC.165
these impressive outcomes, however, less than half of
patients completed all planned treatment, and 51% Systemic treatments
experienced grade 3/4 neutropenia, in a population Attention has increasingly fallen on the use of
in which 75% of cases were gastric or Siewert type immune checkpoint inhibitors in the locally
2/3, and 25% were Siewert type 1. advanced setting for both subtypes of esophageal
Considerable uncertainty exists as to which cancer. Several single arm studies have reported
perioperative chemotherapy or neoadjuvant outcomes following combinations of chemotherapy
chemoradiotherapy is superior for adenocarcinomas. and immune checkpoint inhibitors in EAC, achieving
In the recently published Neo-AEGIS trial, three year pathological complete response rates of between
overall survival was similar for patients treated with 4-33%.166-172 Larger phase 2 and 3 studies are
perioperative chemotherapy (predominantly using the exploring combinations of chemotherapy and
MAGIC regimen) and those managed using neoadjuvant immune checkpoint inhibitors in the neoadjuvant
chemoradiotherapy (using the CROSS regimen), at (KEYNOTE-585, MATTERHORN) and adjuvant
55% versus 57% (hazard ratio 1.03, 95% confidence post-neoadjuvant chemotherapy (VESTIGE,
interval 0.77 to 1.38), respectively.157 No significant ATTRACTION-05) settings.173-176 One unanswered
difference was seen in pattern of recurrence though question is whether treatments that increase levels
pathological complete response, and R0 rates favored of pathologic complete response will have any effect
neoadjuvant chemoradiotherapy. The ongoing ESOPEC on overall survival. A smaller number of studies have
(NCT02509286) and RACE (NCT0437505) studies are focused on the use of combinations of chemotherapy
using a FLOT arm, which will be respectively compared and immune checkpoint inhibitors in ESCC.161 177-179
with CROSS-style neoadjuvant chemoradiotherapy,
or with induction FLOT followed by neoadjuvant Radiation treatment
chemoradiotherapy.143 158 The advantage of concurrent chemotherapy to
For patients who receive chemoradiotherapy, both local control and overall survival outcomes is
adjuvant immune checkpoint inhibition using long established in the context of conventionally
nivolumab for one year was shown to improve fractionated radiotherapy to the esophagus.150 180
outcomes for patients with residual pathologic Building on this advantage, several studies have
disease (primary, nodal, or both) in the CheckMate attempted to define optimal drug-radiotherapy
577 trial.153 An overall doubling of disease free combinations.159 181-183 Currently, most centers
survival compared with placebo (median disease use a chemotherapy backbone comprising a
free survival 22.4 v 11.0 months, hazard ratio platinum inhibitor and either a fluoropyrimidine or
0.69; p<0.001) was reflected by histologic specific microtubule inhibitor.151 181 Targeted radiosensitizers
improvements for both EAC (median disease free are not routinely used following a number of broadly
survival 19.4 v 11.1 months, hazard ratio 0.75, 95% disappointing trials of EGFR, HER2, and PARP
confidence interval 0.59 to 0.96) and ESCC (29.7 v inhibition; however, these trials suggested that EGFR
11.0 months, 0.61, 0.42 to 0.88). Overall survival inhibition might provide benefits in overexpressing
results are awaited. patients.182-184 More recently, the addition of
Patients with locoregionally advanced but immunotherapy to chemoradiotherapy has gained
unresectable cancer, or who are precluded momentum, achieving promising rates of pathologic
from surgery by choice, comorbidities, or poor complete response.185
performance status, can be managed with definitive Radiation dose escalation has also been studied
chemoradiotherapy.149 150 159 as an alternative means to improving local control

in the context of chemoradiotherapy. The early overall survival rates.199-202 Notably, the Ivor Lewis
phase 3 INT-0123 trial found no advantage with and McKeown procedures can also be accomplished
high dose radiotherapy; a finding that was repeated using minimally invasive techniques, including fully
using intensity modulated radiation therapy (IMRT) video assisted minimally invasive esophagectomy,
in the ARTDECO and PRODIGE-26 (CONCORDE) hybrid minimally invasive esophagectomy (HMIE)
studies.186-188 A third trial examining dose escalation involving laparoscopy and thoracotomy, or a
(SCOPE2) has yet to report.189 Consequently, robotic assisted minimally invasive esophagectomy
chemoradiotherapy is generally delivered to 50 Gy in (RAMIE). A complete lymphadenectomy, appropriate
25 fractions in the definitive setting and to 41.4-50.4 for location of tumor, is preferred.
Gy in the neoadjuvant setting.159 181 Some centers The implementation of enhanced recovery after
advocate the use of an intraluminal brachytherapy thoracoscopic surgery (ERATS) pathways has become
boost, particularly in early stage disease.190 an increasingly common buzz term in recent years,
Alongside these developments, target volume but have probably existed as quality improvement
delineation has been improved with the use of PET- projects since Torek’s first esophagectomy. ERATS
CT, as well as four dimensional chemotherapy based incorporates various preoperative and in-hospital
planning. In tandem, the advent of IMRT enables a strategies to improve postoperative outcomes. These
relative reduction in radiation exposure to organs strategies include preoperative measures such as
at risk, including the lungs, kidneys, spleen, and nutritional optimization, physical prehabilitation,
heart, when compared with conventional conformal and smoking cessation, as well as in-hospital
approaches. Adaptive radiotherapy technologies, recommendations such as minimized use of chest
including the use of magnetic resonance linear tubes and drains, multimodal analgesia, early oral
accelerators, are also under investigation for nutrition and mobilization, and targeted timeline
esophageal cancer, and could help spare organs to discharge.203-206 Studies have also shown that a
from radiation.191 These technologies are of potential fast track esophagectomy protocol, which requires
importance, given recognition of the importance of transferring patients to telemetry instead of intensive
radiation related cardiac and pulmonary toxicity care units, can safely reduce hospital length of stay,
to surgical and long term outcomes, in addition perioperative morbidity, and hospital charges.207 208
to evidence for sequalae, such as functional
hyposplenism.192 193 Evolution towards minimally invasive surgery
Proton beam therapy is a potential alternative to TIME is a randomized controlled trial that included
photon based treatment strategies. Protons benefit five centers across three countries evaluating
from a Bragg peak, at which dose rises sharply and patient reported outcome measures (PROMs), and
then falls off. This in theory allows for the radiation clinical and operative characteristics between open
dose to be deposited in the target volume while transthoracic esophagectomy (Ivor Lewis, n=56)
limiting the exposure of surrounding tissues.194 195 and minimally invasive esophagectomy (McKeown,
In a phase 2b trial, patients with esophageal cancer n=59).209 While the authors noted that patients
were randomized to receive proton beam therapy or managed with minimally invasive esophagectomy
IMRT, resulting in a reduction in total toxicity burden benefited from a lower rate of in-hospital pulmonary
for patients managed with proton beam therapy.196 infections (12% v 34% in open group, risk ratio 0.35,
A number of studies are ongoing to define the role 95% confidence interval 0.16 to 0.78; p=0.005),
of protons in esophageal cancer, including the HI- the rate of pneumonia in patients undergoing
SIRI, NRG-GI006 (NCT03801876), and PROTECT transthoracic esophagectomy was abnormally high.
trials.197 198 Additionally, minimally invasive esophagectomy was
shown to have lower intraoperative blood loss (200 v
Surgical management of esophageal cancer 475 mL, p<0.001), shorter hospital length of stay (11
Esophagectomy can be achieved via two v 14 days, p=0.044), and better physical quality of
transthoracic approaches: the Ivor Lewis approach, life (p=0.007). A similar number of lymph nodes were
which entails accessing the abdominal cavity and resected in both groups. In an updated analysis, the
right chest, or the McKeown approach, which entails authors reported no difference in oncologic outcomes
accessing the abdominal cavity, right chest, and left (both overall survival and disease free survival)
neck. Alternatively, a transhiatal approach can be between the groups.210 De Groot and colleagues
employed, in which only the abdominal cavity and surveyed an international group of thoracic surgeons
left neck are operated on, avoiding a thoracic incision. to assess current trends in preferred approaches, and
Randomized controlled trials and comparative noted a majority of surgeons preferring minimally
studies between transthoracic esophagectomy invasive surgery followed by hybrid and total open
and transhiatal esophagectomy have revealed that esophagectomy.211
accessing the thoracic cavity during transthoracic The MIRO trial assessed major complications
esophagectomy has higher nodal resection counts in patients undergoing open transthoracic
and more complete resections (R0), but in some esophagectomy (n=103) compared with HMIE
studies was associated with higher morbidity rates (n=104) where the abdominal portion of the case
owing to increased pulmonary complications, was minimally invasive.212 The authors defined
without significant differences in quality of life or major complications as patients with an event

requiring pharmacotherapy or more (Clavien- between approaches and guiding clinical decision
Dindo grade 2 and above). The incidence of major making. Considering the potential limitations of
complications in HMIE was 36% compared with randomized controlled trials, such as generalizability
64% in transthoracic esophagectomy, major to patient populations managed at smaller centers
pulmonary complications occurred at a rate of or the possibility of confounding variables, is also
18% in the transhiatal esophagectomy, and 30% important.
in the transthoracic esophagectomy group. An
important distinction to be made, however, is Ongoing surgical trials
that the rate of clinically relevant complications Several ongoing clinical trials could provide further
requiring an invasive intervention (Clavien-Dindo clarity on the benefits of minimally invasive surgery
grade 3) was similar across both open and HMIE for esophageal cancer. The ROMIO trial will compare
cohorts. Furthermore, there appeared to be more minimally invasive esophagectomy, HMIE, and
events requiring deviation from standard treatment transthoracic esophagectomy, with primary outcome
(Clavien-Dindo grade 1) in the HMIE cohort. Lastly, measures including patient reported physical
while no significant difference was observed in status at three and six weeks post-resection, as
overall survival between the groups, perhaps because well as three months following esophagectomy.218
the trial was underpowered, patients who underwent Secondary outcomes will include various patient
HMIE trended toward a survival advantage (hazard reported outcomes, oncologic outcomes, operative
ratio 0.67, 95% confidence interval 0.44 to 1.01) outcomes (including complications), and cost.
that appeared stable after five years, with updated REVATE will evaluate RAMIE versus minimally
reporting on overall survival favoring HMIE (0.71, invasive esophagectomy for squamous esophageal
0.48 to 1.06).213 The authors reported no significant cancer, with the primary outcome measure being
difference in recurrence rate or recurrence location the rate of unsuccessful lymph node dissection
between the cohorts. specifically along the left recurrent laryngeal
nerve.219 ROBOT-2 will compare RAMIE with
Robotic assisted minimally invasive esophagectomy minimally invasive esophagectomy for OAC, with
The ROBOT trial conducted a comparative evaluation the primary outcome measure being the number
between the use of robotic and open transthoracic of lymph nodes resected.220 Finally, MIVATE aims
esophagectomy (McKeown) and has concluded to evaluate postoperative morbidity using the
that the use of a robotic approach is associated comprehensive complication index in patients with
with a reduction in total complications (Clavien- esophageal cancer managed with minimally invasive
Dindo grade 2) compared with transthoracic esophagectomy and linear stapled anastomosis,
esophagectomy (59% v 80%, risk ratio 0.74, 95% compared with transthoracic esophagectomy (Ivor
confidence interval 0.57 to 0.96) and pulmonary Lewis) and circular stapled anastomosis.221
complications (0.54, 0.34 to 0.85).214 In addition,
patients who underwent robotic esophagectomy Definitive local regional treatment without surgery:
experienced enhanced functional recovery, as well organ preservation
as improved quality of life at discharge and six weeks Given the long term impact of esophagectomy on
post-resection. A recent update of the trial’s survival health related quality of life, interest has arisen in
data showed comparable overall survival and the development of organ preservation strategies for
disease free survival between the two groups, with patients who show a complete clinical response to
no differences observed in recurrence patterns.215 chemoradiation.222-224 In this paradigm, surgery is
Furthermore, a multicenter international registry only performed after a period of observation in the
has recently highlighted current techniques and self- instance that tumor recurs locoregionally (salvage
reported outcomes from over 800 patients across resection). This approach is under evaluation for
20 centers, and indicated high surgical quality ESCC within the international NEEDS trial, in which
associated with robotic esophagectomy.216 the non-inferiority of definitive chemoradiotherapy
RAMIE is a randomized controlled trial that with surgery as needed is compared with neoadjuvant
compared outcomes between RAMIE (n=181) and chemoradiotherapy and surgery.225 The SANO trial
minimally invasive esophagectomy (n=177) in is also seeking to compare active surveillance with
patients with squamous esophageal cancer. The planned esophagectomy, but in patients with both
study found that robotic assisted resections led to a EACs and ESCCs, using overall survival as the primary
larger number of lymph nodes being evaluated (15 v endpoint.226 Preliminary data indicate no overall
12 lymph nodes, p=0.016), a lower operative time, survival difference when patients who achieved a
no difference in estimated blood loss or conversion complete clinical response were either operated on
rates, and similar rates of complications (Clavien- quickly or delayed until persistence/recurrence of
Dindo grade 3) or anastomotic leaks.217 disease was documented.
While randomized controlled trials can provide The accurate identification of residual or recurrent
the highest level of evidence, carefully defining and disease is central to these trials, but concerns have
interpreting the outcomes used to evaluate different been raised regarding the sensitivity of conventional
surgical approaches is important. Meaningful metrics response assessments.227-229 A recent study showed
are essential for accurately establishing superiority that the use of bite-on-bite biopsies delivers a 20%

