PIIS0140673624022268

Seminar
Oesophageal cancer
Hong Yang, Feng Wang, Christopher L Hallemeier, Toni Lerut, Jianhua Fu
Oesophageal cancer is the seventh leading cause of cancer mortality worldwide. Two major pathological subtypes ex- Lancet 2024; 404: 1991–2005
ist: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Epidemiological studies in the last dec- Department of Thoracic
ade have shown a gradual increase in the incidence of oesophageal adenocarcinoma worldwide. The prognosis of Surgery (Prof H Yang MD PhD,
Prof J Fu MD PhD) and
oesophageal cancer has greatly improved due to breakthroughs in screening, surgical procedures, and novel treat-
Department of Medical
ment modalities. The success achieved with combined modality therapies, including surgery, chemotherapy, and ra- Oncology
diotherapy, to treat locally advanced oesophageal cancer is particularly notable. Immunotherapy has become a crucial (Prof F Wang MD PhD), Sun
treatment for oesophageal cancer, with immune checkpoint inhibitor-based therapies now established as the standard Ya University Cancer
Center, Guangzhou, China;
of care in adjuvant and metastatic first-line settings. This Seminar provides an overview of advances in the screening,
Guangdong Provincial Clinical
diagnosis, and treatment of oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, with a particu- Research Center for Cancer,
lar focus on neoadjuvant therapies for locally advanced oesophageal cancer and immune checkpoint inhibitor-based State Key Laboratory of
therapies. Oncology in South China,
Collaborative Innovation
Centre for Cancer Medicine,
Introduction of scalding foods and beverages are potential risks.5 For Guangzhou, China (Prof H Yang,
Oesophageal cancer, originating from the epithelial oesophageal adenocarcinoma, risk factors include Prof F Wang, Prof J Fu);
cells of the oesophagus, is a major global health burden. smoking, obesity, gastro-oesophageal reflux disease, and Guangdong Esophageal Cancer
Institute, Guangzhou, China
The two major pathological subtypes, oesophageal Barrett’s oesophagus.6 Studies have also shown that (Prof H Yang, Prof J Fu);
squamous cell carcinoma and oesophageal adenocarci eradication of Helicobacter pylori influences the preva Department of Radiation
noma, differ in their geographical distributions and lence of oesophageal adenocarcinoma.7 Oncology, Mayo Clinic,
molecular profiles. Treatment strategies typically involve Modifying risk factors, particularly tobacco use, is Rochester, MN, USA
(Prof C L Hallemeier MD);
a sequential regimen of surgery, chemotherapy, radio considered the most effective strategy to address the Department of Thoracic
therapy, and immunotherapy, under the guidance of growing global burden of oesophageal cancer.2 Some Surgery, University Hospital
a multidisciplinary team. The prognosis of oesophageal medications, such as aspirin, statins, and anti-reflux Leuven, Leuven, Belgium
cancer has improved due to the widespread adoption of agents, could potentially reduce oesophageal adenocarci (Prof T Lerut MD PhD)
combined modality therapies and immune checkpoint noma risk; selenium and other micronutrients could Correspondence to:
Prof Jianhua Fu, Department of
inhibitors. lower the risk of oesophageal squamous cell carcinoma. Thoracic Surgery, Sun Yat-sen
However, the existing evidence supporting these inter University Cancer Center,
Epidemiology, risk factors, and prevention ventions for the primary prevention of oesophageal Guangzhou 510060, China
According to the 2022 Global Cancer Observatory cancer is not yet robust enough for widespread [email protected]
(GLOBOCAN) report, oesophageal cancer ranks as the recommendation.8–10

11th most prevalent cancer and the seventh leading
cause of cancer death worldwide, responsible for
510 716 new cases and approximately 445 129 deaths in Search strategy and selection criteria
2022.1 Pronounced geographical variations exist in the We searched PubMed for articles published from Jan 1, 1990,
distribution of the two major subtypes of the disease: to July 31, 2024. The search terms were “(o)esophageal cancer”
oesophageal squamous cell carcinoma and oesophageal in combination with “adenocarcinoma”, “squamous cell
adenocarcinoma. Oesophageal squamous cell carci carcinoma”, “epidemiology”, “risk factor”, “prevention”,
noma is mostly prevalent in east Asia, south central “pathology”, “diagnosis”, “stage”, “endoscopy treatment”,
Asia, and south Africa, whereas oesophageal adenocar “surgery”, “salvage surgery”, “centralization of surgery”,
cinoma predominates in north Europe and North “minimally invasive surgery”, “robotic surgery”,
America.2 Asian and Latin American countries have had “lymphadenectomy”, “neoadjuvant therapy”, “chemotherapy”,
substantial declines in the incidence of oesophageal “chemoradiotherapy”, “adjuvant therapy”, “immunotherapy”,
squamous cell carcinoma. In contrast, there has been a “radiotherapy”, “nutrition”, “follow-up”, and “recurrence
marked increase in the incidence of oesophageal adeno surveillance”. The searches were not limited to English
carcinoma in most countries in Europe, North America, language publications; the final list included papers published
and Oceania, thereby establishing oesophageal adeno in other languages, such as Chinese. Papers within the past
carcinoma as the predominant subtype of oesophageal 5 years were prioritised, although older, relevant high-quality
cancer in the countries of these regions.3,4 studies were also selected. We also screened the reference lists
These geographical variations have prompted investi of the articles selected by this search strategy to identify
gation into the underlying pathogenic factors of these additional relevant papers. Abstracts and reports from
diseases. Major risk factors for oesophageal squamous meetings were included when they related directly to
cell carcinoma include excessive drinking and smoking. previously published work. Review articles and book chapters
Additionally, nutritional deficiencies, nitrosamine expo are cited to provide readers with further details and references.
sure, achalasia, poor oral hygiene, and the consumption
www.thelancet.com Vol 404 November 16, 2024 1991