improvement in the detection of residual esophageal recommended for treatment naive patients. In older
cancer.230 A separate study (preSINO) is ongoing, or frail patients, the UK GO2 trial showed that when
and will determine the accuracy of radiographic compared with standard dose treatment, reduced
and endoscopic evaluation of clinical complete intensity chemotherapy improved patient experience
response in squamous cell esophageal cancer.231 without significant detriment to cancer control.239
Alternative and augmentative approaches have Only recently, several studies have shown the
also been studied, including through the use of a benefit of the addition of immune checkpoint blockade
non-endoscopic sponge and endoscopic response (table 2).242-245 For patients with HER2 positive EAC,
evaluation guided by artificial intelligence.232 233 the addition of trastuzumab (monoclonal antibody
(mAb) targeting HER2) has produced modest
Management of advanced esophageal cancer overall survival advantage.240 An interim analysis
Oligometastatic disease in the KEYNOTE-811 trial showed a higher objective
Recent evidence suggests that the addition of local response rate when pembrolizumab (mAb targeting
treatment to metastases improves progression free programmed cell death protein 1 (PD1)) was added
survival in patients with oligometastatic ESCC.234 to trastuzumab plus chemotherapy (pembrolizumab
Further trials are awaited to establish the impact 74.4 v placebo 51.9%; p=0.0001).241 In patients with
of metastasis directed treatment in both major HER2 negative EAC, nivolumab (mAb targeting PD1)
esophageal cancer subtypes. In the absence of these plus platinum-fluoropyrimidine doublet resulted
data, the European OligoMetastatic Esophagogastric in considerable overall survival benefit for those
Cancer consortium has identified significant who exhibited high tumoral expression of PDL1
variation among multidisciplinary teams in the (combined positive score ≥5).242 Thus, combination
management of oligometastatic disease, which most of nivolumab and chemotherapy for the PDL1 high
teams define as 1-2 stable metastases in the liver, population has been approved as first line treatment
lung, soft tissue, bone, retroperitoneal lymph nodes, in many regions.
or adrenal gland.235 236 As with EAC, platinum-fluoropyrimidine
doublet has been the standard first line treatment
Metastatic disease for metastatic squamous cell cancer. Recently,
Systemic treatment can relieve symptoms, delay combination treatment of pembrolizumab and
cancer progression, and prolong overall survival of platinum-fluoropyrimidine doublet has emerged
patients with stage IV (M1) esophageal cancer.237 238 based on the phase 3 KEYNOTE-590 trial for
Platinum-fluoropyrimidine doublet has been advanced esophageal cancer.243 This trial included
Table 2 | Landmark clinical trials on systemic treatments in esophageal cancer and gastro-esophageal junction cancers
Trial identifier Treatment Overall survival Progression free survival ORR,
Trial (phase) setting Tumor type Treatment arm (N) Hazard ratio (95% CI), P value Hazard ratio (95% CI), P value %
ToGA240 NCT01041404 First line GEJAC, GAC Trastuzumab + Median OS: 13.8 v 11.1 months Median PFS: 6.7 v 5.5 months 47
(3) (HER2+) chemotherapy (294) 0.74 (0.60 to 0.91), 0.0046 0.71 (0.59 to 0.85), 0.0003
Chemotherapy alone 35
(290)
KEYNOTE-811*241 NCT03615326 First line GEJAC, GAC Pembrolizumab + 74
(3) (HER2+) trastuzumab +
chemotherapy (133)
Placebo + 52
trastuzumab +
chemotherapy (131)
CheckMate 649242 NCT02872116 First line EAC, GEJAC, Nivolumab + CPS ≥5: 14.4 v 11.1 months CPS ≥5: 7.7 v 6.0 months
(3) GAC chemotherapy (789) 0.71 (0.59 to 0.86), <0.0001 0.68 (0.56 to 0.81), <0.0001
CPS ≥1: 14.0 v 11.3 months CPS ≥1: 7.5 v 6.9 months
Chemotherapy alone 0.77 (0.64 to 0.92), <0.0001 0.74 (0.65 to 0.85), NA
(792) All: 13.8 v 11.6 months All: 7.7 v 6.9 months
0.80 (0.68 to 0.94), 0.0002 0.77 (0.68 to 0.87), NA
CPS ≥5: 60 CPS ≥5: 45
All: 58 All: 46
KEYNOTE-590243 NCT03189719 First line ESCC, EAC, Pembrolizumab + ESCC with CPS ≥10: 13.9 v 8.8 months ESCC: 6.3 v 5.8 months 45
(3) GEJAC chemotherapy (373) 0.57 (0.43 to 0.75), <0.0001 0.65 (0.54-0.78), <0.0001
Placebo + ESCC: 12.6 v 9.8 months CPS ≥10: 7.5 v 5.5 months 29
chemotherapy (376) 0.72 (0.60 to 0.88), 0.0006 0.51 (0.41 to 0.65), <0.0001
CPS ≥10: 13.5 v 9.4 months All: 6.3 v 5.8 months
0.62 (0.49 to 0.78), <0.0001 0.65 (0.55 to 0.76), <0.0001
All: 12.4 v 9.8 months
0.73 (0.62 to 0.86), <0.0001
KEYNOTE-859244 NCT03675737 First line GEJAC, GAC Pembrolizumab + Median OS: 12.9 v 11.5 months Median PFS: 6.9 v 5.6 months 51
(3) chemotherapy (790) 0.78 (0.70 to 0.87), <0.0001 0.76 (0.67 to 0.85), <0.0001
Placebo + 42
chemotherapy (789)
(Continued)

Table 2 | Continued
Trial identifier Treatment Overall survival Progression free survival ORR,
Trial (phase) setting Tumor type Treatment arm (N) Hazard ratio (95% CI), P value Hazard ratio (95% CI), P value %
CheckMate 648245 NCT03143153 First line ESCC Nivolumab + (Nivolumab + chemotherapy v (Nivolumab + chemotherapy v
(3) chemotherapy (321) chemotherapy alone) chemotherapy alone)
TPS ≥1%: 15.4 v 9.1 months TPS ≥1%: 6.9 v 4.4 months
0.54 (0.37 to 0.80), <0.001 0.65 (0.46 to 0.92), 0.002
All: 13.2 v 10.7 months All: 5.8 v 5.6 months
0.74 (0.58 to 0.96), 0.002 0.81 (0.64 to 1.04), 0.04
(Nivolumab + ipilimumab v (Nivolumab + ipilimumab v
chemotherapy alone) chemotherapy alone)
TPS ≥1%: 13.7 v 9.1 months TPS ≥1%: 4.0 v 4.4 months
0.64 (0.46 to 0.90), 0.001 1.02 (0.73 to 1.43), 0.90
0.78 (0.62 to 0.98), 0.01 1.26 (1.04 to 1.52), NA
TPS ≥1: 53
All: 47
Nivolumab + TPS ≥1: 35
ipilimumab (325) All: 28
Chemotherapy alone TPS ≥1: 20
(324) All: 27
SPOTLIGHT246 NCT03504397 First line GEJAC, GAC Zolbetuximab + Median OS: 18.23 v 15.54 months Median PFS: 10.61 v 8.67 months 48
(3) (CLDN18.2+) mFOLFOX6 (283) 0.75 (0.601 to 0.936), 0.0053 0.751 (0.598 to 0.942), 0.0066
Placebo + mFLOFOX6 48
(282)
GLOW247 NCT03653507 First line GEJAC, GAC Zolbetuximab + Median OS: 14.39 v 12.16 months Median PFS: 8.21 v 6.80 months 54
(3) (CLDN18.2+) CAPOX (254) 0.771 (0.615 to 0.965), 0.0118 0.687 (0.544 to 0.866), 0.0007
Placebo + CAPOX 49
(253)
FIGHT248 NCT03694522 First line GEJAC, GAC Bemarituzumab + Median OS: 19.2 v 13.5 months Median PFS: 9.5 v 7.4 months 47
(2) (FGFR2b+) mFOLFOX6 (77) 0.60 (0.38 to 0.94), NA 0.68 (0.44 to 1.04), 0.073
Placebo + mFLOFOX6 33
(78)
DisTinGuish*249 NCT04363801 First line GEJAC, GAC DKN-01 + 71
(2) tislelizumab + CAPOX
(25)
ATTRACTION-3250 NCT02569242 Second line ESCC Nivolumab (210) Median OS: 10.9 v 8.4 months Median PFS: 1.7 v 3.4 months 19
(3) or later Chemotherapy (209) 0.77 (0.62 to 0.96). 0.019 1.08 (0.87 to 1.34), NA 22
KEYNOTE-181251 NCT02564263 Second line ESCC, EAC Pembrolizumab CPS >10 : 9.3 v 6.7 months CPS >10 : 2.6 v 3.0 months
(2) or later (314) 0.69 (0.52 to 0.93), 0.0074 0.73 (0.54 to 0.97), NA
ESCC: 8.2 v 7.1 months ESCC: 2.2 v 3.1 months
0.78 (0.63 to 0.96), 0.0095 0.92 (0.75 to 1.13), NA
0.89 (0.75 to 1.05), 0.0560 1.11 (0.94 to 1.31), NA
CPS >10: 22
All: 13
Chemotherapy (314) CPS >10: 6
All: 7
REGARD252 NCT00917384 Second line GEJAC, GAC Ramcirumab (238) Median OS: 5.2 v 3.8 months Median PFS: 2.1 v 1.3 months 3
(3) or later Placebo (117) 0.776 (0.603 to 0.998), 0.047 0.483 (0.376 to 0.620), <0.0001 3
RAINBOW253 NCT01170663 Second line GEJAC, GAC Ramcirumab + Median OS: 9.6 v 7.4 months Median PFS: 4.4 v 2.9 months 28
(3) or later paclitaxel (330) 0.807 (0.678 to 0.962), 0.017 0.635 (0.536 to 0.752), <0.0001
Placebo + paclitaxel 18
(335)
AdvanTIG-203254 NCT04732494 Second line ESCC Tislelizumab + Recruiting
(3) or later (PD-L1 CPS ociperlimab
>10) Placebo +
ociperlimab
DESTINY- NCT03329690 Third line GEJAC, GAC Trastuzumab Median OS: 12.5 v 8.4 months Median PFS: 5.6 v 3.5 months 51
Gastric01255 (3) or later (HER2+) Deruxtecan (125) 0.59 (0.39 to 0.88), 0.01 0.47 (0.31 to 0.71), NA
Chemotherapy (62) 14
CI=confidence interval; CLDN18.2=Claudin18.2; CPS=combined positive score; GAC=gastric adenocarcinoma; GEJAC=gastro-esophageal junction adenocarcinoma; mFOLFOX6=5-fluorouracil,
leucovorin, oxaliplatin; NA=not available; EAC=esophageal adenocarcinoma; ORR=overall/objective response rate; OS=overall survival; ESCC=esophageal squamous cell carcinoma;
PFS=progression free survival; TPS=tumor proportion score.
*The primary endpoints of overall survival and progression free survival will be assessed later in accordance with the statistical analysis plan.
more than 70% squamous cell cancer in each cohort, positive score ≥10 (median overall survival 12.6 v
and the results showed superior overall survival 9.8 months; median progression free survival 6.3 v
and progression free survival for pembrolizumab 5.8 months). More recently, the phase 3 CheckMate
plus chemotherapy compared with placebo plus 648 trial evaluated patients with advanced ESCC
chemotherapy in patients with ESCC, and combined and showed that both first line treatment with

nivolumab plus chemotherapy and nivolumab plus Biomarkers

ipilimumab, an anti-CTLA4 mAb, resulted in survival Assessment of biomarkers has improved treatment
advantage over chemotherapy alone (median selection for patients with esophageal cancer. For
overall survival: nivolumab plus chemotherapy 13.2 patients with EAC, it might be appropriate to assess
months; nivolumab plus ipilimumab 12.7 months; HER2, PDL1, MSI/MMR status, TMB-H status, RET
chemotherapy alone 10.7 months).245 fusion, BRAF mutation, and NTRK gene fusions. We
Second line treatment varies by disease type expect this list to expand in the future. Early detection
and consists of nivolumab or pembrolizumab for and intervention requires proactive measures, and
patients with squamous cell cancer patients who remains a promising area. Use of minimally invasive
are immune checkpoint blockade naive.250 251 In tests (tissue based or blood based) is promising, with
the event of PD1 blockade resistance, paclitaxel or biotechnology improving.
irinotecan can be used.256-258 For patients with EAC,
the preferred second line treatment is ramucirumab Liquid biopsy
plus paclitaxel.252 253 For patients with EAC who Liquid biopsy based analyses of circulating cell
have HER2 positivity, trastuzumab-deruxitecan is free RNA/circulating tumor DNA (cfRNA/ctDNA)
available in some regions, and might offer a survival and miRNAs hold additional promise in both EAC
benefit.255 and squamous cell cancer, predominantly for
Claudin18.2 is a novel biomarker targeted by monitoring response to treatment, and occasionally
zolbetuximab (mAb targeting Claudin18), which for identifying targetable drivers.85 100 265 This
has shown benefit in untreated advanced patients approach assesses ctDNA, circulating tumor cells,
with EAC. In the phase 3 SPOTLIGHT trial, the circulating cfRNA, extracellular vehicles, or tumor
addition of zolbetuximab to 5-fluorouracil, educated platelets, and will undoubtedly continue to
leucovorin, oxaliplatin (mFOLFOX6) prolonged expand.266-269
overall survival and progression free survival over
placebo (median overall survival 18.23 v 15.54 Treatments
months; median progression free survival 10.61 v Novel targeted treatments include antibody-drug
8.67 months).246 Another phase 3 trial (GLOW) also conjugates, bispecific or trispecific antibody, and
showed prolonged overall survival and progression bispecific T cell engager.270-272 Fam-trastuzumab
free survival of zolbetuximab plus capecitabine deruxtecan-nxki is an antibody-drug conjugate
and oxaliplatin over placebo (median overall consisting of trastuzumab and a topoisomerase I
survival 14.39 v 12.16 months; median progression inhibitor joined by a cleavable tetrapeptide based
free survival 8.21 v 6.80 months).247 Many new linker.255 Vaccines and cell treatments, with further
treatment targets are also being explored in the refinements, hold considerable promise. Future
clinic, such as FGFR2b, KRAS amplification, TIGIT, strategies should include targeting of oncoprotein
and DKK-1 (table 2).248 249 254 and immune components simultaneously.
Outside of systemic treatment, options for
symptom control include esophageal stenting, Guidelines
typically using self-expanding metal stents Throughout this review, society guidelines that
(SEMS), as well as external beam radiotherapy reflect the current standard of care are discussed.
and endoluminal brachytherapy. An international NCCN has published evidence based guidelines
multicenter randomized controlled trial showed encompassing diagnostics and treatments for the
that the addition of concurrent chemotherapy management of dysplasia, early stage esophageal
(cisplatin/5-fluorouracil) to radiotherapy (30-35 cancer, and advanced stage esophageal cancer.273
Gy in 10-15 fractions) achieved minimal added
symptom benefit compared with radiotherapy Conclusion
alone, but caused significantly more toxicity.259 Esophageal cancer, a common illness globally,
Furthermore, data from the ROCS study suggest no remains a challenge for patients, caregivers, and
benefit to maintaining swallow function from the treatment teams alike. Many opportunities exist for
use of radiotherapy in patients who have had SEMS its early detection, which could allow elimination
inserted.260 of cancer and premalignant lesions endoscopically.
Improving knowledge of molecular and immune
Emerging areas underpinnings of both ESCC and EAC has allowed us
Insights into the disease to focus on biomarkers, next generation sequencing,
Unlike traditional approaches that analyze bulk and liquid biopsy to manage these cancers more
cell populations, single cell RNA analysis provided rationally and effectively. A lack of uniform specialized
new insights into tumor heterogeneity.261 262 Small centers to treat esophageal cancer has also led to
endoscopic biopsies impose many challenges. Spatial diverse outcomes.274 A multidisciplinary approach
transcriptomic platforms provide spatial and single in developing a consensus on initial treatment
cell analyses.263 264 Emerging multiplex technologies approach might have improved recommendation
that include transcriptome and proteomics are of effective treatment in many large centers, as
likely to provide a higher level of understanding of might the availability of newly developed drugs to
esophageal cancer. prolong survival. However, access to such resources