Seminar
Genomic alterations have been identified as key older than 50 years, White race, tobacco smoking,
drivers of oesophageal carcinoma initiation, progres obesity, and a family history of Barrett’s oesophagus or
sion, and metastasis (figure). Inactivation of aldehyde oesophageal adenocarcinoma in a first-degree relative.15
dehydrogenase 2 (ALDH2) is strongly associated with an Furthermore, non-endoscopic methods, such as
increased prevalence of oesophageal squamous cell sponge cytology sampling, have been shown to be safe
carcinoma.11 Common alterations in oesophageal and feasible for screening of squamous neoplasia.16 The
squamous cell carcinoma include inactivation of trefoil factor 3 test conducted on the basis of sponge
CDKN2A, amplification of CCND1, and loss of RB1. cytology can help detect and monitor Barrett’s oesopha
However, according to reports from The Cancer Genome gus.17 Risk stratification tools incorporating clinical
Atlas Network, CCND1 amplification occurs in 57% of information, sponge cytology, or both, have been
squamous cell carcinoma, but accounts for only 15% of developed for pre-endoscopy screening of oesophageal
oesophageal adenocarcinoma cases,12 highlighting cell cancer.18 The use of artificial intelligence as an auxiliary
cycle kinases as potential therapeutic targets specific for tool has shown potential in detecting oesophageal
oesophageal squamous cell carcinoma. Conversely, squamous cell carcinoma and precancerous lesions.19,20
oesophageal adenocarcinoma often exhibits frequent Moreover, DNA methylation assays of cytosponge
oncogenic amplification—eg, amplification of HER2 samples show promise for improving diagnostic
(also known as ERBB2) in approximately 32% of accuracy of Barrett’s oesophagus;21 however, further
cases13—which is rarely observed in oesophageal research is essential for broader validation and prospec
squamous cell carcinoma, indicating distinct molecular tive studies.
vulnerabilities. Both oesophageal squamous cell
carcinoma and oesophageal adenocarcinoma show Pathology and molecular typing
alterations in chromatin-modifying enzymes. Oesophageal squamous cell carcinoma and oesophageal
Amplifications of chromosome 3q with genes essential adenocarcinoma are typically considered two distinct
for squamous cell maturation are frequent in oesopha disease entities with different tissues of origin
geal squamous cell carcinoma, whereas oesophageal and molecular hallmarks.2,22 Generally, oesophageal
adenocarcinoma usually exhibits amplifications of squamous cell carcinoma arises from epithelial cells,
GATA4 and GATA6, which are associated with gastric and oesophageal adenocarcinoma arises from glandular
See Online for appendix adenocarcinoma (appendix p 1).12,13 Advances in single- cells in the lower part of the oesophagus.
cell sequencing technologies have also provided novel The molecular taxonomy of oesophageal cancer has
insights into the cancer biology of oesophageal cancer made rapid progress; studies in the last decade have
(appendix p 1). uncovered distinct molecular subtypes that have great
potential for prognosis stratification and treatment
Population screening strategy guidance.23 Molecular biomarkers, such as
Studies published in the last decade underscore endo microsatellite instability-high, mismatch repair defi
scopic screening as a key approach for the early detection ciency, and high tumour mutational burden, are
and timely treatment of oesophageal cancer and its associated with favourable responses to immunother
precursor lesions in populations at high risk.14 The apy.23 Microsatellite instability or mismatch repair
criteria to identify populations at high risk for oesopha testing is recommended for oesophagogastric junction
geal squamous cell carcinoma and oesophageal adenocarcinomas but is not yet standard in oesophageal
adenocarcinoma are quite different. Individuals who are squamous cell carcinoma treatment guidelines.
at high risk for oesophageal squamous cell carcinoma Furthermore, the roles of human epidermal growth
include those aged 40 years and older living in high- factor receptor 2 (HER2), programmed death-ligand 1
incidence areas or those with a history of cancer, a family (PD-L1), and other novel genomic markers, are increas
history of oesophageal cancer, or other relevant risk ingly recognised, providing more diverse and
factors, such as smoking, heavy alcohol consumption, a personalised treatment options for patients with
history of squamous cancer of the head and neck, and a oesophageal cancer than previously available.
preference for very hot or pickled food. For these indi
viduals, chromoendoscopy coupled with biopsy of HER2
suspicious regions is the recommended screening The proportion of patients with HER2-overexpressing
approach to reduce oesophageal squamous cell carci oesophagogastric junction adenocarcinoma ranges
noma-related mortality.14 between 10% and 20% according to different studies.24
For Barrett’s oesophagus and oesophageal adenocarci Patients with HER2-positive oesophageal adenocarci
noma, the American College of Gastroenterology noma—defined as immunohistochemical expression 2+
guidelines advocate a single screening endoscopy for (ie, weak to moderate, complete staining in more than
individuals with chronic gastro-oesophageal reflux 10% of cells) or 3+ (ie, strong, complete membrane
disease symptoms and three or more additional risk staining in more than 10% of cells) combined with
factors for Barrett’s oesophagus, including male sex, age positive fluorescent in-situ hybridisation verification
1992 www.thelancet.com Vol 404 November 16, 2024

Seminar
Cell cycle Squamous cell maturation Wnt pathway

• CCND1 • SOX1 • DVL3
• CDNK2A • p63 • LRP5
• CDK6 • ZNF750 • LRP6
20 cm
• E2F1 • NOTCH1 • SFRP4 Oesophageal squamous cell carcinoma
Cell cycle Chromatin remodelling DNA repair • Loss of CDKN2A

• PIK3CA • KDM6A • TP53 • Chromosome 3q gain
Upper
• KRAS and MRAS • KMT2D
thoracic
• EGFR • KMT2C
• AKT p53 aberrations
25 cm
Toxins, tobacco
Middle
thoracic
Oesophagus
30 cm
Lower
thoracic
Healthy epithelium Intraepithelial neoplasia Oesophageal squamous cell carcinoma
40 cm Oesophageal adenocarcinoma
Squamocolumnar
junction
Oesophagogastric
junction
RTK pathway Cell cycle
42 cm • KRAS • CDKN2A
• HER2 • MYC
• EGFR • CCND1
Stomach • PIKSCA • CDK6
Gastrointestinal
development factor
• GATA4
Oncogene • GATA6
Tumour suppressor gene • MUC6
TGF-β Chromatin remodelling
• SMAD4 • ARID1A
• SMARCA4 DNA damage repair Chromatin instability
• ARID2 • TP53 • Hypermethylation
Wnt
• ARID1B • MDM2 • High driving oncogene burden
• APT
Healthy epithelium Barrett's oesophagus Oesophageal adenocarcinoma
Figure: Genomic changes during the development of oesophageal cancer

Oesophageal squamous cell carcinoma and oesophageal adenocarcinoma are the two major histological types of oesophageal cancer. Oesophageal squamous cell carcinoma typically arises in the upper
and middle oesophagus, whereas oesophageal adenocarcinoma predominates near the oesophagogastric junction. Oesophageal squamous cell carcinoma develops from malignant transformation of
the squamous epithelium due to chronic exposure to tobacco and alcohol, with environmental carcinogens inducing DNA damage and somatic mutations. Key drivers include TP53 mutations, somatic
copy number alterations, and inactivation of cell cycle regulators, such as CDKN2A, leading to intraepithelial neoplasia. Genomic instability in intraepithelial neoplasia disrupts key pathways, such as
RTK signalling, squamous cell maturation, and Wnt signalling, and causes chromatin remodelling, which can progress to oesophageal squamous cell carcinoma. In contrast, oesophageal
adenocarcinoma arises from intestinal metaplasia at the squamocolumnar junction due to chronic gastric acid reflux, forming Barrett’s oesophagus. Dysplasia of gland cells, driven by TP53 mutations
and oncogene alterations (eg, HER2), leads to oesophageal adenocarcinoma. Oncogene activation and tumour suppressor gene inactivation result in the malignant transformation from Barrett’s
oesophagus to oesophageal adenocarcinoma, through dysregulation of the RTK, TGF-β, and Wnt signalling pathways and chromatin remodelling. Genomically, oesophageal adenocarcinoma shares
similarities with gastro-oesophageal adenocarcinoma of the chromatin instability type. RTK=receptor tyrosine kinase.
(ie, ratio of HER2 copy number and number of chromo proportion score, combined positive score, and tumour
some 17 centromeres within the nucleus ≥2 or average area positivity. Tumour proportion score measures PD-L1
HER2 copy number ≥6)—can benefit from anti-HER2 positivity only in tumour cells, whereas combined
targeted therapies.25 positive score provides a more biologically relevant
assessment by including PD-L1 staining in tumour cells,
PD-L1 lymphocytes, and macrophages (appendix p 10). With its
PD-L1 is one of the most extensively studied biomarkers increasing use in clinical trials, combined positive score
in studies investigating immunotherapy responders. has been endorsed by the National Comprehensive
Currently adopted scoring systems include tumour Cancer Network (NCCN) guidelines and is supported by

Seminar
the US Food and Drug Administration (FDA), which early-stage oesophageal cancer with increased specificity,
approved PD-L1 immunohistochemical 22C3 pharmDx particularly in the upper oesophagus, where tumours are
(Agilent, Santa Clara, CA, USA) as a surrogate for PD-L1 frequently missed by Lugol’s solution.31
positivity. The widely used eighth edition of the American Joint
Although cutoffs for PD-L1 expression vary across trials, Committee TNM cancer staging system introduces pre
overall survival was consistently prolonged with immune treatment, surgery-alone, and post-treatment
checkpoint inhibitor monotherapy versus chemotherapy pathological TNM stagings to accommodate the use of
as the second-line treatment for patients with high PD-L1 neoadjuvant therapy.32 Endoscopic ultrasound is
expression. However, first-line treatment trials reported a powerful tool to detect tumour invasion depth and
disputable results regarding the predictive value of PD-L1 lymph node metastasis.33,34 One study proposed that
expression for chemoimmunotherapy. As presented in submucosal saline injection can increase the diagnostic
the KEYNOTE-590 and CheckMate-648 trials, patients accuracy of endoscopic ultrasound in discriminating T1a
with high PD-L1 expression had better overall survival (ie, tumours invading the lamina propria or muscularis
with PD-1 inhibitors plus chemotherapy compared with mucosae) and T1b (ie, tumours invading the submucosa)
chemotherapy alone. Conversely, the benefit was absent tumours from 66% to 94%.35 Moreover, endoscopic
in individuals with low PD-L1 expression.26,27 mucosal resection aids diagnosis of T1b tumours. MRI
Furthermore, the post-hoc analysis of the JUPITER-06 is valuable for detecting tumour invasion to adjacent
trial and meta-analysis supported the superiority of organs (T4a and T4b),36 whereas endobronchial ultra
PD-1 antibodies plus chemotherapy over chemotherapy sound can facilitate the diagnosis of airway invasion
alone in patients with low PD-L1 expression.28 These with high sensitivity and specificity,33,37 especially for
findings challenge the notion that PD-L1 expression is tumours situated at the cervical, thoracic superior, and
an unequivocal biomarker for chemoim muno therapy middle segments of the oesophagus. Both CT and
response in oesophageal squamous cell carcinoma, PET-CT, despite their wide use, show poor performance
underscoring the necessity for more reliable molecular for primary tumour staging, with accuracies below 50%.38
typing biomarkers. Antibodies for other therapeutic CT and PET-CT might complement endoscopic ultra
targets, such as claudin-18 isoform 2 (CLDN18.2), show sound in the detection of lymph node metastasis with
promising potential in treating oesophageal adenocarci overall sensitivities of 50% and 57%, and specificities
noma, as evidenced by the SPOTLIGHT and GLOW of 83% and 85% respectively.39 PET-CT is useful for
trials (appendix p 2).29,30 Novel therapeutic targets, evaluation of systemic metastasis, although it has less
including FGFR, and molecular classifications based on clinical value in staging early oesophageal cancer.40
multi-omics technologies are also discussed in the Ultrasound shows high accuracy in diagnosing nodal
appendix (p 2). involvement in the neck, which can facilitate aspiration
biopsy. However, one meta-analysis reported that these
Symptoms and signs of oesophageal cancer imaging techniques are insufficiently accurate for
Because of the inaccessibility of the oesophagus to staging after neoadjuvant treatment.41
clinical examination, obtaining a detailed history from
the patient is of paramount importance. Treatment principles
The most common symptom of oesophageal cancer is On diagnosis, patients should undergo comprehensive
difficulty swallowing (dysphagia). As the oesophageal assessments to determine pathological subtype, TNM
tumour grows, it might progressively impede the passage stage, tumour location, and performance status,
of solid and subsequently semisolid food, and liquids in including cardiorespiratory fitness and treatment toler
later stages. Dysphagia typically manifests insidiously ability. Optimal therapeutic strategies vary by TNM stage
and becomes apparent when the tumour has infiltrated and substantially affect prognosis, making stage-specific
about two-thirds of the circumference of the oesophagus, therapy recommendations essential for both oesophageal
often indicating locally advanced disease. Other squamous cell carcinoma and oesophageal adenocarci
commonly observed symptoms include heartburn and noma patients (table 1).
unintended weight loss (appendix p 3). Superficial oesophageal cancer denotes tumours
limited to the submucosal layer without lymph node
Diagnostic and staging considerations metastasis. Optimal treatment for T1a tumours is endo
As with other solid tumours, therapy recommendations scopic therapy, such as endoscopic mucosal resection or
for oesophageal cancer depend on accurate diagnosis endoscopic submucosal dissection. Radiofrequency
and staging. For symptomatic patients, radioscopy radi ablation is also used for treatment of dysplasia or very
ography with barium swallow contrast helps to identify early-stage adenocarcinoma in high-income countries.57
cancer location and obstruction severity. Endoscopy is However, the role of endoscopic submucosal dissection
performed to ascertain lesion size and location and to in managing T1b oesophageal cancer remains under
obtain tissue for pathological diagnosis. Additionally, debate, given that nodal involvement is observed in
narrow-band imaging has improved the detection of 16·6% of patients, nearly three-fold the rate in

Seminar
Optimal treatment
cTis-1aN0M0
Oesophageal squamous cell Endoscopic submucosal dissection or endoscopic mucosal resection or endoscopic radiofrequency ablation
carcinoma
Oesophageal adenocarcinoma Endoscopic submucosal dissection or endoscopic mucosal resection or endoscopic radiofrequency ablation
cT1b-2N0M0
Oesophageal squamous cell Oesophagectomy options include two-field lymphadenectomy including recurrent laryngeal nerve lymph node, minimally
carcinoma invasive oesophagectomy,42–44 or robot-assisted minimally invasive oesophagectomy,45 rather than open surgery; adjuvant
chemotherapy if patients staged as pN1–3;46 postoperative radiation for patients without R0 resection
Oesophageal adenocarcinoma Oesophagectomy options include two-field lymphadenectomy including recurrent laryngeal nerve lymph node, minimally
invasive oesophagectomy,42–44 or robot-assisted minimally invasive oesophagectomy,45 rather than open surgery; adjuvant
chemotherapy if patients staged as pN1–3;46 postoperative radiation for patients without R0 resection
cT1-4aN1-3M0 or cT3-4aN0M0
Oesophageal squamous cell Neoadjuvant chemoradiotherapy and surgery (paclitaxel and platinum and 41·4 Gy radiation)47,48 or neoadjuvant triplet
carcinoma chemotherapy (fluorouracil, platinum, and docetaxel);49 adjuvant single-agent immune checkpoint inhibitors for patients
without pathological complete response after neoadjuvant therapy;50 postoperative radiation for patients without R0
resection
Oesophageal adenocarcinoma Perioperative chemotherapy (fluorouracil, leucovorin, oxaliplatin, and docetaxel)51 or neoadjuvant chemoradiotherapy and
surgery (paclitaxel and platinum and 41·4 Gy radiation);48 adjuvant single-agent immune checkpoint inhibitors for patients
without pathological complete response after neoadjuvant therapy;50 postoperative radiation for patients without R0
resection
cT4bN0-3M0
Oesophageal squamous cell Definitive chemoradiotherapy (50·4 Gy radiation, FOLFOX or paclitaxel and platinum);52,53 surgery for persistent and recurrent
carcinoma disease54,55
Oesophageal adenocarcinoma Definitive chemoradiotherapy (50·4 Gy radiation, FOLFOX or paclitaxel and platinum);52,53 surgery for persistent and recurrent
disease54,55
cTanyNanyM1
Oesophageal squamous cell For patients with low PD-L1 expression, chemoimmunotherapy combining paclitaxel, platinum, and immune checkpoint
carcinoma inhibitors remains a recommended approach;28 however, the survival benefit in this group is less pronounced than individuals
with high PD-L1 expression*
Oesophageal adenocarcinoma If HER2-positive and PD-L1-high, anti-HER2 trastuzumab and chemoimmunotherapy (fluorouracil and cisplatin and immune
checkpoint inhibitors);56 if HER2-negative and PD-L1-high, chemoimmunotherapy (fluorouracil and cisplatin and immune
checkpoint inhibitors); if HER2-negative and PD-L1-low: chemotherapy (fluorouracil and cisplatin) and immune checkpoint
inhibitors†
Pathological diagnosis for staging is by endoscopic biopsy, with endoscopic ultrasound to diagnose tumour (T) stage, endoscopic ultrasound or CT to diagnose node (N)
stage, and PET-CT to diagnose metastasis (M) stage. For molecular diagnosis, PD-L1 testing is used for oesophageal squamous cell carcinoma. For oesophageal
adenocarcinoma, PD-L1 and HER2 is used, as well as microsatellite, tumour mutation burden, CLDN18, and FGFR2b testing. FOLFOX=leucovorin, fluorouracil, and oxaliplatin.
*The cutoff of high expression of PD-L1 varies across clinical trials; commonly seen criteria include combined positive score of at least 10 or tumour area positivity of at least
1. †The US Food and Drug Administration approved the use of immune checkpoint inhibitors combined with chemotherapy in patients with a combined positivity score less
than 5, whereas the European Medicines Agency did not approve its use for patients with a combined positivity score less than 5.
Table 1: Standard treatment for different stages of the two subtypes of oesophageal cancer
T1a disease.58 Therefore, current evidence and the NCCN In patients with T4 tumours encroaching on adjacent
guidelines prefer oesophagectomy in most patients with organs, including the lung, bronchus, azygos vein, pre
T1b oesophageal cancer. vertebral fascia, inferior pulmonary vein, and
For oesophageal cancer invading the muscular layer pericardium, induction therapies are still encouraged to
without other metastases (ie, T2N0M0), oesophagectomy render borderline-resectable tumours potentially
with lymph node dissection is the standard treatment.34 operable. Compared with chemoradiotherapy alone,
For locally advanced disease characterised by high tumour radical surgery might improve the prognosis for these
burden and nodal involvement (ie, T1-4N1-3M0), pre patients.62 Moreover, for patients who have persistent
operative treatment, including chemotherapy and disease or recurrence after definitive chemoradiotherapy,
chemoradiotherapy, is recommended.47,48,59–61 Neoadjuvant salvage oesophagectomy can have a favourable prognosis
chemoradiotherapy is the preferred scheme for oesophageal if the tumour is resectable.54 Definitive chemoradiother
squamous cell carcinoma based on existing literature,47,48 apy is the primary option for non-surgical candidates
and both preoperative and perioperative chemotherapies with cervical segment oesophageal cancer, supraclavicu
are endorsed for oesophageal adenocarcinoma.59–61 For lar or retroperitoneal lymph node metastasis, or an
those who receive neoadjuvant chemoradiotherapy intolerance for or refusal of surgery. For patients afflicted
plus oesophagectomy without a pathological complete with distant metastasis, systemic therapy should be indi
response, adjuvant therapy with the anti-PD-1 antibody vidualised in the context of performance status and
nivolumab can reduce recurrence risk.50 tumour genetics.