is not uniform and needs to improve. Outcomes are JAA and WH are joint corresponding authors on this paper.
poor for most patients with esophageal cancer, and We thank Rebecca Fitzgerald for her review of and helpful comments
on an earlier draft of this manuscript.
much remains to be accomplished. Particularly, we
should avoid empiric approaches that assume that Patient involvement: No patients were involved in the writing of this
article.
all patients are alike and have disease that behaves
Competing interests: We have read and understood the BMJ policy
similarly. on declaration of interests and declare the following interests: CMJ is
Continued emphasis on detailed molecular supported by a clinical lectureship part funded by Cancer Research UK
and immunologic interrogations will improve our RadNet Cambridge. All other authors have no conflicts of interest to
declare. WH is the guarantor.
understanding of esophageal cancer, and novel but
Contributors: All authors contributed equally to the design,
rational treatments are likely to emerge. development, and writing of this manuscript. All authors
contributed to the editing process as well as the collation and
examination of the data. All authors attest and are accountable for
RESEARCH QUESTIONS the accuracy of the data that are presented and gave final approval
of the work.
• What novel approaches can be developed and implemented for the early detection
Provenance and peer review: commissioned; externally peer
of precursor lesions, such as squamous dysplasia and Barrett’s esophagus, reviewed.
considering their pivotal role in the progression to esophageal adenocarcinoma
(EAC) and esophageal squamous cell carcinoma (ESCC)? 1 Cancer Genome Atlas Research NetworkAnalysis Working
Group: Asan UniversityBC Cancer AgencyBrigham and Women’s
• What specific molecular mechanisms underlie the distinct pathophysiology of ESCC, HospitalBroad InstituteBrown UniversityCase Western Reserve
particularly regarding the interplay among somatic mutant clones? How can this UniversityDana-Farber Cancer InstituteDuke UniversityGreater
Poland Cancer CentreHarvard Medical SchoolInstitute for
knowledge be leveraged to identify treatment targets?
Systems BiologyKU LeuvenMayo ClinicMemorial Sloan Kettering
• Given the associations of ESCC with alcohol use and tylosis, and those of EAC Cancer CenterNational Cancer InstituteNationwide Children’s
with obesity and gastro-esophageal reflux, what targeted prevention and HospitalStanford UniversityUniversity of AlabamaUniversity
of MichiganUniversity of North CarolinaUniversity of
chemoprevention strategies, including the use of proton pump inhibitors and PittsburghUniversity of RochesterUniversity of Southern
non-steroidal anti-inflammatory drugs, can be developed to mitigate the risk and CaliforniaUniversity of Texas MD Anderson Cancer CenterUniversity
progression of these subtypes? of WashingtonVan Andel Research InstituteVanderbilt
UniversityWashington UniversityGenome Sequencing Center:
• In the context of locally advanced esophageal cancer, how can the current treatment Broad InstituteWashington University in St LouisGenome
modalities, including neoadjuvant chemotherapy, chemoradiotherapy, and Characterization Centers: BC Cancer AgencyBroad InstituteHarvard
immunotherapy, be optimized for improved outcomes? Medical SchoolSidney Kimmel Comprehensive Cancer Center at
Johns Hopkins UniversityUniversity of North CarolinaUniversity
of Southern California Epigenome CenterUniversity of Texas MD
Anderson Cancer CenterVan Andel Research InstituteGenome Data
Analysis Centers: Broad InstituteBrown UniversityHarvard Medical
GLOSSARY OF ABBREVIATIONS SchoolInstitute for Systems BiologyMemorial Sloan Kettering
Cancer CenterUniversity of California Santa CruzUniversity of
• EAC: esophageal adenocarcinoma Texas MD Anderson Cancer CenterBiospecimen Core Resource:
• ESCC: esophageal squamous cell carcinoma International Genomics ConsortiumResearch Institute at
Nationwide Children’s HospitalTissue Source Sites: Analytic Biologic
• GERD: gastro-esophageal reflux disease ServicesAsan Medical CenterAsterand BioscienceBarretos Cancer
• NCCN: National Comprehensive Cancer Network HospitalBioreclamationIVTBotkin Municipal ClinicChonnam National
• NDBE: non-dysplastic Barrett’s esophagus University Medical SchoolChristiana Care Health SystemCurelineDuke
UniversityEmory UniversityErasmus UniversityIndiana University
• SNVs/Mb: single nucleotide variants per megabase School of MedicineInstitute of Oncology of MoldovaInternational
• APOBEC: apolipoprotein B mRNA editing enzyme, catalytic polypeptide Genomics ConsortiumInvidumedIsraelitisches Krankenhaus
• ecDNA: extrachromosomal DNA HamburgKeimyung University School of MedicineMemorial Sloan
Kettering Cancer CenterNational Cancer Center GoyangOntario
• PARP: poly ADP ribose polymerase Tumour BankPeter MacCallum Cancer CentrePusan National
• miRNA: microRNA University Medical SchoolRibeirão Preto Medical SchoolSt Joseph’s
• lncRNA: long non-coding RNA Hospital &Medical CenterSt Petersburg Academic UniversityTayside
Tissue BankUniversity of DundeeUniversity of Kansas Medical
• cfDNA: cell free DNA CenterUniversity of MichiganUniversity of North Carolina at
• TFF3: trefoil factor 3 Chapel HillUniversity of Pittsburgh School of MedicineUniversity of
Texas MD Anderson Cancer CenterDisease Working Group: Duke
• PDL1: programmed death ligand 1 UniversityMemorial Sloan Kettering Cancer CenterNational Cancer
• PET-CT: positron emission tomography-computed tomography InstituteUniversity of Texas MD Anderson Cancer CenterYonsei
• DCF: docetaxel, cisplatin, fluorouracil University College of MedicineData Coordination Center: CSRA
IncProject Team: National Institutes of Health. Integrated genomic
• ECF: epirubicin, cisplatin, fluorouracil characterization of oesophageal carcinoma. Nature 2017;541:169-
• CF: cisplatin, fluorouracil 75. doi:10.1038/nature20805
• FLOT: fluorouracil, leucovorin, oxaliplatin, docetaxel 2 Njei B, McCarty TR, Birk JW. Trends in esophageal cancer survival in
United States adults from 1973 to 2009: A SEER database analysis. J
• IMRT: intensity modulated radiation therapy Gastroenterol Hepatol 2016;31:1141-6. doi:10.1111/jgh.13289
• HMIE: hybrid minimally invasive esophagectomy 3 GBD 2017 Oesophageal Cancer Collaborators. The global, regional,
and national burden of oesophageal cancer and its attributable risk
• RAMIE: robotic assisted minimally invasive esophagectomy factors in 195 countries and territories, 1990-2017: a systematic
• ERATS: enhanced recovery after thoracoscopic surgery analysis for the Global Burden of Disease Study 2017. Lancet
• PROM: patient reported outcome measure Gastroenterol Hepatol 2020;5:582-97. doi:10.1016/S2468-
1253(20)30007-8
• mAb: monoclonal antibody 4 Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020:
• PD1: programmed cell death protein 1 GLOBOCAN estimates of incidence and mortality worldwide for
• mFOLFOX6: 5-fluorouracil, leucovorin, oxaliplatin 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.
doi:10.3322/caac.21660
• SEMS: self-expanding metal stents 5 Arnold M, Ferlay J, van Berge Henegouwen MI, Soerjomataram I.
• cfRNA: circulating cell free RNA Global burden of oesophageal and gastric cancer by histology
• ctDNA: circulating tumor DNA and subsite in 2018. Gut 2020;69:1564-71. doi:10.1136/
gutjnl-2020-321600

6 Morgan E, Soerjomataram I, Rumgay H, et al. The global landscape of 29 Curtius K, Rubenstein JH, Chak A, Inadomi JM. Computational
esophageal squamous cell carcinoma and esophageal adenocarcinoma modelling suggests that Barrett’s oesophagus may be the precursor
incidence and mortality in 2020 and projections to 2040: new of all oesophageal adenocarcinomas. Gut 2020;70:1435-40.
estimates from GLOBOCAN 2020. Gastroenterology 2022;163:649- doi:10.1136/gutjnl-2020-321598
658.e2. doi:10.1053/j.gastro.2022.05.054 30 McDonald SA, Graham TA, Lavery DL, Wright NA, Jansen M.
7 Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of The Barrett’s gland in phenotype space. Cell Mol Gastroenterol
the esophagus among white Americans by sex, stage, and age. J Natl Hepatol 2014;1:41-54. doi:10.1016/j.jcmgh.2014.10.001
Cancer Inst 2008;100:1184-7. doi:10.1093/jnci/djn211 31 Quante M, Bhagat G, Abrams JA, et al. Bile acid and inflammation
8 Sun D, Liu C, Zhu Y, et al, China Kadoorie Biobank Collaborative activate gastric cardia stem cells in a mouse model of Barrett-
Group. Long-term exposure to fine particulate matter and incidence like metaplasia. Cancer Cell 2012;21:36-51. doi:10.1016/j.
of esophageal cancer: a prospective study of 0.5 million Chinese ccr.2011.12.004
adults. Gastroenterology 2023;165:61-70.e5. doi:10.1053/j. 32 Hutchinson L, Stenstrom B, Chen D, et al. Human Barrett’s
gastro.2023.03.233 adenocarcinoma of the esophagus, associated myofibroblasts,
9 Petrelli F, De Santi G, Rampulla V, et al. Human papillomavirus and endothelium can arise from bone marrow-derived cells after
(HPV) types 16 and 18 infection and esophageal squamous cell allogeneic stem cell transplant. Stem Cells Dev 2011;20:11-7.
carcinoma: a systematic review and meta-analysis. J Cancer Res Clin doi:10.1089/scd.2010.0139
Oncol 2021;147:3011-23. doi:10.1007/s00432-021-03738-9 33 Minacapelli CD, Bajpai M, Geng X, et al. Barrett’s metaplasia develops
10 Ludmir EB, Stephens SJ, Palta M, Willett CG, Czito BG. Human from cellular reprograming of esophageal squamous epithelium
papillomavirus tumor infection in esophageal squamous cell due to gastroesophageal reflux. Am J Physiol Gastrointest Liver
carcinoma. J Gastrointest Oncol 2015;6:287-95. doi:10.3978/j. Physiol 2017;312:G615-22. doi:10.1152/ajpgi.00268.2016
issn.2078-6891.2015.001 34 Liu Y, Sethi NS, Hinoue T, et al, Cancer Genome Atlas Research
11 Domper Arnal MJ, Ferrández Arenas Á, Lanas Arbeloa Á. Esophageal Network. Comparative molecular analysis of gastrointestinal
cancer: Risk factors, screening and endoscopic treatment in Western adenocarcinomas. Cancer Cell 2018;33:721-735.e8. doi:10.1016/j.
and Eastern countries. World J Gastroenterol 2015;21:7933-43. ccell.2018.03.010
doi:10.3748/wjg.v21.i26.7933 35 Li X, Galipeau PC, Paulson TG, et al. Temporal and spatial evolution
12 Martincorena I, Fowler JC, Wabik A, et al. Somatic mutant clones of somatic chromosomal alterations: a case-cohort study of
colonize the human esophagus with age. Science 2018;362:911-7. Barrett’s esophagus. Cancer Prev Res (Phila) 2014;7:114-27.
doi:10.1126/science.aau3879 doi:10.1158/1940-6207.CAPR-13-0289
13 Yokoyama A, Kakiuchi N, Yoshizato T, et al. Age-related 36 Ross-Innes CS, Becq J, Warren A, et al. Whole-genome
remodelling of oesophageal epithelia by mutated cancer drivers. sequencing provides new insights into the clonal architecture
Nature 2019;565:312-7. doi:10.1038/s41586-018-0811-x of Barrett’s esophagus and esophageal adenocarcinoma. Nat
14 Colom B, Herms A, Hall MWJ, et al. Mutant clones in normal Genet 2015;47:1038-46. doi:10.1038/ng.3357
epithelium outcompete and eliminate emerging tumours. 37 Hvid-Jensen F, Pedersen L, Drewes AM, Sørensen HT, Funch-Jensen P.
Nature 2021;598:510-4. doi:10.1038/s41586-021-03965-7 Incidence of adenocarcinoma among patients with Barrett’s
15 Colom B, Alcolea MP, Piedrafita G, et al. Spatial competition shapes esophagus. N Engl J Med 2011;365:1375-83. doi:10.1056/
the dynamic mutational landscape of normal esophageal epithelium. NEJMoa1103042
Nat Genet 2020;52:604-14. doi:10.1038/s41588-020-0624-3 38 Bhat S, Coleman HG, Yousef F, et al. Risk of malignant progression in
16 Abby E, Dentro SC, Hall MWJ, et al. Notch1 mutations drive clonal Barrett’s esophagus patients: results from a large population-based
expansion in normal esophageal epithelium but impair tumor growth. study. J Natl Cancer Inst 2011;103:1049-57. doi:10.1093/jnci/
Nat Genet 2023;55:232-45. doi:10.1038/s41588-022-01280-z djr203
17 Dawsey SM, Lewin KJ, Wang GQ, et al. Squamous esophageal 39 Peters Y, Honing J, Kievit W, et al. Incidence of progression of
histology and subsequent risk of squamous cell carcinoma of persistent nondysplastic Barrett’s esophagus to malignancy. Clin
the esophagus. A prospective follow-up study from Linxian, Gastroenterol Hepatol 2019;17:869-877.e5. doi:10.1016/j.
China. Cancer 1994;74:1686-92. doi:10.1002/1097- cgh.2018.08.033
0142(19940915)74:6<1686::AID-CNCR2820740608>3.0.CO;2-V 40 Stachler MD, Taylor-Weiner A, Peng S, et al. Paired exome analysis of
18 Wang JW, Guan CT, Wang LL, et al. Natural history analysis of Barrett’s esophagus and adenocarcinoma. Nat Genet 2015;47:1047-
101 severe dysplasia and esophageal carcinoma cases by 55. doi:10.1038/ng.3343
endoscopy. Gastroenterol Res Pract 2017;2017:9612854. 41 Killcoyne S, Gregson E, Wedge DC, et al. Genomic copy number
doi:10.1155/2017/9612854 predicts esophageal cancer years before transformation. Nat
19 Liao G, Dai N, Xiong T, et al. Single-cell transcriptomics provides Med 2020;26:1726-32. doi:10.1038/s41591-020-1033-y
insights into the origin and microenvironment of human oesophageal 42 Killcoyne S, Fitzgerald RC. Evolution and progression of Barrett’s
high-grade intraepithelial neoplasia. Clin Transl Med 2022;12:e874. oesophagus to oesophageal cancer. Nat Rev Cancer 2021;21:731-
doi:10.1002/ctm2.874 41. doi:10.1038/s41568-021-00400-x
20 Wu C, Kraft P, Zhai K, et al. Genome-wide association analyses 43 Alexandrov LB, Nik-Zainal S, Wedge DC, et al, Australian Pancreatic
of esophageal squamous cell carcinoma in Chinese identify Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-
multiple susceptibility loci and gene-environment interactions. Nat Seq ConsortiumICGC PedBrain. Signatures of mutational processes
Genet 2012;44:1090-7. doi:10.1038/ng.2411 in human cancer. Nature 2013;500:415-21. doi:10.1038/
21 Hashibe M, McKay JD, Curado MP, et al. Multiple ADH genes nature12477
are associated with upper aerodigestive cancers. Nat 44 Li M, Zhang Z, Wang Q, Yi Y, Li B. Integrated cohort of esophageal
Genet 2008;40:707-9. doi:10.1038/ng.151 squamous cell cancer reveals genomic features underlying clinical
22 Blaydon DC, Etheridge SL, Risk JM, et al. RHBDF2 mutations are characteristics. Nat Commun 2022;13:5268. doi:10.1038/s41467-
associated with tylosis, a familial esophageal cancer syndrome. Am J 022-32962-1
Hum Genet 2012;90:340-6. doi:10.1016/j.ajhg.2011.12.008 45 Chen Y, Zhu S, Liu T, et al. Epithelial cells activate fibroblasts to
23 Lindor NM, McMaster ML, Lindor CJ, et al. Concise handbook of promote esophageal cancer development. Cancer Cell 2023;41:903-
familial cancer susceptibility syndromes. 2nd ed. J Natl Cancer Inst 918.e8. doi:10.1016/j.ccell.2023.03.001
Monogr, 2008: 1-93, doi:10.1093/jncimonographs/lgn001 46 Zheng Y, Chen Z, Han Y, et al. Immune suppressive landscape in the
24 Dulai GS, Guha S, Kahn KL, Gornbein J, Weinstein WM. Preoperative human esophageal squamous cell carcinoma microenvironment. Nat
prevalence of Barrett’s esophagus in esophageal adenocarcinoma: a Commun 2020;11:6268. doi:10.1038/s41467-020-20019-0
systematic review. Gastroenterology 2002;122:26-33. doi:10.1053/ 47 Cui S, McGranahan N, Gao J, et al. Tracking the evolution of
gast.2002.30297 esophageal squamous cell carcinoma under dynamic immune
25 Bhat SK, McManus DT, Coleman HG, et al. Oesophageal selection by multi-omics sequencing. Nat Commun 2023;14:892.
adenocarcinoma and prior diagnosis of Barrett’s oesophagus: doi:10.1038/s41467-023-36558-1
a population-based study. Gut 2015;64:20-5. doi:10.1136/ 48 Tsukamoto S, Koma YI, Kitamura Y, et al. Matrix metalloproteinase
gutjnl-2013-305506 9 induced in esophageal squamous cell carcinoma cells via close
26 Sawas T, Killcoyne S, Iyer PG, et al, OCCAMS Consortium. Identification contact with tumor-associated macrophages contributes to cancer
of prognostic phenotypes of esophageal adenocarcinoma in 2 progression and poor prognosis. Cancers (Basel) 2023;15:2987.
independent cohorts. Gastroenterology 2018;155:1720-1728.e4. doi:10.3390/cancers15112987
doi:10.1053/j.gastro.2018.08.036 49 Shao D, Vogtmann E, Liu A, et al. Microbial characterization
27 Nowicki-Osuch K, Zhuang L, Cheung TS, et al. Single-cell RNA of esophageal squamous cell carcinoma and gastric
sequencing unifies developmental programs of esophageal and cardia adenocarcinoma from a high-risk region of China.
gastric intestinal metaplasia. Cancer Discov 2023;13:1346-63. Cancer 2019;125:3993-4002. doi:10.1002/cncr.32403
doi:10.1158/2159-8290.CD-22-0824 50 Gao S, Li S, Ma Z, et al. Presence of Porphyromonas gingivalis
28 Nowicki-Osuch K, Zhuang L, Jammula S, et al. Molecular phenotyping in esophagus and its association with the clinicopathological
reveals the identity of Barrett’s esophagus and its malignant characteristics and survival in patients with esophageal cancer. Infect
transition. Science 2021;373:760-7. doi:10.1126/science.abd1449 Agent Cancer 2016;11:3. doi:10.1186/s13027-016-0049-x

51 Newell F, Patel K, Gartside M, et al. Complex structural 72 Ko KP, Huang Y, Zhang S, et al. Key genetic determinants driving
rearrangements are present in high-grade dysplastic Barrett’s esophageal squamous cell carcinoma initiation and immune
oesophagus samples. BMC Med Genomics 2019;12:31. evasion. Gastroenterology 2023;165:613-628.e20. doi:10.1053/j.
doi:10.1186/s12920-019-0476-9 gastro.2023.05.030
52 Sharpe BP, Hayden A, Manousopoulou A, et al. Phosphodiesterase 73 Martinez P, Timmer MR, Lau CT, et al. Dynamic clonal equilibrium
type 5 inhibitors enhance chemotherapy in preclinical models and predetermined cancer risk in Barrett’s oesophagus. Nat
of esophageal adenocarcinoma by targeting cancer-associated Commun 2016;7:12158. doi:10.1038/ncomms12158
fibroblasts. Cell Rep Med 2022;3:100541. doi:10.1016/j. 74 Stachler MD, Bao C, Tourdot RW, et al. Genomic
xcrm.2022.100541 signatures of past and present chromosomal instability
53 Lind A, Siersema PD, Kusters JG, Van der Linden JAM, Knol EF, in the evolution of Barrett’s esophagus to esophageal
Koenderman L. The immune cell composition in Barrett’s adenocarcinoma.bioRxiv 2023:2021.03.26.437288.
metaplastic tissue resembles that in normal duodenal tissue. PLoS doi:10.1101/2021.03.26.437288
One 2012;7:e33899. doi:10.1371/journal.pone.0033899 75 Douville C, Moinova HR, Thota PN, et al. Massively parallel
54 Strasser M, Gibbs DL, Gascard P, et al. Concerted epithelial and sequencing of esophageal brushings enables an aneuploidy-
stromal changes during progression of Barrett’s Esophagus based classification of patients with barrett’s esophagus.
to invasive adenocarcinoma exposed by multi-scale, Gastroenterology 2021;160:2043-2054.e2. doi:10.1053/j.
multi-omics analysis.bioRxiv 2023:2023.06.08.544265. gastro.2021.01.209
doi:10.1101/2023.06.08.544265 76 Weaver JMJ, Ross-Innes CS, Shannon N, et al, OCCAMS consortium.
55 Lind A, Siersema PD, Kusters JG, Konijn T, Mebius RE, Koenderman L. Ordering of mutations in preinvasive disease stages of esophageal
The microenvironment in Barrett’s esophagus tissue is characterized carcinogenesis. Nat Genet 2014;46:837-43. doi:10.1038/
by high FOXP3 and RALDH2 levels. Front Immunol 2018;9:1375. ng.3013
doi:10.3389/fimmu.2018.01375 77 Dulak AM, Stojanov P, Peng S, et al. Exome and whole-genome
56 Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliott M, Saeed IT, Burnham WR, sequencing of esophageal adenocarcinoma identifies recurrent driver
Farthing MJG. Diversity in the oesophageal phenotypic response events and mutational complexity. Nat Genet 2013;45:478-86.
to gastro-oesophageal reflux: immunological determinants. doi:10.1038/ng.2591
Gut 2002;50:451-9. doi:10.1136/gut.50.4.451 78 Fitzgerald RC, di Pietro M, Ragunath K, et al, British Society of
57 Sundaram S, Kim EN, Jones GM, et al. Deciphering the immune Gastroenterology. British Society of Gastroenterology guidelines
complexity in esophageal adenocarcinoma and pre-cancerous on the diagnosis and management of Barrett’s oesophagus.
lesions with sequential multiplex immunohistochemistry and sparse Gut 2014;63:7-42. doi:10.1136/gutjnl-2013-305372
subspace clustering approach. Front Immunol 2022;13:874255. 79 Luebeck J, Ng AWT, Galipeau PC, et al. Extrachromosomal
doi:10.3389/fimmu.2022.874255 DNA in the cancerous transformation of Barrett’s oesophagus.
58 Lagisetty KH, McEwen DP, Nancarrow DJ, et al. Immune Nature 2023;616:798-805. doi:10.1038/s41586-023-05937-5
determinants of Barrett’s progression to esophageal 80 Schröder J, Chegwidden L, Maj C, et al, Wellcome Trust Case Control
adenocarcinoma. JCI Insight 2021;6:e143888. doi:10.1172/jci. Consortium 2 (WTCCC2)Esophageal Adenocarcinoma Genetics
insight.143888 Consortium (EAGLE)Barrett’s and Esophageal Adenocarcinoma
59 M Naeini M, Newell F, Aoude LG, et al. Multi-omic features of Consortium (BEACON). GWAS meta-analysis of 16 790 patients with
oesophageal adenocarcinoma in patients treated with preoperative Barrett’s oesophagus and oesophageal adenocarcinoma identifies
neoadjuvant therapy. Nat Commun 2023;14:3155. doi:10.1038/ 16 novel genetic risk loci and provides insights into disease aetiology
s41467-023-38891-x beyond the single marker level. Gut 2023;72:612-23. doi:10.1136/
60 Derks S, de Klerk LK, Xu X, et al. Characterizing diversity in the gutjnl-2021-326698
tumor-immune microenvironment of distinct subclasses of 81 Secrier M, Li X, de Silva N, et al, Oesophageal Cancer Clinical and
gastroesophageal adenocarcinomas. Ann Oncol 2020;31:1011-20. Molecular Stratification (OCCAMS) Consortium. Mutational signatures
doi:10.1016/j.annonc.2020.04.011 in esophageal adenocarcinoma define etiologically distinct
61 Elliott DRF, Walker AW, O’Donovan M, Parkhill J, Fitzgerald RC. A subgroups with therapeutic relevance. Nat Genet 2016;48:1131-41.
non-endoscopic device to sample the oesophageal microbiota: a doi:10.1038/ng.3659
case-control study. Lancet Gastroenterol Hepatol 2017;2:32-42. 82 Frankell AM, Jammula S, Li X, et al, Oesophageal Cancer Clinical and
doi:10.1016/S2468-1253(16)30086-3 Molecular Stratification (OCCAMS) Consortium. The landscape of
62 Snider EJ, Compres G, Freedberg DE, et al. Alterations to the selection in 551 esophageal adenocarcinomas defines genomic
esophageal microbiome associated with progression from Barrett’s biomarkers for the clinic. Nat Genet 2019;51:506-16. doi:10.1038/
esophagus to esophageal adenocarcinoma. Cancer Epidemiol s41588-018-0331-5
Biomarkers Prev 2019;28:1687-93. doi:10.1158/1055-9965.EPI- 83 Mourikis TP, Benedetti L, Foxall E, et al, Oesophageal Cancer Clinical
19-0008 and Molecular Stratification (OCCAMS) Consortium. Patient-specific
63 Liu X, Zhang M, Ying S, et al. Genetic alterations in cancer genes contribute to recurrently perturbed pathways and
esophageal tissues from squamous dysplasia to carcinoma. establish therapeutic vulnerabilities in esophageal adenocarcinoma.
Gastroenterology 2017;153:166-77. doi:10.1053/j. Nat Commun 2019;10:3101. doi:10.1038/s41467-019-10898-3
gastro.2017.03.033 84 Ishii T, Murakami J, Notohara K, et al. Oesophageal squamous cell
64 Chen XX, Zhong Q, Liu Y, et al. Genomic comparison of esophageal carcinoma may develop within a background of accumulating DNA
squamous cell carcinoma and its precursor lesions by multi-region methylation in normal and dysplastic mucosa. Gut 2007;56:13-9.
whole-exome sequencing. Nat Commun 2017;8:524. doi:10.1038/ doi:10.1136/gut.2005.089813
s41467-017-00650-0 85 Qin Y, Wu CW, Taylor WR, et al. Discovery, validation, and application
65 Agrawal N, Jiao Y, Bettegowda C, et al. Comparative genomic analysis of novel methylated DNA markers for detection of esophageal cancer
of esophageal adenocarcinoma and squamous cell carcinoma. in plasma. Clin Cancer Res 2019;25:7396-404. doi:10.1158/1078-
Cancer Discov 2012;2:899-905. doi:10.1158/2159-8290.CD-12- 0432.CCR-19-0740
0189 86 Yu Q, Xia N, Zhao Y, et al. Genome-wide methylation profiling
66 Song Y, Li L, Ou Y, et al. Identification of genomic alterations in identify hypermethylated HOXL subclass genes as potential markers
oesophageal squamous cell cancer. Nature 2014;509:91-5. for esophageal squamous cell carcinoma detection. BMC Med
doi:10.1038/nature13176 Genomics 2022;15:247. doi:10.1186/s12920-022-01401-x
67 Lin DC, Hao JJ, Nagata Y, et al. Genomic and molecular 87 Hoshimoto S, Takeuchi H, Ono S, et al. Genome-wide
characterization of esophageal squamous cell carcinoma. Nat hypomethylation and specific tumor-related gene hypermethylation
Genet 2014;46:467-73. doi:10.1038/ng.2935 are associated with esophageal squamous cell carcinoma
68 Gao YB, Chen ZL, Li JG, et al. Genetic landscape of esophageal outcome. J Thorac Oncol 2015;10:509-17. doi:10.1097/
squamous cell carcinoma. Nat Genet 2014;46:1097-102. JTO.0000000000000441
doi:10.1038/ng.3076 88 Kawano H, Saeki H, Kitao H, et al. Chromosomal instability associated
69 Zhang L, Zhou Y, Cheng C, et al. Genomic analyses reveal mutational with global DNA hypomethylation is associated with the initiation
signatures and frequently altered genes in esophageal squamous and progression of esophageal squamous cell carcinoma. Ann Surg
cell carcinoma. Am J Hum Genet 2015;96:597-611. doi:10.1016/j. Oncol 2014;21(Suppl 4):S696-702. doi:10.1245/s10434-014-
ajhg.2015.02.017 3818-z
70 Cheng C, Zhou Y, Li H, et al. Whole-genome sequencing reveals 89 Ma K, Cao B, Guo M. The detective, prognostic, and predictive value
diverse models of structural variations in esophageal squamous of DNA methylation in human esophageal squamous cell carcinoma.
cell carcinoma. Am J Hum Genet 2016;98:256-74. doi:10.1016/j. Clin Epigenetics 2016;8:43. doi:10.1186/s13148-016-0210-9
ajhg.2015.12.013 90 Yun T, Liu Y, Gao D, et al. Methylation of CHFR sensitizes esophageal
71 Deng J, Chen H, Zhou D, et al. Comparative genomic analysis of squamous cell cancer to docetaxel and paclitaxel. Genes
esophageal squamous cell carcinoma between Asian and Caucasian Cancer 2015;6:38-48. doi:10.18632/genesandcancer.46
patient populations. Nat Commun 2017;8:1533. doi:10.1038/ 91 Iwagami S, Baba Y, Watanabe M, et al. LINE-1 hypomethylation
s41467-017-01730-x is associated with a poor prognosis among patients with