Seminar
Endoscopic treatments Surgical approaches and minimally invasive procedure

Endoscopic interventions, including endoscopic Generally, oesophagectomy can be performed through
resection, endoscopic radiofrequency ablation, and transthoracic—eg, Ivor Lewis procedure (intrathoracic
photodynamic therapy, have indispensable roles in anastomosis), McKeown procedure (cervical anastomo
managing precancerous lesions and early-stage oesoph sis), or Sweet procedure (left intrathoracic operation)—or
ageal cancer. Numerous studies have shown the transhiatal approaches. Transthoracic surgery is
importance of endoscopic radiofrequency ablation as preferred for patients with favourable overall health con
a preventive and therapeutic treatment for Barrett’s ditions, as it achieves a greater rate of R0 resection,
oesophagus and early-stage oesophageal adenocarci a broader extent of lymph node dissection, and superior
noma, with a 25% reduction in the risk of progression survival outcomes compared with transhiatal proce
to high-grade dysplasia or oesophageal adenocarci dures.73 For patients with oesophagogastric junction
noma.63 Endoscopic resection procedures, notably adenocarcinoma and reduced performance status, tran
endoscopic mucosal resection and endoscopic submu shiatal operation is a safer and more tolerable alternative,
cosal dissection, initially used for pathological due to the reduced extent of dissection required.74
diagnosis, have gradually evolved into foundational With the rapid advancement of thoracoscopic tech
therapies for superficial oesophageal cancer (appendix niques, there has been a transition from open-chest
p 4). Endoscopic submucosal dissection, which outper procedures to minimally invasive oesophagectomy.
forms endoscopic mucosal resection in efficacy, has Multiple trials have shown that minimally invasive
higher rates of complete resection (92·3% vs 52·7%) oesophagectomy reduces postoperative complications
and lower rates of local recurrence (0·3% vs 11·5%), without compromising survival compared with open
albeit at the cost of a 5% risk of stenosis.64,65 Advances in procedures.42,43,45,75,76 The MIRO study also showed the
endoscopic traction techniques have broadened the superiority of hybrid minimally invasive oesophagec
applicability of endoscopic submucosal dissection to tomy over open procedures in reducing postoperative
more extensive and circumferential lesions.66 These complications.43 Currently, the clinical application of
oesophagus-sparing procedures offer survival outcomes robotic surgery systems for oesophageal cancer is still in
comparable to oesophagectomy with superior health- the nascent stage. The ROBOT trial, which randomly
related quality of life, hence their endorsement for assigned patients to robot-assisted minimally invasive
treating T1a oesophageal adenocarcinoma in clinical oesophagectomy or open surgery, reported fewer cardio
guidelines.67 However, T1a oesophageal squamous cell pulmonary complications, reduced postoperative
carcinoma with high-risk features and T1b oesophageal discomfort, and improved short-term health-related
squamous cell carcinoma discovered accidently by quality of life and functional recovery in the robot-
endoscopic resection warrant additional treatment assisted minimally invasive oesophagectomy group than
with oesophagectomy or chemoradiotherapy.68 The the open surgery group.45 These promising results
JCOG0508 trial highlighted the efficacy of endoscopic prompted the initiation of the ROBOT-2 trial to compare
resection followed by chemoradiotherapy in SM1 or robot-assisted minimally invasive oesophagectomy with
SM2 cancer, yielding a promising 3-year overall survival traditional minimally invasive oesophagectomy.75
rate (92·6%) with low rates of adverse events.69
Photodynamic therapy can be considered a treatment Lymphadenectomy
for tumour recurrence after surgery or radiotherapy, Squamous cell carcinoma
with a complete response rate of 63·0% and a 2-year Unlike oesophageal adenocarcinoma, oesophageal
overall survival rate of 79·5%.70 The increasing recogni squamous cell carcinoma often presents with lymph
tion of endoscopic techniques reflects their irreplaceable node metastases in the upper mediastinal and cervical
role in minimally invasive treatment. More details regions, primarily involving the bilateral recurrent
regarding endoscopic treatment can be found in various laryngeal nerve lymph nodes, with an incidence ranging
international guidelines.15,68 from 15% to 34%.77,78 In one clinical trial (NCT01047111)
regarding the extent of lymph node dissection, patients
Surgical treatments receiving total mediastinal lymphadenectomy (including
Surgical resection is the foundational treatment for bilateral recurrent laryngeal nerve lymph nodes) had
localised and locally advanced oesophageal cancer. better overall survival and disease-free survival than
Standard radical surgery typically involves oesophagec those with standard mediastinal lymphadenectomy.79
tomy and lymphadenectomy followed by digestive tract Moreover, three-field lymphadenectomy (thoracic,
reconstruction, commonly using the stomach (appendix abdominal, and neck fields) does not confer a survival
p 5). The incidence of complications associated with advantage over two-field (thoracic and abdominal fields)
oesophagectomy ranged from 17% to 74%.71 The manage lymphadenectomy in patients with tumours located in
ment of complications and practices of enhanced the middle and distal oesophagus.80 Therefore, two-field
recovery after surgery have been extensively reviewed lymphadenectomy with thorough bilateral recurrent
elsewhere.71,72 laryngeal nerve lymph node dissection is recommended