curatively resected esophageal squamous cell carcinoma. Ann 112 Han J, Guo X, Zhao L, et al. Development and validation of esophageal
Surg 2013;257:449-55. doi:10.1097/SLA.0b013e31826d8602 squamous cell carcinoma risk prediction models based on an
92 Yuan Y, Wang Q, Cao F, Han B, Xu L. MiRNA-134 suppresses endoscopic screening program. JAMA Netw Open 2023;6:e2253148.
esophageal squamous cell carcinoma progression by targeting doi:10.1001/jamanetworkopen.2022.53148
FOXM1. Int J Clin Exp Pathol 2019;12:2130-8. 113 Fitzgerald RC, di Pietro M, O’Donovan M, et al, BEST3 Trial team.
93 Harada K, Baba Y, Ishimoto T, et al. The role of microRNA in Cytosponge-trefoil factor 3 versus usual care to identify Barrett’s
esophageal squamous cell carcinoma. J Gastroenterol 2016;51:520- oesophagus in a primary care setting: a multicentre, pragmatic,
30. doi:10.1007/s00535-016-1161-9 randomised controlled trial. Lancet 2020;396:333-44. doi:10.1016/
94 Rogerson C, Britton E, Withey S, Hanley N, Ang YS, Sharrocks AD. S0140-6736(20)31099-0
Identification of a primitive intestinal transcription factor network 114 Gao Y, Xin L, Lin H, et al. Machine learning-based automated
shared between esophageal adenocarcinoma and its precancerous sponge cytology for screening of oesophageal squamous cell
precursor state. Genome Res 2019;29:723-36. doi:10.1101/ carcinoma and adenocarcinoma of the oesophagogastric junction:
gr.243345.118 a nationwide, multicohort, prospective study. Lancet Gastroenterol
95 Rogerson C, Ogden S, Britton E, Ang Y, Sharrocks AD, OCCAMS Hepatol 2023;8:432-45. doi:10.1016/S2468-1253(23)00004-3
Consortium. Repurposing of KLF5 activates a cell cycle signature 115 Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV, CCGA
during the progression from a precursor state to oesophageal Consortium. Sensitive and specific multi-cancer detection and
adenocarcinoma. Elife 2020;9:e57189. doi:10.7554/eLife.57189 localization using methylation signatures in cell-free DNA. Ann
96 Krause L, Nones K, Loffler KA, et al. Identification of the CIMP-like Oncol 2020;31:745-59. doi:10.1016/j.annonc.2020.02.011
subtype and aberrant methylation of members of the chromosomal 116 Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted
segregation and spindle assembly pathways in esophageal methylation-based multi-cancer early detection test using an
adenocarcinoma. Carcinogenesis 2016;37:356-65. doi:10.1093/ independent validation set. Ann Oncol 2021;32:1167-77.
carcin/bgw018 doi:10.1016/j.annonc.2021.05.806
97 Jammula S, Katz-Summercorn AC, Li X, et al, Oesophageal Cancer 117 Jankowski JAZ, de Caestecker J, Love SB, et al, AspECT Trial Team.
Clinical and Molecular Stratification (OCCAMS) consortium. Esomeprazole and aspirin in Barrett’s oesophagus (AspECT): a
Identification of subtypes of Barrett’s esophagus and esophageal randomised factorial trial. Lancet 2018;392:400-8. doi:10.1016/
adenocarcinoma based on DNA methylation profiles and integration of S0140-6736(18)31388-6
transcriptome and genome data. Gastroenterology 2020;158:1682- 118 Qumseya BJ, Wani S, Gendy S, Harnke B, Bergman JJ, Wolfsen H.
1697.e1. doi:10.1053/j.gastro.2020.01.044 Disease progression in Barrett’s low-grade dysplasia with
98 Yu M, Moinova HR, Willbanks A, et al. Novel DNA methylation radiofrequency ablation compared with surveillance: systematic
biomarker panel for detection of esophageal adenocarcinoma review and meta-analysis. Am J Gastroenterol 2017;112:849-65.
and high-grade dysplasia. Clin Cancer Res 2022;28:3761-9. doi:10.1038/ajg.2017.70
doi:10.1158/1078-0432.CCR-22-0445 119 Knabe M, Wetzka J, Welsch L, et al. Radiofrequency ablation
99 Moinova HR, LaFramboise T, Lutterbaugh JD, et al. Identifying DNA versus hybrid argon plasma coagulation in Barrett’s esophagus:
methylation biomarkers for non-endoscopic detection of Barrett’s a prospective randomised trial. Surg Endosc 2023;37:7803-11.
esophagus. Sci Transl Med 2018;10:eaao5848. doi:10.1126/ doi:10.1007/s00464-023-10313-5
scitranslmed.aao5848 120 Thota PN, Arora Z, Dumot JA, et al. Cryotherapy and radiofrequency
100 Clark RJ, Craig MP, Agrawal S, Kadakia M. microRNA involvement ablation for eradication of Barrett’s esophagus with dysplasia or
in the onset and progression of Barrett’s esophagus: a intramucosal cancer. Dig Dis Sci 2018;63:1311-9. doi:10.1007/
systematic review. Oncotarget 2018;9:8179-96. doi:10.18632/ s10620-018-5009-4
oncotarget.24145 121 Participants in the Paris Workshop. The Paris endoscopic
101 Maag JLV, Fisher OM, Levert-Mignon A, et al. Novel aberrations classification of superficial neoplastic lesions: esophagus,
uncovered in Barrett’s esophagus and esophageal adenocarcinoma stomach, and colon: November 30 to December 1, 2002.
using whole transcriptome sequencing. Mol Cancer Gastrointest Endosc 2003;58(Suppl):S3-43. doi:10.1016/S0016-
Res 2017;15:1558-69. doi:10.1158/1541-7786.MCR-17-0332 5107(03)02159-X
102 Shaheen NJ, Falk GW, Iyer PG, et al. Diagnosis and management 122 Cen P, Hofstetter WL, Correa AM, et al. Lymphovascular invasion
of Barrett’s esophagus: an updated ACG guideline. Am as a tool to further subclassify T1b esophageal adenocarcinoma.
J Gastroenterol 2022;117:559-87. doi:10.14309/ Cancer 2008;112:1020-7. doi:10.1002/cncr.23265
ajg.0000000000001680 123 Badreddine RJ, Prasad GA, Lewis JT, et al. Depth of submucosal
103 Fitzgerald RC, Saeed IT, Khoo D, Farthing MJ, Burnham WR. Rigorous invasion does not predict lymph node metastasis and survival
surveillance protocol increases detection of curable cancers of patients with esophageal carcinoma. Clin Gastroenterol
associated with Barrett’s esophagus. Dig Dis Sci 2001;46:1892-8. Hepatol 2010;8:248-53. doi:10.1016/j.cgh.2009.11.016
doi:10.1023/A:1010678913481 124 Terheggen G, Horn EM, Vieth M, et al. A randomised trial of
104 Verbeek RE, Leenders M, Ten Kate FJ, et al. Surveillance of Barrett’s endoscopic submucosal dissection versus endoscopic mucosal
esophagus and mortality from esophageal adenocarcinoma: a resection for early Barrett’s neoplasia. Gut 2017;66:783-93.
population-based cohort study. Am J Gastroenterol 2014;109:1215- doi:10.1136/gutjnl-2015-310126
22. doi:10.1038/ajg.2014.156 125 Pouw R, Nieuwenhuis E, Jansen M, et al. 300. Endoscopic
105 Qu JY, Li Y, Liu GQ, et al. Optimal concentration of Lugol’s solution for follow-up of radically resected submucosal esophageal
detecting early esophageal carcinoma: A randomized controlled trial. adenocarcinoma: preliminary results of an ongoing prospective,
J Gastroenterol Hepatol 2023;38:962-9. doi:10.1111/jgh.16190 international, multicenter cohort registry (PREFER trial). Dis
106 Wang XY, Liu SZ, Xu HF, et al. A cluster randomized controlled trial to Esophagus 2023;36:44-5. doi:10.1093/dote/doad052.126
evaluate the efficacy of esophageal and gastric cancer screening in 126 Akutsu Y, Kato K, Igaki H, et al. the prevalence of overall
mortality reduction in a non-high-incidence area: methodology and and initial lymph node metastases in clinical T1N0 thoracic
initial results. Ann Transl Med 2022;10:994. doi:10.21037/atm-22- esophageal cancer: from the results of JCOG0502, a prospective
4052 multicenter study. Ann Surg 2016;264:1009-15. doi:10.1097/
107 Gabriëls RY, van Heijst LE, Hooghiemstra WTR, et al. Detection SLA.0000000000001557
of early esophageal neoplastic Barrett lesions with quantified 127 Sgourakis G, Gockel I, Lang H. Endoscopic and surgical resection
fluorescence molecular endoscopy using Cetuximab-800CW. J Nucl of T1a/T1b esophageal neoplasms: a systematic review. World J
Med 2023;64:803-8. doi:10.2967/jnumed.122.264656 Gastroenterol 2013;19:1424-37. doi:10.3748/wjg.v19.i9.1424
108 van Munster SN, Leclercq P, Haidry R, et al. Wide-area 128 Guo HM, Zhang XQ, Chen M, Huang SL, Zou XP. Endoscopic
transepithelial sampling with computer-assisted analysis to submucosal dissection vs endoscopic mucosal resection for
detect high grade dysplasia and cancer in Barrett’s esophagus: superficial esophageal cancer. World J Gastroenterol 2014;20:5540-
a multicenter randomized study. Endoscopy 2023;55:303-10. 7. doi:10.3748/wjg.v20.i18.5540
doi:10.1055/a-1949-9542 129 Minashi K, Nihei K, Mizusawa J, et al. Efficacy of endoscopic
109 Pilonis ND, Killcoyne S, Tan WK, et al. Use of a Cytosponge biomarker resection and selective chemoradiotherapy for stage I esophageal
panel to prioritise endoscopic Barrett’s oesophagus surveillance: squamous cell carcinoma. Gastroenterology 2019;157:382-390.e3.
a cross-sectional study followed by a real-world prospective doi:10.1053/j.gastro.2019.04.017
pilot. Lancet Oncol 2022;23:270-8. doi:10.1016/S1470- 130 Pisula JI, Datta RR, Valdez LB, et al. Predicting the HER2 status in
2045(21)00667-7 oesophageal cancer from tissue microarrays using convolutional
110 Rumiato E, Boldrin E, Malacrida S, et al. Detection of genetic neural networks. Br J Cancer 2023;128:1369-76. doi:10.1038/
alterations in cfDNA as a possible strategy to monitor the neoplastic s41416-023-02143-y
progression of Barrett’s esophagus. Transl Res 2017;190:16-24.e1. 131 Tolkach Y, Wolgast LM, Damanakis A, et al. Artificial intelligence
doi:10.1016/j.trsl.2017.09.004 for tumour tissue detection and histological regression grading
111 Vaughan TL, Fitzgerald RC. Precision prevention of oesophageal in oesophageal adenocarcinomas: a retrospective algorithm
adenocarcinoma. Nat Rev Gastroenterol Hepatol 2015;12:243-8. development and validation study. Lancet Digit Health 2023;5:e265-
doi:10.1038/nrgastro.2015.24 75. doi:10.1016/S2589-7500(23)00027-4