Seminar
for patients with oesophageal squamous cell carcinoma survival for those who received surgery alone was
(appendix p 6).78 From this perspective, the McKeown 21·1 months, whereas the median overall survival of
oesophagectomy might provide a more comprehensive patients in the chemoradiotherapy group was
lymphadenectomy for the bilateral recurrent laryngeal 81·6 months (HR 0·48, 95% CI 0·28–0·83, p=0·008).
nerve than the Ivor Lewis procedure does. However, the Moreover, compared with surgery alone, preoperative
McKeown procedure poses an increased risk of post chemoradiotherapy did not adversely affect short-term or
operative complications, such as recurrent laryngeal long-term health-related quality of life.93
nerve injury and anastomotic leakage. Further studies In another study, NEOCRTEC5010, 451 patients with
are warranted to compare the two procedures. oesophageal squamous cell carcinoma were randomly
assigned to surgery alone or neoadjuvant chemoradio
Adenocarcinoma therapy followed by surgery. The chemotherapy regimen
The extent of lymphadenectomy for oesophageal adeno of vinorelbine and cisplatin were administered every
carcinoma remains a crucial topic of academic debate. three weeks for two cycles delivered concurrently with a
Transthoracic oesophagectomy with en-bloc (ie, removed radiotherapy regimen of 40 Gy in 20 fractions.47,90
with surrounding adipose tissue) two-field lymphadenec Participants treated with surgery alone had a median
tomy stands as a prevailing consensus, with the NCCN overall survival of 66·5 months, compared with
guidelines recommending resection of at least 15 lymph 100·1 months for participants in the chemoradiotherapy
nodes for adenocarcinoma.34 The optimal extent and group (HR 0·71 [95% CI 0·53–0·96]; p=0·025).90
locations for lymph node dissection are still being inves Building on the NEOCRTEC5010 trial, another study
tigated by the ongoing TIGER trial.81 In the context of showed that neoadjuvant chemoradiotherapy plus
neoadjuvant therapy, some studies underscore the surgery is a cost-effective strategy.94 These results have
importance of dissecting an adequate number of lymph led to the adoption of neoadjuvant chemoradiotherapy
nodes.82 The effects of surgery occuring mostly in high- as the standard of care for numerous patients with
volume hospitals and cancer centres are discussed in the locally advanced oesophageal squamous cell carcinoma
appendix (p 6). scheduled for oesophagectomy.
Chemotherapy is another neoadjuvant alternative.
Neoadjuvant therapy The JCOG9907 trial showed that preoperative chemo
In the last two decades, neoadjuvant therapy has greatly therapy (ie, cisplatin plus fluorouracil) offered superior
reshaped the treatment landscape of locally advanced overall survival than postoperative chemotherapy in
oesophageal cancer (table 2). A meta-analysis of oesophageal squamous cell carcinoma.83 As for direct
26 randomised trials revealed that, compared with comparison between the neoadjuvant chemoradio
surgery alone, both neoadjuvant chemotherapy and therapy and chemotherapy, the CMISG1701 trial
chemoradiotherapy improved overall survival (hazard reported a 9% non-significant increase of 3-year overall
ratio [HR] for chemotherapy 0·86, 95% CI 0·75–0·99, survival rate with the addition of radiotherapy with neo
p=0·03; HR for chemoradiotherapy 0·77, 0·68–0·87, adjuvant chemotherapy (cisplatin and paclitaxel) in
p<0·001).88 According to the findings of the CROSS and cT3-4aN0-1M0 oesophageal cancer;87 the conclusions of
NEOCRTEC5010 trials, preoperative chemoradiotherapy this study might be further compromised due to the
plus surgery is recommended as a standard treatment for small sample size and the exclusion of patients who
locally advanced oesophageal cancer.89,90 To date, potential were staged as cN2–3.
candidates for neoadjuvant therapy are patients with The three-arm JCOG1109 trial49 found that neoadjuvant
stage T1-4N1-3M0 disease. For patients with T1b-T2N0M0 platinum triplet therapy (docetaxel plus cisplatin plus
tumours (ie, tumours invading the muscular layer fluorouracil) significantly improved median overall
without other metastases), the role of neo adjuvant survival compared with the cisplatin plus fluorouracil
therapy is not clear; the FFCD9901 trial showed that pre regimen (docetaxel plus cisplatin plus fluorouracil overall
operative chemoradiotherapy did not improve R0 survival not reached vs cisplatin plus fluorouracil
resection rate and survival, but exacerbated postoperative overall survival of 5·6 years; HR 0·68 [95% CI 0·50–0·92];
mortality in these patients.91 Restaging before p=0·006). There was no statistically significant difference
oesophagectomy is recommended for all patients taking regarding median overall survival between the cisplatin
neoadjuvant treatment.92 plus fluorouracil group (5·6 years) and the chemoradio
therapy group (7·0 years; HR 0·84 [0·63–1·12]; p=0·12).
Squamous cell carcinoma The docetaxel plus cisplatin plus fluorouracil group had
The CROSS randomised controlled trial evaluated the higher rates of grade 3 or 4 haematological adverse
efficacy of a regimen involving five cycles of weekly events—ie, 167 (85%) of 196 patients with neutropenia
chemotherapy (carboplatin and paclitaxel) combined and 32 (16%) of 196 patients with febrile neutropenia.
with concurrent radiotherapy (41·4 Gy over Regarding cause of mortality, the chemoradiotherapy
23 fractions).48,84,89 Of 84 patients diagnosed with oeso group had higher rates of non-cancer-related
phageal squamous cell carcinoma, the median overall deaths (ie, 23 [26%] of 89 patients) than the docetaxel plus

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Number of Tumour histology Treatment Overall survival Progression-free

participants rate (%);* survival or disease-free
HR (95% CI) survival rate (%);* HR
(95% CI)
Neoadjuvant chemotherapy
OEO259 802 Oesophageal squamous cell carcinoma (247), Neoadjuvant chemotherapy (fluorouracil and platinum) 17% vs 23%; NR; NR
oesophageal adenocarcinoma (533), vs surgery 0·84 (0·72–0·98)
undifferentiated or unknown cancer (22)
JCOG990783 330 Oesophageal squamous cell carcinoma Neoadjuvant chemotherapy (fluorouracil and platinum) 55% vs 43%; Progression-free
vs adjuvant chemotherapy (fluorouracil and platinum) 0·73 (0·54–0·99)† survival 44% vs 39%;
0·84 (0·63–1·11)†
Perioperative chemotherapy
MAGIC61 503 Gastro-oesophageal junction (131), gastric cancer Perioperative chemotherapy (fluorouracil and platinum) 36% vs 23%; Progression-free
(372) vs surgery 0·66 (0·53–0·81) survival NR;
0·75 (0·60–0·93)
FNCLCC– 224 Oesophageal adenocarcinoma (25), gastro- Perioperative chemotherapy (fluorouracil and platinum) 38% vs 24%; Disease-free survival
FFCD60 oesophageal junction (144), gastric cancer (55) vs surgery 0·69 (0·50–0·95) 34% vs 19%;
0·65 (0·48–0·89)
FLOT451 716 Gastro-oesophageal junction (398), gastric Fluorouracil, leucovorin, oxaliplatin, and docetaxel vs 45% vs 36%; Disease-free survival
cancer (318) epirubicin, cisplatin, and either fluorouracil or 0·77 (0·63–0·94) NR;
capecitabine 0·75 (0·62–0·91)
Preoperative chemoradiotherapy
CROSS48,84 366 Oesophageal squamous cell carcinoma (84), Neoadjuvant chemoradiotherapy (paclitaxel and 38% vs 25%; Progression-free
oesophageal adenocarcinoma (275), platinum) vs surgery 0·70 (0·55–0·89)† survival 44% vs 27%;
undifferentiated cancer (7) 0·69 (0·52–0·92)
NEOCRTEC501047 451 Oesophageal squamous cell carcinoma Neoadjuvant chemoradiotherapy (vinorelbine and 60% vs 49%; Disease-free survival
platinum) vs surgery 0·73 (0·55–0·97) 64% vs 43%;
0·55 (0·40–0·74)
Chemotherapy vs chemoradiotherapy
Neo-AEGIS85 362 Low oesophagus or type I gastro-oesophageal Perioperative chemotherapy‡ vs 55% vs 57%; Disease-free survival
junction (249), type II gastro-oesophageal neoadjuvant chemoradiotherapy (paclitaxel and 1·03 (0·77–1·38)§ NR;
junction (84), type III gastro-oesophageal platinum) 0·89 (0·68–1·17)
junction (29)
NeoRes86¶ 181 Squamous cell carcimona (50), adenocarcinoma Neoadjuvant chemoradiotherapy 49% vs 47%; Progression-free
(131) vs chemotherapy (fluorouracil and platinum) NR§ survival 44% vs 44%;
NR§
CMISG170187 264 Oesophageal squamous cell carcinoma Neoadjuvant chemoradiotherapy 64% vs 55%; Progression-free
vs chemotherapy (paclitaxel and platinum) 0·82 (0·58–1·18) survival 54·3% vs
49·8%;
0·83 (0·59–1·16)
JCOG110949 601 Oesophageal squamous cell carcinoma (591), Neoadjuvant chemoradiotherapy 68% vs 63%; Progression-free
basal cell cancer (8), oesophageal adenocarcinoma vs chemotherapy (fluorouracil and platinum) 0·84 (0·63–1·12)§ survival 62% vs 48%;
(2) 0·77 (0·59–1·01)
JCOG110949 601 Oesophageal squamous cell carcinoma (591), Neoadjuvant chemotherapy (fluorouracil, platinum, and 72% vs 63%; Progression-free
basal cell cancer (8), oesophageal adenocarcinoma docetaxel) vs chemotherapy (fluorouracil and platinum) 0·68 (0·50–0·92)§ survival 59% vs 48%;
(2) 0·67 (0·51–0·88)
HR=hazard ratio. NR=not reported. *5-year survival rate unless specified otherwise. †10-year survival. ‡Oxaliplatin and fluorouracil or capecitabine before 2018; and fluorouracil, leucovorin, oxaliplatin, and
docetaxel regimen after 2018. §3-year survival. ¶NeoRes trial is a phase 2 trial.
Table 2: Key randomised clinical trials of preoperative or perioperative therapy for resectable oesophageal cancer
cisplatin plus fluorouracil group (ie, seven [9%] of oesophagus and enhance health-related quality of life
74 patients) and the cisplatin plus fluorouracil (appendix p 7).
group (ie, 13 [13%] of 98 patients). This finding might
partly be due to the prophylactic irradiation of the middle Adenocarcinoma
and lower mediastinal lymph nodes, which might increase Since the 1980s, neoadjuvant chemotherapy has become
toxicity. the standard for managing oesophageal adenocarcinoma,
Given the high pathological complete response rates primarily using platinum–fluoropyrimidine
with neoadjuvant chemoradiotherapy, especially in combinations. Advancements have emerged from
oesophageal squamous cell carcinoma populations, three pivotal randomised controlled trials exploring
investigators have explored the potential of a so-called preoperative chemotherapy (OEO2 trial) and
watch-and-wait approach for patients who respond to perioperative chemotherapy (MAGIC and FNCLCC–
treatment. This approach aims to preserve the FFCD trials), which showed improved survival

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outcomes.59–61 The FLOT4 trial attempted to identify the radiotherapy, the role of postoperative radiotherapy and
optimal drug combinations between the fluorouracil, chemoradiotherapy has diminished in individuals
leucovorin, oxaliplatin, plus docetaxel (ie, FLOT) regimen receiving radical resection. However, patients with
and the pharmorubicin, cisplatin, plus either fluorouracil positive margins should be considered for postoperative
or capecitabine (ie, ECF/ECX) regimen; the trial showed chemoradiotherapy if radiotherapy was not administered
a statistically significant 9% increase in both the 3-year preoperatively.
and 5-year overall survival rates in patients with Single-agent immune checkpoint inhibitors are
adenocarcinoma who received FLOT.51 Preoperative appealing options in the adjuvant setting due to their
chemoradiotherapy is also a standard approach for locally reduced toxicity compared with cytotoxic chemotherapy.
advanced oesophageal adenocarcinoma. In the subgroup The CheckMate-577 trial showed efficacy of a 12-month
analysis of 275 patients with adenocarcinoma from the nivolumab course in patients with residual disease after
CROSS trial, chemoradiotherapy significantly improved neoadjuvant chemoradiotherapy and oesophagectomy.50
overall survival (HR 0·73 [95% CI 0·55–0·98]; p=0·038), Compared with placebo, adjuvant nivolumab signifi
translating to an approximate 10% increase in 5-year and cantly improved disease-free survival (HR 0·69, 95% CI
10-year overall survival rates.48,84,89 0·56–0·86, p<0·001) with manageable toxicity and low
The comparative effectiveness of neoadjuvant chemo impact on health-related quality of life,50 and is now
radiotherapy and chemotherapy has emerged as a focal recommended in this setting. Future analysis of the
topic in oesophageal adenocarcinoma in the last decade. mature overall survival data will further confirm the role
The Neo-AEGIS study compared perioperative chemo of adjuvant immune checkpoint inhibitors in
therapy using the adjusted MAGIC regimen (epirubicin patients with oesophageal cancer receiving trimodality
plus cisplatin or oxaliplatin plus fluorouracil or capecit treatments.
abine) with that of neoadjuvant chemoradiotherapy used
in the CROSS regimen.85 Despite the higher rates of Radiotherapy
pathological complete response, major pathological For over a century, radiotherapy has been a foundational
response, and R0 resection in the neoadjuvant chemora treatment for oesophageal cancer. In the 1920s, Vinson
diotherapy group, median overall survival did not and colleagues pioneered the use of brachytherapy,
significantly differ between the two groups (neoadjuvant placing radium radioisotopes in proximity to the
chemoradiotherapy 48·0 months vs perioperative chem tumours. Modern clinics have used increasingly sophisti
otherapy 49·2 months; HR 1·03, 0·77–1·38, p=0·82) cated external-beam radiotherapy techniques, which
and 3-year overall survival rates were 55% in the neoad have been refined over the past three decades through
juvant chemoradiotherapy group versus 57% in the the evolution of computer-based treatment planning and
perioperative chemotherapy group. The ongoing delivery technologies.
ESOPEC trial is further exploring this comparison For patients with oesophageal cancer ineligible for
(NCT02509286). surgical resection, the standard treatment is definitive
The advent of immune checkpoint inhibitors marks chemoradiotherapy, which consists of external-beam
a new frontier in cancer therapy. Preliminary results radiotherapy (50·0–50·4 Gy in 1·8–2 Gy fractions over
from phase 1/2 trials have shown promising pathological 5–6 weeks) and concurrent chemotherapy. Common
complete response rates, particularly in oesophageal regimens include biweekly fluorouracil and oxaliplatin
squamous cell carcinoma, when immune checkpoint either with or without leucovorin (FOLFOX) or weekly
inhibitors are combined with neoadjuvant therapies carboplatin and paclitaxel.52,53 Initially reported in 1992,
(appendix p 7). Several randomised phase 3 studies are the RTOG 8501 multi-institutional phase 3 randomised
currently under way, including NEOCRTEC2101 controlled trial showed superior efficacy of chemoradio
(NCT05357846), iCROSS (NCT04973306), KEYSTONE- therapy (50 Gy in 25 fractions with concurrent cisplatin
002 (NCT04807673), JUPITER-14 (NCT04848753), and fluorouracil chemotherapy) compared with radio
NCT03221426, NCT03604991, and NCT02743494. therapy alone (64 Gy in 32 fractions) for patients with
localised oesophageal carcinoma.96 Chemoradiotherapy
Adjuvant therapy resulted in reduced local and distant recurrence, with
Postoperative chemotherapy is a key treatment for a 2-year overall survival rate of 38%, compared with the
patients with oesophageal adenocarcinoma. For oeso rate of 10% observed in patients treated with radiotherapy
phageal squamous cell carcinoma, postoperative alone (p<0·001), although chemoradiotherapy resulted
chemotherapy, radiotherapy, and chemoradiotherapy are in more treatment-related adverse events.
common. For patients receiving surgery alone, one pre Subsequent phase 3 randomised controlled trials have
vailing notion suggests that adjuvant chemotherapy or investigated whether escalating the external-beam radio
chemoradiotherapy are potentially only beneficial for therapy dose from 50 Gy to 60–65 Gy with concurrent
node-positive oesophageal squamous cell carcinoma chemotherapy could improve prognosis, but these
populations, as presented in meta-analyses and clinical yielded negative results.52,97 For example, in the
trials.46,95 With the widespread use of preoperative ARTDECO trial conducted in the Netherlands, patients