132 Foley KG, Franklin J, Jones CM, et al. The impact of endoscopic chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin
ultrasound on the management and outcome of patients with in patients with oesophageal cancer (PRODIGE5/ACCORD17): final
oesophageal cancer: an update of a systematic review. Clin results of a randomised, phase 2/3 trial. Lancet Oncol 2014;15:305-
Radiol 2022;77:e346-55. doi:10.1016/j.crad.2022.02.001 14. doi:10.1016/S1470-2045(14)70028-2
133 National Comprehensive Cancer Network. Esophageal and 152 Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by
esophagogastric junction cancers (Version 2.2023). 2023. https:// surgery compared with chemoradiation alone in squamous cancer
www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf of the esophagus: FFCD 9102. J Clin Oncol 2007;25:1160-8.
134 Obermannová R, Alsina M, Cervantes A, et al, ESMO Guidelines doi:10.1200/JCO.2005.04.7118
Committee. Electronic address: clinicalguidelines@esmo. 153 Kelly RJ, Ajani JA, Kuzdzal J, et al, CheckMate 577 Investigators.
org. Oesophageal cancer: ESMO Clinical Practice Guideline for Adjuvant nivolumab in resected esophageal or gastroesophageal
diagnosis, treatment and follow-up. Ann Oncol 2022;33:992-1004. junction cancer. N Engl J Med 2021;384:1191-203. doi:10.1056/
doi:10.1016/j.annonc.2022.07.003 NEJMoa2032125
135 Kitagawa Y, Uno T, Oyama T, et al. Esophageal cancer practice 154 Eyck BM, van Lanschot JJB, Hulshof MCCM, et al, CROSS Study Group.
guidelines 2017 edited by the Japan Esophageal Society: part 1. Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery
Esophagus 2019;16:1-24. doi:10.1007/s10388-018-0641-9 for esophageal cancer: the randomized controlled CROSS trial. J Clin
136 Kitagawa Y, Uno T, Oyama T, et al, Esophageal cancer practice Oncol 2021;39:1995-2004. doi:10.1200/JCO.20.03614
guidelines 2017 edited by the Japan esophageal society: part 2. 155 Nakamura K, Kato K, Igaki H, et al, Japan Esophageal Oncology
Esophagus 2019;16:25-43. doi:10.1007/s10388-018-0642-8 Group/Japan Clinical Oncology Group. Three-arm phase III trial
137 Cunningham D, Allum WH, Stenning SP, et al, MAGIC Trial Participants. comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus
Perioperative chemotherapy versus surgery alone for resectable 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative
gastroesophageal cancer. N Engl J Med 2006;355:11-20. therapy for locally advanced esophageal cancer (JCOG1109, NExT
doi:10.1056/NEJMoa055531 study). Jpn J Clin Oncol 2013;43:752-5. doi:10.1093/jjco/hyt061
138 Al-Batran SE, Homann N, Pauligk C, et al, FLOT4-AIO Investigators. 156 Hara H, Tahara M, Daiko H, et al. Phase II feasibility study of
Perioperative chemotherapy with fluorouracil plus leucovorin, preoperative chemotherapy with docetaxel, cisplatin, and
oxaliplatin, and docetaxel versus fluorouracil or capecitabine fluorouracil for esophageal squamous cell carcinoma. Cancer
plus cisplatin and epirubicin for locally advanced, resectable Sci 2013;104:1455-60. doi:10.1111/cas.12274
gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): 157 Reynolds JV, Preston SR, O’Neill B, et al, Neo-AEGIS Investigators and
a randomised, phase 2/3 trial. Lancet 2019;393:1948-57. Trial Group. Trimodality therapy versus perioperative chemotherapy
doi:10.1016/S0140-6736(18)32557-1 in the management of locally advanced adenocarcinoma of
139 Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy the oesophagus and oesophagogastric junction (Neo-AEGIS):
compared with surgery alone for resectable gastroesophageal an open-label, randomised, phase 3 trial. Lancet Gastroenterol
adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Hepatol 2023;8:1015-27. doi:10.1016/S2468-1253(23)00243-1
Clin Oncol 2011;29:1715-21. doi:10.1200/JCO.2010.33.0597 158 Lorenzen S, Biederstädt A, Ronellenfitsch U, et al. RACE-trial:
140 van Hagen P, Hulshof MC, van Lanschot JJ, et al, CROSS Group. neoadjuvant radiochemotherapy versus chemotherapy for patients
Preoperative chemoradiotherapy for esophageal or junctional cancer. with locally advanced, potentially resectable adenocarcinoma of the
N Engl J Med 2012;366:2074-84. doi:10.1056/NEJMoa1112088 gastroesophageal junction - a randomized phase III joint study of
141 Yang H, Liu H, Chen Y, et al, AME Thoracic Surgery Collaborative the AIO, ARO and DGAV. BMC Cancer 2020;20:886. doi:10.1186/
Group. Neoadjuvant chemoradiotherapy followed by surgery versus s12885-020-07388-x
surgery alone for locally advanced squamous cell carcinoma of the 159 Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without
esophagus (NEOCRTEC5010): a phase III multicenter, randomized, cetuximab in patients with oesophageal cancer (SCOPE1): a
open-label clinical trial. J Clin Oncol 2018;36:2796-803. multicentre, phase 2/3 randomised trial. Lancet Oncol 2013;14:627-
doi:10.1200/JCO.2018.79.1483 37. doi:10.1016/S1470-2045(13)70136-0
142 Reynolds JV, Preston SR, O’Neill B, et al. Neo-AEGIS (Neoadjuvant 160 Lordick F, Ott K, Krause BJ, et al. PET to assess early metabolic
Trial in Adenocarcinoma of the Esophagus and Esophago-Gastric response and to guide treatment of adenocarcinoma of the
Junction International Study): final primary outcome analysis. J Clin oesophagogastric junction: the MUNICON phase II trial. Lancet
Oncol 2023;41(suppl):295. doi:10.1200/JCO.2023.41.4_suppl.295 Oncol 2007;8:797-805. doi:10.1016/S1470-2045(07)70244-9
143 Hoeppner J, Lordick F, Brunner T, et al. ESOPEC: prospective 161 Goodman KA, Ou FS, Hall NC, et al. Randomized phase II study of
randomized controlled multicenter phase III trial comparing PET response-adapted combined modality therapy for esophageal
perioperative chemotherapy (FLOT protocol) to neoadjuvant cancer: mature results of the CALGB 80803 (Alliance) trial. J Clin
chemoradiation (CROSS protocol) in patients with adenocarcinoma Oncol 2021;39:2803-15. doi:10.1200/JCO.20.03611
of the esophagus (NCT02509286). BMC Cancer 2016;16:503. 162 zum Büschenfelde CM, Herrmann K, Schuster T, et al. (18)F-FDG PET-
doi:10.1186/s12885-016-2564-y guided salvage neoadjuvant radiochemotherapy of adenocarcinoma
144 Medical Research Council Oesophageal Cancer Working Group. of the esophagogastric junction: the MUNICON II trial. J Nucl
Surgical resection with or without preoperative chemotherapy Med 2011;52:1189-96. doi:10.2967/jnumed.110.085803
in oesophageal cancer: a randomised controlled trial. 163 Lorenzen S, Quante M, Rauscher I, et al. PET-directed combined
Lancet 2002;359:1727-33. doi:10.1016/S0140-6736(02)08651- modality therapy for gastroesophageal junction cancer: Results of
8 the multicentre prospective MEMORI trial of the German Cancer
145 Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term Consortium (DKTK). Eur J Cancer 2022;175:99-106. doi:10.1016/j.
results of a randomized trial of surgery with or without preoperative ejca.2022.07.027
chemotherapy in esophageal cancer. J Clin Oncol 2009;27:5062-7. 164 Barbour AP, Walpole ET, Mai GT, et al, DOCTOR investigators.
doi:10.1200/JCO.2009.22.2083 Preoperative cisplatin, fluorouracil, and docetaxel with or without
146 Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by radiotherapy after poor early response to cisplatin and fluorouracil
surgery compared with surgery alone for localized esophageal for resectable oesophageal adenocarcinoma (AGITG DOCTOR):
cancer. N Engl J Med 1998;339:1979-84. doi:10.1056/ results from a multicentre, randomised controlled phase II trial. Ann
NEJM199812313392704 Oncol 2020;31:236-45. doi:10.1016/j.annonc.2019.10.019
147 Klevebro F, Alexandersson von Döbeln G, Wang N, et al. A 165 Mukherjee S, Hurt CN, Adams R, et al. Efficacy of early PET-CT
randomized clinical trial of neoadjuvant chemotherapy versus directed switch to carboplatin and paclitaxel based definitive
neoadjuvant chemoradiotherapy for cancer of the oesophagus chemoradiotherapy in patients with oesophageal cancer
or gastro-oesophageal junction. Ann Oncol 2016;27:660-7. who have a poor early response to induction cisplatin and
doi:10.1093/annonc/mdw010 capecitabine in the UK: a multi-centre randomised controlled
148 Kato K, Ito Y, Daiko H, et al. A randomized controlled phase III trial phase II trial. EClinicalMedicine 2023;61:102059. doi:10.1016/j.
comparing two chemotherapy regimen and chemoradiotherapy eclinm.2023.102059
regimen as neoadjuvant treatment for locally advanced esophageal 166 Raufi AG, Lee S, May M, et al. Abstract CT009: Phase II trial of
cancer, JCOG1109 NExT study. J Clin Oncol 2022;40(suppl):238. perioperative pembrolizumab plus capecitabine and oxaliplatin
doi:10.1200/JCO.2022.40.4_suppl.238 followed by adjuvant pembrolizumab for resectable gastric and
149 Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy gastroesophageal junction (GC/GEJ) adenocarcinoma. Cancer
and radiotherapy compared with radiotherapy alone in patients Res 2022;82:CT009. doi:10.1158/1538-7445.AM2022-CT009
with cancer of the esophagus. N Engl J Med 1992;326:1593-8. 167 Ding X, Li B, Xue Q, et al. Perioperative sintilimab combination
doi:10.1056/NEJM199206113262403 with SOX for resectable locally advanced gastric/gastroesophageal
150 Cooper JS, Guo MD, Herskovic A, et al, Radiation Therapy Oncology junction cancer(GC/GEJC): Initial findings of a single-arm phase
Group. Chemoradiotherapy of locally advanced esophageal cancer: II trial. J Clin Oncol 2022;40:294. doi:10.1200/JCO.2022.40.4_
long-term follow-up of a prospective randomized trial (RTOG 85-01). suppl.294
JAMA 1999;281:1623-7. doi:10.1001/jama.281.17.1623 168 Sun W, Veeramachaneni N, Al-Rajabi R, et al. A phase II study
151 Conroy T, Galais MP, Raoul JL, et al, Fédération Francophone de of perioperative mFOLFOX chemotherapy plus pembrolizumab
Cancérologie Digestive and UNICANCER-GI Group. Definitive combination in patients with potentially resectable adenocarcinoma