Seminar
with locally advanced oesophageal cancer were randomly first-line treatment with fluoropyrimidines (such as
assigned to receive either standard-dose external-beam capecitabine or fluorouracil), platinum agents (such as
radiotherapy (50·4 Gy in 28 fractions) or escalated-dose cisplatin or oxaliplatin), and PD-1 inhibitors has been
external-beam radiotherapy (61·6 Gy in 28 fractions), shown to improve clinical outcomes over chemotherapy
along with concurrent weekly carboplatin and paclitaxel alone, especially in patients with high PD-L1 expression,
chemotherapy. The 3-year local progression-free survival based on the results from CheckMate-649, ORIENT-16,
rates were 70% for the standard-dose group and 73% for and RATIONALE-305.106,108,110 However, whether the
the escalated-dose group, and the overall survival rates benefit of anti-PD-1 antibodies can be extended to patients
were 42% for the standard and 39% for the escalated.52 with low or unknown PD-L1 expression remains
Other topics, including novel radiotherapy techniques, controversial; thus, treatment decisions for these patients
palliative radiotherapy, and oesophagus-preservation should be carefully considered. For HER2-positive
approaches, using definitive chemoradiotherapy are oesophagogastric junction adenocarcinoma, the ToGA
discussed in the appendix (p 8). trial showed that addition of the anti-HER2 antibody
trastuzumab to chemotherapy improved overall survival,
Systemic therapy progression-free survival, and overall response rate.25
First-line systemic therapy Additionally, for HER2-positive oeso phagogastric
The goals of systemic therapy in patients with advanced junction adenocarcinoma accompanied by a combined
oesophageal cancer are to relieve symptoms, improve positive score of at least 1, pembrolizumab, combined
health-related quality of life, and prolong survival. Data with trastuzumab and chemotherapy, was approved by
have evidenced the survival benefit of systemic chemo the US FDA as a first-line treatment.111 For patients with
therapy for patients with advanced oesophageal cancer.98,99 mismatch repair deficiency or microsatellite instability-
Platinum-based combination regimens are the standard high oesophagogastric junction adenocarcinoma,
first-line therapy for oesophageal cancer. However, irrespective of PD-L1 expression, immunotherapy plus
advancements in the last decade in immune checkpoint systemic chemotherapy or pembrolizumab monotherapy
inhibitors have brought hope for potential cures for are both acceptable first-line treatments.
patients with advanced disease.
Chemoimmunotherapy has become a new standard Second-line and subsequent systemic therapy
first-line treatment for inoperable or metastatic oesopha Docetaxel, paclitaxel, or irinotecan are the recommended
geal cancer, including oesophageal squamous cell second-line and subsequent systemic treatments.112
carcinoma and oesophageal adenocarcinoma. Findings Owing to the development of immune checkpoint
from phase 3 clinical trials reported improved patient inhibitors in the last decade, therapeutic options have
survival when PD-1 inhibitors are added to chemotherapy diversified and largely depend on patients’ previous
(table 3).27,100–110 The selection of chemotherapy drugs and treatment history of immunotherapy in first-line therapy.
immune checkpoint inhibitors varies across different For patients with oesophageal squamous cell carcinoma
regions and patient conditions. In the USA and European without previous immunotherapy, PD-1 inhibitors, such
countries, the combination of cisplatin or oxaliplatin as pembrolizumab, nivolumab, and tislelizumab, have
with fluorouracil is preferred as the front-line chemo shown superior efficacy to standard chemotherapy in
therapy for treating adenocarcinoma. However, in Asian second-line treatment, according to the KEYNOTE-181,
countries where oesophageal squamous cell carcinoma ATTRACTION-3, and RATIONALE-302 trials.113–115 For
is more prevalent, particularly in China, the combination patients with advanced oesophagogastric junction ade
of paclitaxel and cisplatin is favoured, as evidenced by nocarcinoma who progress on previous chemotherapy
several first-line studies focused on oesophageal with or without trastuzumab, optional regimens include
squamous cell carcinoma. Currently, the overall impact ramucirumab plus paclitaxel, the FOLFIRI (ie, fluoro
of these distinct chemotherapy regimens on treatment uracil, leucovorin, and irinotecan) regimen with or
efficacy remains unclear and warrants further research. without ramucirumab, and single-agent chemotherapy.
Moreover, the diversity in the choice of PD-1 inhibitor In addition, for HER2-positive advanced oesophagogas
presents a challenge, as there are no head-to-head clinical tric junction adenocarcinoma, numerous innovative
trials directly comparing the specific efficacies of various HER2-targeted agents, such as margetuximab, trastu
PD-1 inhibitors. Thus, treatment decisions for specific zumab deruxtecan, and tucatinib, which are potentially
chemotherapy regimens and PD-1 inhibitors in patients more effective at inhibiting the HER2 pathway, have
with advanced oesophageal squamous cell carcinoma been investigated in late-line settings.
should be considered on a patient-specific basis.
Owing to disparities in tumour biology and molecular Immunotherapy for oesophageal cancer
profiles, the treatment of advanced oesophagogastric Immunotherapy, mainly immune checkpoint blockades,
junction adenocarcinoma differs slightly from have become prominent and effective treatments for
that of oesophageal squamous cell carcinoma. For HER2- oesophageal cancer. Following these advancements, we
negative oesophagogastric junction adenocarci noma, discuss several themes, including the chemotherapy