of the esophageal, gastroesophageal junction (GEJ), and stomach. 185 Tang Z, Wang Y, Liu D, et al. The Neo-PLANET phase II trial of
J Clin Oncol 2022;12:16098-107. doi:10.1200/JCO.2022.40.4_ neoadjuvant camrelizumab plus concurrent chemoradiotherapy in
suppl.329 locally advanced adenocarcinoma of stomach or gastroesophageal
169 Liu Y, Han G, Li H, et al. Camrelizumab combined with FLOFOX as junction. Nat Commun 2022;13:6807. doi:10.1038/s41467-022-
neoadjuvant therapy for resectable locally advanced gastric and 34403-5
gastroesophageal junction adenocarcinoma: updated results of 186 Hulshof MCCM, Geijsen ED, Rozema T, et al. randomized study
efficacy and safety. J Clin Oncol 2021;39:4036. doi:10.1200/ on dose escalation in definitive chemoradiation for patients with
JCO.2021.39.15_suppl.4036 locally advanced esophageal cancer (ARTDECO Study). J Clin
170 Tang J, Huang J, Zhang B, et al. Perioperative chemotherapy with Oncol 2021;39:2816-24. doi:10.1200/JCO.20.03697
LP002, an anti-PD-L1 antibody, in patients with resectable gastric 187 Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy
and gastroesophageal junction cancer: a prospective, open- Oncology Group 94-05) phase III trial of combined-modality
label, phase Ib trial. J Clin Oncol 2022;40:4041. doi:10.1200/ therapy for esophageal cancer: high-dose versus standard-dose
JCO.2022.40.16_suppl.4041 radiation therapy. J Clin Oncol 2002;20:1167-74. doi:10.1200/
171 Verschoor YL, Kodach L, van den Berg J, et al. Neoadjuvant JCO.2002.20.5.1167
atezolizumab plus docetaxel/oxaliplatin/capecitabine in non- 188 Crehange G, M’vondo C, Bertaut A, et al. exclusive
metastatic gastric and gastroesophageal junction adenocarcinoma: chemoradiotherapy with or without radiation dose escalation
the PANDA trial. J Clin Oncol 2022;40:4059. doi:10.1200/ in esophageal cancer: multicenter phase 2/3 randomized trial
JCO.2022.40.16_suppl.4059 CONCORDE (PRODIGE-26). Int J Radiat Oncol Biol Phys 2021;111:S5.
172 Al-Batran SE, Lorenzen S, Thuss-Patience PC, et al. Surgical and doi:10.1016/j.ijrobp.2021.07.045
pathological outcome, and pathological regression, in patients 189 Bridges S, Thomas B, Radhakrishna G, et al. SCOPE 2 - still answering
receiving perioperative atezolizumab in combination with FLOT the unanswered questions in oesophageal radiotherapy? Scope 2:
chemotherapy versus FLOT alone for resectable esophagogastric a randomised phase II/III trial to study radiotherapy dose escalation
adenocarcinoma: Interim results from DANTE, a randomized, in patients with oesophageal cancer treated with definitive
multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer chemoradiation with an embedded phase II trial for patients
Group and Swiss SAKK. J Clin Oncol 2022;40:4003. doi:10.1200/ with a poor early response using positron emission tomography/
JCO.2022.40.16_suppl.4003 computed tomography. Clin Oncol (R Coll Radiol) 2022;34:e269-80.
173 Bang YJ, Van Cutsem E, Fuchs CS, et al. KEYNOTE-585: Phase III study doi:10.1016/j.clon.2022.03.019
of perioperative chemotherapy with or without pembrolizumab for 190 Choe SI, Lee Y, Habashi R, et al. The role of brachytherapy
gastric cancer. Future Oncol 2019;15:943-52. doi:10.2217/fon- in treatment of stage I esophageal cancer: A systematic
2018-0581 review. Brachytherapy 2022;21:877-86. doi:10.1016/j.
174 Janjigian YY, Van Cutsem E, Muro K, et al. MATTERHORN: phase III brachy.2022.05.007
study of durvalumab plus FLOT chemotherapy in resectable gastric/ 191 Boekhoff MR, Bouwmans R, Doornaert PAH, et al. Clinical
gastroesophageal junction cancer. Future Oncol 2022;18:2465-73. implementation and feasibility of long-course fractionated MR-guided
doi:10.2217/fon-2022-0093 chemoradiotherapy for patients with esophageal cancer: An R-IDEAL
175 Smyth E, Knödler M, Giraut A, et al. VESTIGE: adjuvant stage 1b/2a evaluation of technical innovation. Clin Transl Radiat
immunotherapy in patients with resected esophageal, Oncol 2022;34:82-9. doi:10.1016/j.ctro.2022.03.008
gastroesophageal junction and gastric cancer following 192 Wang X, Palaskas NL, Yusuf SW, et al. incidence and onset of severe
preoperative chemotherapy with high risk for recurrence (N+ and/ cardiac events after radiotherapy for esophageal cancer. J Thorac
or R1): an open label randomized controlled phase-2-study. Front Oncol 2020;15:1682-90. doi:10.1016/j.jtho.2020.06.014
Oncol 2020;9:1320. doi:10.3389/fonc.2019.01320 193 Ellis R, Cole AJ, O’Hare J, Whitten G, Crowther K, Harrison C.
176 Terashima M, Kim Y-W, Yeh T-S, et al. ATTRACTION-05 (ONO- Coincidental splenic irradiation and risk of functional hyposplenism
4538-38/BMS CA209844): a randomized, multicenter, double- in oesophageal cancer treatment. J Med Imaging Radiat
blind, placebo- controlled Phase 3 study of Nivolumab (Nivo) in Oncol 2021;65:925-30. doi:10.1111/1754-9485.13310
combination with adjuvant chemotherapy in pStage III gastric and 194 Lin SH, Komaki R, Liao Z, et al. Proton beam therapy and concurrent
esophagogastric junction (G/EGJ) cancer. Ann Oncol 2017;28:V266- chemotherapy for esophageal cancer. Int J Radiat Oncol Biol
7. doi:10.1093/annonc/mdx369.160 Phys 2012;83:e345-51. doi:10.1016/j.ijrobp.2012.01.003
177 Li X, Xu C, Qiu H, et al. A single-arm, multicenter, phase II clinical 195 Warren S, Partridge M, Bolsi A, et al. An analysis of plan robustness
study of tislelizumab plus albumin-bound paclitaxel/cisplatin as for esophageal tumors: comparing volumetric modulated arc therapy
neoadjuvant therapy for borderline resectable esophageal squamous plans and spot scanning proton planning. Int J Radiat Oncol Biol
cell carcinoma. Ann Transl Med 2022;10:263. doi:10.21037/atm- Phys 2016;95:199-207. doi:10.1016/j.ijrobp.2016.01.044
21-6931 196 Lin SH, Hobbs BP, Verma V, et al. Randomized phase iib trial of proton
178 Shang X, Zhang W, Zhao G, et al. Pembrolizumab combined with beam therapy versus intensity-modulated radiation therapy for
neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy locally advanced esophageal cancer. J Clin Oncol 2020;38:1569-79.
followed by surgery for locally advanced oesophageal squamous doi:10.1200/JCO.19.02503
cell carcinoma: protocol for a multicentre, prospective, randomized- 197 Lertbutsayanukul C, Kitpanit S, Kannarunimit D, et al. High-dose
controlled, phase iii clinical study (Keystone-002). Front Intensity-modulated proton therapy versus Standard-dose
Oncol 2022;12:831345. doi:10.3389/fonc.2022.831345 Intensity-modulated RadIation therapy for esophageal squamous
179 Yan X, Duan H, Ni Y, et al. Tislelizumab combined with cell carcinoma (HI-SIRI): study protocol for a randomized controlled
chemotherapy as neoadjuvant therapy for surgically resectable clinical trial. Trials 2022;23:897. doi:10.1186/s13063-022-06822-
esophageal cancer: A prospective, single-arm, phase II study 8
(TD-NICE). Int J Surg 2022;103:106680. doi:10.1016/j. 198 Hoffmann L, Mortensen H, Shamshad M, et al. Treatment planning
ijsu.2022.106680 comparison in the PROTECT-trial randomising proton versus photon
180 Ji Y, Du X, Zhu W, et al. Efficacy of concurrent chemoradiotherapy beam therapy in oesophageal cancer: Results from eight European
with S-1 vs radiotherapy alone for older patients with esophageal centres. Radiother Oncol 2022;172:32-41. doi:10.1016/j.
cancer: a multicenter randomized phase 3 clinical trial. JAMA radonc.2022.04.029
Oncol 2021;7:1459-66. doi:10.1001/jamaoncol.2021.2705 199 Sasako M, Sano T, Yamamoto S, et al, Japan Clinical Oncology Group
181 Mukherjee S, Hurt C, Radhakrishna G, et al. Oxaliplatin/capecitabine (JCOG9502). Left thoracoabdominal approach versus abdominal-
or carboplatin/paclitaxel-based preoperative chemoradiation for transhiatal approach for gastric cancer of the cardia or subcardia:
resectable oesophageal adenocarcinoma (NeoSCOPE): Long-term a randomised controlled trial. Lancet Oncol 2006;7:644-51.
results of a randomised controlled trial. Eur J Cancer 2021;153:153- doi:10.1016/S1470-2045(06)70766-5
61. doi:10.1016/j.ejca.2021.05.020 200 Wei M-T, Zhang Y-C, Deng X-B, Yang T-H, He Y-Z, Wang Z-Q.
182 Xie C, Jing Z, Luo H, et al. Chemoradiotherapy with extended nodal Transthoracic vs transhiatal surgery for cancer of the esophagogastric
irradiation and/or erlotinib in locally advanced oesophageal junction: a meta-analysis. World J Gastroenterol 2014;20:10183-92.
squamous cell cancer: long-term update of a randomised phase 3 doi:10.3748/wjg.v20.i29.10183
trial. Br J Cancer 2020;123:1616-24. doi:10.1038/s41416-020- 201 de Boer AG, van Lanschot JJ, van Sandick JW, et al. Quality of life
01054-6 after transhiatal compared with extended transthoracic resection for
183 Sheikh H, Ryder D, Bateman A, Chalmers A, Jackson A. Radiotherapy adenocarcinoma of the esophagus. J Clin Oncol 2004;22:4202-8.
and olaparib in combination for carcinoma of the oesophagus: doi:10.1200/JCO.2004.11.102
A phase I study. Clin Transl Radiat Oncol 2023;40:100614. 202 Omloo JM, Lagarde SM, Hulscher JB, et al. Extended transthoracic
doi:10.1016/j.ctro.2023.100614 resection compared with limited transhiatal resection for
184 Safran HP, Winter K, Ilson DH, et al. Trastuzumab with trimodality adenocarcinoma of the mid/distal esophagus: five-year survival of a
treatment for oesophageal adenocarcinoma with HER2 randomized clinical trial. Ann Surg 2007;246:992-1000, discussion
overexpression (NRG Oncology/RTOG 1010): a multicentre, 1000-1. doi:10.1097/SLA.0b013e31815c4037
randomised, phase 3 trial. Lancet Oncol 2022;23:259-69. 203 Preston SR, Markar SR, Baker CR, Soon Y, Singh S, Low DE.
doi:10.1016/S1470-2045(21)00718-X Impact of a multidisciplinary standardized clinical pathway on

perioperative outcomes in patients with oesophageal cancer. Br J DRKS00016773. Trials 2021;22:41. doi:10.1186/s13063-020-
Surg 2013;100:105-12. doi:10.1002/bjs.8974 04966-z
204 Blom RLGM, van Heijl M, Bemelman WA, et al. Initial experiences 222 O’Connell L, Coleman M, Kharyntiuk N, Walsh TN. Quality of life
of an enhanced recovery protocol in esophageal surgery. World J in patients with upper GI malignancies managed by a strategy of
Surg 2013;37:2372-8. doi:10.1007/s00268-013-2135-1 chemoradiotherapy alone versus surgery. Surg Oncol 2019;30:33-9.
205 Schmidt HM, El Lakis MA, Markar SR, Hubka M, Low DE. doi:10.1016/j.suronc.2019.05.021
accelerated recovery within standardized recovery pathways after 223 Avery KN, Metcalfe C, Barham CP, Alderson D, Falk SJ, Blazeby JM.
esophagectomy: a prospective cohort study assessing the effects Quality of life during potentially curative treatment for locally
of early discharge on outcomes, readmissions, patient satisfaction, advanced oesophageal cancer. Br J Surg 2007;94:1369-76.
and costs. Ann Thorac Surg 2016;102:931-9. doi:10.1016/j. doi:10.1002/bjs.5888
athoracsur.2016.04.005 224 Markar SR, Zaninotto G, Castoro C, et al. Lasting symptoms after
206 Low DE, Allum W, De Manzoni G, et al. Guidelines for perioperative esophageal resection (LASER): European multicenter cross-
care in esophagectomy: Enhanced Recovery After Surgery (Eras®) sectional study. Ann Surg 2022;275:e392-400. doi:10.1097/
society recommendations. World J Surg 2019;43:299-330. SLA.0000000000003917
doi:10.1007/s00268-018-4786-4 225 Nilsson M, Olafsdottir H, Alexandersson von Döbeln G, et al.
207 Zhao G, Cao S, Cui J. Fast-track surgery improves postoperative Neoadjuvant chemoradiotherapy and surgery for esophageal
clinical recovery and reduces postoperative insulin resistance squamous cell carcinoma versus definitive chemoradiotherapy with
after esophagectomy for esophageal cancer. Support Care salvage surgery as needed: the study protocol for the randomized
Cancer 2014;22:351-8. doi:10.1007/s00520-013-1979-0 controlled NEEDS trial. Front Oncol 2022;12:917961. doi:10.3389/
208 Shewale JB, Correa AM, Baker CM, et al, University of Texas MD fonc.2022.917961
Anderson Esophageal Cancer Collaborative Group. Impact of a 226 Noordman BJ, Wijnhoven BPL, Lagarde SM, et al, SANO-study
fast-track esophagectomy protocol on esophageal cancer patient group. Neoadjuvant chemoradiotherapy plus surgery versus active
outcomes and hospital charges. Ann Surg 2015;261:1114-23. surveillance for oesophageal cancer: a stepped-wedge cluster
doi:10.1097/SLA.0000000000000971 randomised trial. BMC Cancer 2018;18:142. doi:10.1186/s12885-
209 Biere SSAY, van Berge Henegouwen MI, Maas KW, et al. Minimally 018-4034-1
invasive versus open oesophagectomy for patients with oesophageal 227 Noordman BJ, Spaander MCW, Valkema R, et al, SANO study group.
cancer: a multicentre, open-label, randomised controlled trial. Detection of residual disease after neoadjuvant chemoradiotherapy
Lancet 2012;379:1887-92. doi:10.1016/S0140-6736(12)60516- for oesophageal cancer (preSANO): a prospective multicentre,
9 diagnostic cohort study. Lancet Oncol 2018;19:965-74.
210 Straatman J, van der Wielen N, Cuesta MA, et al. minimally invasive doi:10.1016/S1470-2045(18)30201-8
versus open esophageal resection three-year follow-up of the 228 Neishaboori N, Wadhwa R, Nogueras-González GM, et al. Distribution
previously reported randomized controlled trial: the TIME trial. Ann of resistant esophageal adenocarcinoma in the resected specimens
Surg 2017;266:232-6. doi:10.1097/SLA.0000000000002171 of clinical stage III patients after chemoradiation: its clinical
211 de Groot EM, Goense L, Kingma BF, Haverkamp L, Ruurda JP, van implications. Oncology 2015;89:65-9. doi:10.1159/000371889
Hillegersberg R. Trends in surgical techniques for the treatment of 229 Cheedella NK, Suzuki A, Xiao L, et al. Association between clinical
esophageal and gastroesophageal junction cancer: the 2022 update. complete response and pathological complete response after
Dis Esophagus 2023;36:doac099. doi:10.1093/dote/doac099 preoperative chemoradiation in patients with gastroesophageal
212 Mariette C, Markar SR, Dabakuyo-Yonli TS, et al, Fédération de cancer: analysis in a large cohort. Ann Oncol 2013;24:1262-6.
Recherche en Chirurgie (FRENCH) and French Eso-Gastric Tumors doi:10.1093/annonc/mds617
(FREGAT) Working Group. Hybrid minimally invasive esophagectomy 230 van der Bogt RD, van der Wilk BJ, Oudijk L, et al. Bite-on-bite
for esophageal cancer. N Engl J Med 2019;380:152-62. biopsies for the detection of residual esophageal cancer after
doi:10.1056/NEJMoa1805101 neoadjuvant chemoradiotherapy. Endoscopy 2022;54:1131-8.
213 Nuytens F, Dabakuyo-Yonli TS, Meunier B, et al, Fédération de doi:10.1055/a-1846-1025
Recherche en Chirurgie (FRENCH) and French Eso-Gastric Tumors 231 Zhang X, Eyck BM, Yang Y, et al. Accuracy of detecting residual
(FREGAT) Working Groups. Five-year survival outcomes of hybrid disease after neoadjuvant chemoradiotherapy for esophageal
minimally invasive esophagectomy in esophageal cancer: results of squamous cell carcinoma (preSINO trial): a prospective multicenter
the MIRO randomized clinical trial. JAMA Surg 2021;156:323-32. diagnostic cohort study. BMC Cancer 2020;20:194. doi:10.1186/
doi:10.1001/jamasurg.2020.7081 s12885-020-6669-y
214 van der Sluis PC, van der Horst S, May AM, et al. Robot-assisted 232 Matsuda S, Irino T, Kawakubo H, et al. Evaluation of endoscopic
minimally invasive thoracolaparoscopic esophagectomy versus response using deep neural network in esophageal cancer
open transthoracic esophagectomy for resectable esophageal patients who received neoadjuvant chemotherapy. Ann Surg
cancer : a randomized controlled trial. Ann Surg 2019;269:621-30. Oncol 2023;30:3733-42. doi:10.1245/s10434-023-13140-z
doi:10.1097/SLA.0000000000003031 233 Jones CM, O’Connor H, O’Donovan M, et al. Use of a non-
215 de Groot EM, van der Horst S, Kingma BF, et al. Robot-assisted endoscopic immunocytological device (Cytosponge™) for post
minimally invasive thoracolaparoscopic esophagectomy versus open chemoradiotherapy surveillance in patients with oesophageal
esophagectomy: long-term follow-up of a randomized clinical trial. cancer in the UK (CYTOFLOC): A multicentre feasibility
Dis Esophagus 2020;33(Supplement_2):doaa079. doi:10.1093/ study. EClinicalMedicine 2022;53:101664. doi:10.1016/j.
dote/doaa079 eclinm.2022.101664
216 Kingma BF, Grimminger PP, van der Sluis PC, et al, UGIRA Study 234 Liu Q, Chen J, Lin Y, et al. Systemic therapy with or without local
Group. Worldwide techniques and outcomes in Robot-assisted intervention for oligometastatic oesophageal squamous cell
Minimally Invasive Esophagectomy (RAMIE): results from the carcinoma (ESO-Shanghai 13): an open-label, randomised, phase
multicenter international registry. Ann Surg 2022;276:e386-92. 2 trial. Lancet Gastroenterol Hepatol 2024;9:45-55. doi:10.1016/
doi:10.1097/SLA.0000000000004550 S2468-1253(23)00316-3
217 Yang Y, Li B, Yi J, et al. Robot-assisted versus conventional minimally 235 Kroese TE, van Hillegersberg R, Schoppmann S, et al, OMEC working
invasive esophagectomy for resectable esophageal squamous cell group. Definitions and treatment of oligometastatic oesophagogastric
carcinoma: early results of a multicenter randomized controlled cancer according to multidisciplinary tumour boards in Europe. Eur J
trial: the RAMIE trial. Ann Surg 2022;275:646-53. doi:10.1097/ Cancer 2022;164:18-29. doi:10.1016/j.ejca.2021.11.032
SLA.0000000000005023 236 Kroese TE, van Rossum PSN, Nilsson M, et al, OMEC-working group
218 Brierley RC, Gaunt D, Metcalfe C, et al. Laparoscopically assisted (Supplementary File 1). Study protocol for the OligoMetastatic
versus open oesophagectomy for patients with oesophageal cancer- Esophagogastric Cancer (OMEC) project: A multidisciplinary European
the Randomised Oesophagectomy: Minimally Invasive or Open consensus project on the definition and treatment for oligometastatic
(ROMIO) study: protocol for a randomised controlled trial (RCT). BMJ esophagogastric cancer. Eur J Surg Oncol 2023;49:21-8.
Open 2019;9:e030907. doi:10.1136/bmjopen-2019-030907 doi:10.1016/j.ejso.2022.09.012
219 Chao YK, Li ZG, Wen YW, et al. Robotic-assisted Esophagectomy 237 Ford HE, Marshall A, Bridgewater JA, et al, COUGAR-02 Investigators.
vs Video-Assisted Thoracoscopic Esophagectomy (REVATE): study Docetaxel versus active symptom control for refractory
protocol for a randomized controlled trial. Trials 2019;20:346. oesophagogastric adenocarcinoma (COUGAR-02): an open-label,
doi:10.1186/s13063-019-3441-1 phase 3 randomised controlled trial. Lancet Oncol 2014;15:78-86.
220 Tagkalos E, van der Sluis PC, Berlth F, et al. Robot-assisted doi:10.1016/S1470-2045(13)70549-7
minimally invasive thoraco-laparoscopic esophagectomy versus 238 Janmaat VT, Steyerberg EW, van der Gaast A, et al. Palliative
minimally invasive esophagectomy for resectable esophageal chemotherapy and targeted therapies for esophageal and
adenocarcinoma, a randomized controlled trial (ROBOT-2 trial). BMC gastroesophageal junction cancer. Cochrane Database Syst
Cancer 2021;21:1060. doi:10.1186/s12885-021-08780-x Rev 2017;11:CD004063. doi:10.1002/14651858.CD004063.pub4
221 Nickel F, Probst P, Studier-Fischer A, et al. Minimally Invasive 239 Hall PS, Swinson D, Cairns DA, et al, GO2 Trial Investigators. Efficacy
Versus open AbdominoThoracic Esophagectomy for esophageal of reduced-intensity chemotherapy with oxaliplatin and capecitabine
carcinoma (MIVATE) - study protocol for a randomized controlled trial on quality of life and cancer control among older and frail patients

with advanced gastroesophageal cancer: the GO2 phase 3 with advanced or recurrent esophageal squamous cell carcinoma
randomized clinical trial. JAMA Oncol 2021;7:869-77. doi:10.1001/ (ESCC) expressing programmed death-ligand 1 (PD-L1). J Clin
jamaoncol.2021.0848 Oncol 2022;40:TPS370. doi:10.1200/JCO.2022.40.4_suppl.TPS370
240 Bang YJ, Van Cutsem E, Feyereislova A, et al, ToGA Trial Investigators. 255 Shitara K, Bang YJ, Iwasa S, et al, DESTINY-Gastric01 Investigators.
Trastuzumab in combination with chemotherapy versus Trastuzumab deruxtecan in previously treated HER2-positive
chemotherapy alone for treatment of HER2-positive advanced gastric gastric cancer. N Engl J Med 2020;382:2419-30. doi:10.1056/
or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, NEJMoa2004413
randomised controlled trial. Lancet 2010;376:687-97. doi:10.1016/ 256 Ajani JA, Ilson DH, Daugherty K, Pazdur R, Lynch PM, Kelsen DP.
S0140-6736(10)61121-X Activity of taxol in patients with squamous cell carcinoma and
241 Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of adenocarcinoma of the esophagus. J Natl Cancer Inst 1994;86:1086-
dual PD-1 and HER2 blockade in HER2-positive gastric cancer. 91. doi:10.1093/jnci/86.14.1086
Nature 2021;600:727-30. doi:10.1038/s41586-021-04161-3 257 Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival
242 Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus advantage for irinotecan versus best supportive care as second-
chemotherapy versus chemotherapy alone for advanced gastric, line chemotherapy in gastric cancer--a randomised phase III study
gastro-oesophageal junction, and oesophageal adenocarcinoma of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J
(CheckMate 649): a randomised, open-label, phase 3 trial. Cancer 2011;47:2306-14. doi:10.1016/j.ejca.2011.06.002
Lancet 2021;398:27-40. doi:10.1016/S0140-6736(21)00797-2 258 Hironaka S, Ueda S, Yasui H, et al. Randomized, open-label, phase
243 Sun JM, Shen L, Shah MA, et al, KEYNOTE-590 Investigators. III study comparing irinotecan with paclitaxel in patients with
Pembrolizumab plus chemotherapy versus chemotherapy advanced gastric cancer without severe peritoneal metastasis after
alone for first-line treatment of advanced oesophageal cancer failure of prior combination chemotherapy using fluoropyrimidine
(KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. plus platinum: WJOG 4007 trial. J Clin Oncol 2013;31:4438-44.
Lancet 2021;398:759-71. doi:10.1016/S0140-6736(21)01234-4 doi:10.1200/JCO.2012.48.5805
244 Rha SY, Wyrwicz LS, Weber PEY, et al. VP1-2023: Pembrolizumab 259 Penniment MG, De Ieso PB, Harvey JA, et al, TROG 03.01/CCTG
(pembro) plus chemotherapy (chemo) as first-line therapy for ES.2 group. Palliative chemoradiotherapy versus radiotherapy
advanced HER2-negative gastric or gastroesophageal junction (G/ alone for dysphagia in advanced oesophageal cancer: a multicentre
GEJ) cancer: phase III KEYNOTE-859 study. Ann Oncol 2023;34:319- randomised controlled trial (TROG 03.01). Lancet Gastroenterol
20. doi:10.1016/j.annonc.2023.01.006 Hepatol 2018;3:114-24. doi:10.1016/S2468-1253(17)30363-1
245 Doki Y, Ajani JA, Kato K, et al, CheckMate 648 Trial Investigators. 260 Adamson D, Byrne A, Porter C, et al. Palliative radiotherapy after
Nivolumab combination therapy in advanced esophageal squamous- oesophageal cancer stenting (ROCS): a multicentre, open-label,
cell carcinoma. N Engl J Med 2022;386:449-62. doi:10.1056/ phase 3 randomised controlled trial. Lancet Gastroenterol
NEJMoa2111380 Hepatol 2021;6:292-303. doi:10.1016/S2468-1253(21)00004-2
246 Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 261 Zhang X, Peng L, Luo Y, et al. Dissecting esophageal squamous-cell
in patients with CLDN18.2-positive, HER2-negative, untreated, carcinoma ecosystem by single-cell transcriptomic analysis. Nat
locally advanced unresectable or metastatic gastric or gastro- Commun 2021;12:5291. doi:10.1038/s41467-021-25539-x
oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, 262 Dinh HQ, Pan F, Wang G, et al. Integrated single-cell transcriptome
randomised, double-blind, phase 3 trial. Lancet 2023;401:1655-68. analysis reveals heterogeneity of esophageal squamous cell
doi:10.1016/S0140-6736(23)00620-7 carcinoma microenvironment. Nat Commun 2021;12:7335.
247 Shitara K, Ajani JA, Bang Y-J, et al. Zolbetuximab + CAPOX in doi:10.1038/s41467-021-27599-5
1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) 263 Rao A, Barkley D, França GS, Yanai I. Exploring tissue architecture
or metastatic gastric or gastroesophageal junction (mG/GEJ) using spatial transcriptomics. Nature 2021;596:211-20.
adenocarcinoma: primary phase 3 results from GLOW. J Clin doi:10.1038/s41586-021-03634-9
Oncol 2023;41:405736-36. doi:10.1200/JCO.2023.41.16_ 264 Guo W, Zhou B, Yang Z, et al. Integrating microarray-based
suppl.4035 spatial transcriptomics and single-cell RNA-sequencing
248 Wainberg ZA, Enzinger PC, Kang YK, et al. Bemarituzumab in reveals tissue architecture in esophageal squamous cell
patients with FGFR2b-selected gastric or gastro-oesophageal carcinoma. EBioMedicine 2022;84:104281. doi:10.1016/j.
junction adenocarcinoma (FIGHT): a randomised, double-blind, ebiom.2022.104281
placebo-controlled, phase 2 study. Lancet Oncol 2022;23:1430-40. 265 Li M, Wu F, Ji Y, Yang L, Li F. Meta-analysis of microRNAs as potential
doi:10.1016/S1470-2045(22)00603-9 biomarkers for detecting esophageal carcinoma in Asian populations.
249 Klempner SJ, Chao J, Uronis HE, et al. DKN-01 and tislelizumab ± Int J Biol Markers 2017;32:e375-83. doi:10.5301/ijbm.5000296
chemotherapy as a first-line (1L) and second-line (2L) investigational 266 Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future
therapy in advanced gastroesophageal adenocarcinoma (GEA): perspectives of liquid biopsies in genomics-driven oncology. Nat Rev
DisTinGuish Trial. J Clin Oncol 2022;40:292. doi:10.1200/ Genet 2019;20:71-88. doi:10.1038/s41576-018-0071-5
JCO.2022.40.4_suppl.292 267 Wan JCM, Massie C, Garcia-Corbacho J, et al. Liquid biopsies come
250 Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy of age: towards implementation of circulating tumour DNA. Nat Rev
in patients with advanced oesophageal squamous cell carcinoma Cancer 2017;17:223-38. doi:10.1038/nrc.2017.7
refractory or intolerant to previous chemotherapy (ATTRACTION-3): 268 Alix-Panabières C, Pantel K. Challenges in circulating tumour cell
a multicentre, randomised, open-label, phase 3 trial. Lancet research. Nat Rev Cancer 2014;14:623-31. doi:10.1038/nrc3820
Oncol 2019;20:1506-17. doi:10.1016/S1470-2045(19)30626-6 269 Keller L, Pantel K. Unravelling tumour heterogeneity by single-cell
251 Kojima T, Shah MA, Muro K, et al, KEYNOTE-181 Investigators. profiling of circulating tumour cells. Nat Rev Cancer 2019;19:553-67.
Randomized phase III KEYNOTE-181 study of pembrolizumab doi:10.1038/s41568-019-0180-2
versus chemotherapy in advanced esophageal cancer. J Clin 270 Einsele H, Borghaei H, Orlowski RZ, et al. The BiTE (bispecific
Oncol 2020;38:4138-48. doi:10.1200/JCO.20.01888 T-cell engager) platform: Development and future potential
252 Fuchs CS, Tomasek J, Yong CJ, et al, REGARD Trial Investigators. of a targeted immuno-oncology therapy across tumor types.
Ramucirumab monotherapy for previously treated advanced gastric Cancer 2020;126:3192-201. doi:10.1002/cncr.32909
or gastro-oesophageal junction adenocarcinoma (REGARD): an 271 Saxena M, van der Burg SH, Melief CJM, Bhardwaj N. Therapeutic
international, randomised, multicentre, placebo-controlled, phase 3 cancer vaccines. Nat Rev Cancer 2021;21:360-78. doi:10.1038/
trial. Lancet 2014;383:31-9. doi:10.1016/S0140-6736(13)61719- s41568-021-00346-0
5 272 Lin MJ, Svensson-Arvelund J, Lubitz GS, et al. Cancer vaccines:
253 Wilke H, Muro K, Van Cutsem E, et al, RAINBOW Study Group. the next immunotherapy frontier. Nat Cancer 2022;3:911-26.
Ramucirumab plus paclitaxel versus placebo plus paclitaxel doi:10.1038/s43018-022-00418-6
in patients with previously treated advanced gastric or gastro- 273 National Comprehensive Cancer Network. Esophageal and
oesophageal junction adenocarcinoma (RAINBOW): a double- esophagogastric junction cancers (version 4.2023). 2023. https://
blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224-35. www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
doi:10.1016/S1470-2045(14)70420-6 274 Rhodin KE, Raman V, Jensen CW, et al. The effect of center
254 Xu R-h, Kim S-B, Tougeron D, et al. AdvanTIG-203: A randomized esophagectomy volume on outcomes in clinical stage I-III
phase 2 study comparing anti-TIGIT ociperlimab plus tislelizumab esophageal cancer. Ann Surg 2023;278:79-86. doi:10.1097/
versus tislelizumab plus placebo as second-line treatment in patients SLA.0000000000005681

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STATE OF THE ART REVIEW

Advances in diagnosis and management of cancer

the bmj | BMJ 2024;385:e074962 | doi: 10.1136/bmj‑2023-074962 1

Sources and selection criteria response to chronic exposure to injurious acidic

2 doi: 10.1136/bmj‑2023-074962 | BMJ 2024;385:e074962 | the bmj

Squamous cell carcinoma development

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Surgery is the definitive treatment of choice for neoadjuvant chemoradiotherapy appeared to be

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For ESCCs, the JCOG1109 NExT study is comparing Personalized treatment

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nivolumab plus chemotherapy and nivolumab plus Biomarkers

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