Seminar
Number of Tumour histology Treatment* Overall survival Progression-free

patients (months); survival (months);
HR (95% CI)† HR (95% CI)
KEYNOTE-59026 749 Oesophageal squamous cell carcinoma (548), Pembrolizumab and chemotherapy vs chemotherapy 12·4 vs 9·8; 6·3 vs 5·8;
oesophageal adenocarcinoma (201) (fluorouracil and cisplatin) 0·73 (0·62–0·86) 0·65 (0·54–0·78)
CheckMate-64827 970 HER2-negative oesophageal adenocarcinoma Nivolumab and chemotherapy vs chemotherapy (fluorouracil 13·2 vs 10·7; 5·8 vs 5·6;
and cisplatin) 0·74 (0·58–0·96) 0·81 (0·64–1·04)
CheckMate-64827 970 HER2-negative oesophageal adenocarcinoma Nivolumab and ipilimumab vs chemotherapy (fluorouracil and 12·7 vs 10·7; 2·9 vs 5·6;
cisplatin) 0·78 (0·62–0·98) 1·26 (1·04–1·52)
ESCORT-1st100 596 Oesophageal squamous cell carcinoma Camrelizumab and chemotherapy vs chemotherapy (paclitaxel 15·3 vs 12·0; 6·9 vs 5·6;
and cisplatin) 0·70 (0·56–0·88) 0·56 (0·46–0·68)
JUPITER-06101 514 Oesophageal squamous cell carcinoma Toripalimab and chemotherapy vs chemotherapy (paclitaxel and 17·0 vs 11·0; 5·7 vs 5·5;
cisplatin) 0·58 (0·43–0·78) 0·58 (0·46–0·74)
ORIENT-15102 659 Oesophageal squamous cell carcinoma Sintilimab and chemotherapy vs 16·7 vs 12·5; 7·2 vs 5·7;
chemotherapy (paclitaxel and cisplatin) 0·63 (0·51–0·78) 0·56 (0·46–0·68)
RATIONALE-306103 649 Oesophageal squamous cell carcinoma Tislelizumab and chemotherapy vs chemotherapy (investigator- 17·2 vs 10·6; 7·3 vs 5·6;
chosen doublet) 0·66 (0·54–0·80) 0·62 (0·52–0·75)
ASTRUM-007104 551 Oesophageal squamous cell carcinoma Serplulimab and chemotherapy vs chemotherapy (fluorouracil 15·3 vs 11·8; 5·8 vs 5·3;
and cisplatin) 0·68 (0·53–0·87) 0·60 (0·48–0·75)
GEMSTONE-304105 540 Oesophageal squamous cell carcinoma Sugemalimab and chemotherapy vs chemotherapy (fluorouracil 15·3 vs 11·5; 6·2 vs 5·4;
and cisplatin) 0·70 (0·55–0·90) 0·67 (0·54–0·82)
CheckMate649106 2031 HER2-negative oesophageal adenocarcinoma Nivolumab and chemotherapy vs chemotherapy (oxaliplatin and 13·7 vs 11·6; 7·7 vs 6·9;
capecitabine either with or without leucovorin) 0·79 (0·71–0·88) 0·79 (0·71–0·89)
CheckMate649106 2031 HER2-negative oesophageal adenocarcinoma Nivolumab and ipilimumab vs chemotherapy (oxaliplatin and 11·7 vs 11·8; 2·8 vs 7·1;
capecitabine or fluorouracil either with or without leucovorin) 0·91 (0·77–1·07) 1·66 (1·40–1·95)
Attraction-4107 724 HER2-negative gastric or gastro-oesophageal Nivolumab and chemotherapy vs chemotherapy (capecitabine 17·45 vs 17·15; 10·45 vs 8·03;
junction cancer and oxaliplatin or S1 and oxaliplatin) 0·9 (0·75–1·08) 0·68 (0·51–0·90)
ORIENT-16108 650 All gastric or gastro-oesophageal junction Sintilimab and chemotherapy vs chemotherapy (capecitabine 15·2 vs 12·3; 7·7 vs 5·8;
cancer and oxaliplatin) 0·66 (0·50–0·86) 0·63 (0·49–0·80)
KEYNOTE-859109 1579 HER2-negative gastric or gastro-oesophageal Pembrolizumab and chemotherapy vs chemotherapy (CAPOX 12·9 vs 11·5; 6·9 vs 5·6;
junction cancer [ie, capecitabine and oxaliplatin or fluorouracil and cisplatin] or 0·78 (0·70–0·87) 0·76 (0·67–0·85)
fluorouracil and cisplatin)
RATIONALE-305110 997 HER2-negative gastric or gastro-oesophageal Tislelizumab and chemotherapy vs 15·0 vs 12·9; 6·9 vs 6·2;
junction cancer chemotherapy (capecitabine and oxaliplatin or fluorouracil and 0·80 (0·70–0·92) 0·78 (0·67–0·90)
cisplatin)
KEYNOTE-811111 698 HER2-positive gastric or gastro-oesophageal Pembrolizumab and trastuzumab and chemotherapy vs 20·0 vs 16·8; 10·0 vs 8·1;
junction cancer trastuzumab and chemotherapy (capecitabine and oxaliplatin or 0·84 (0·70–1·01) 0·73 (0·61–0·87)
fluorouracil and cisplatin)
HR=hazard ratio. *Investigator-chosen chemotherapy doublet: a platinum agent (cisplatin or oxaliplatin) and a fluoropyrimidine (fluorouracil or capecitabine) or paclitaxel. †Survival data summarised in the table
is from overall or intent-to-treat population without selection by PD-L1 status.
Table 3: Summary of the key phase 3 clinical trials of immune checkpoint inhibitors in advanced oesophageal cancer
regimen, emerging novel immune checkpoint inhibi Palliative treatment and best supportive care
tors, and biomarkers of immunotherapy responses Despite advances in the screening and treatment of
(appendix p 9). oesophageal cancer, a considerable proportion of patients
remain ineligible for curative treatment, and more than
Follow-up and recurrence surveillance half of patients treated with curative intent will inevitably
Given the high recurrence potential of oesophageal have uncontrolled tumour recurrence.47 Palliative therapy
cancer, ongoing surveillance is essential for timely for the purpose of relieving suffering and improving the
treatment on recurrence. Although a previous study has health-related quality of life of patients is often necessary.
established the survival benefits of regular radiological Patients with extensive distant metastasis and poor per
monitoring,116 the optimal surveillance strategy for formance status, especially those with a short life
patients with oesophageal cancer with successful therapy expectancy, are typically candidates for palliative therapy
remains undefined. Typically, follow-up schedules last (appendix p 11).
5 years after treatment, as recurrence beyond this period
is relatively rare in patients with oesophageal cancer.117 Nutritional support
Intensified surveillance should be performed within the Compared with other cancers, patients with oesophageal
first 2 years after treatment since most recurrences occur cancer have a greater risk of malnutrition, because
during this timeframe (appendix p 11). dysphagia exacerbates during disease progression.117

Seminar
Contributors
Panel: Remaining research questions on oesophageal cancer Conceptualisation: JF and HY. Data curation: HY, FW, CLH, and TL.
Writing (original draft): HY, FW, CLH, and TL. Visualisation:
• What are the genetic determinants in oesophageal cancer development, progression, HY and FW. Funding acquisition: JF and HY. Supervision: JF.
and recurrence?
Declaration of interests
• What is the effective screening approach for individuals with high risk of oesophageal CLH has received travel support to attend the National Comprehensive
cancer? Cancer Network Neuroendocrine and Adrenal Tumor Panel annual
• What is the standard lymph node dissection for oesophageal adenocarcinoma? meeting, the ECOG-ACRIN Data Safety Monitoring Committee annual
meeting, and ASTRO-Veteran’s Health Administration Radiation
• Does immunotherapy in the neoadjuvant setting provide survival benefits? Oncology Quality Surveillance Program–Liver Cancer Panel outside the
• How can we enhance the diagnostic accuracy of clinical complete response after submitted work; and served as a member of the ECOG-ACRIN Data
neoadjuvant therapy? Safety Monitoring Committee and the National Cancer Institute Data
• Is the so-called watch-and-wait strategy appropriate for squamous cell carcinoma Safety Monitoring Board, Imaging and Radiation Therapy Committee
outside the submitted work. All other authors declare no competing
patients with clinical complete response? interests.
• What is the optimal treatment for patients with pathological complete response after
Acknowledgments
neoadjuvant therapy and surgery? Should the treatment be observation or adjuvant We thank Mian Xi (Department of Radiation Oncology, Sun Yat-sen
immunotherapy? University Cancer Center, China) for instruction on the writing of the
• Is adjuvant immunotherapy appropriate for patients who received perioperative radiotherapy section. We thank Changsen Leng (Department of Thoracic
chemotherapy plus surgery? Surgery, Sun Yat-sen University Cancer Center, China) for assisting with
preparation of figure materials. We thank Zihang Mai (Department of
• Is adjuvant immunotherapy appropriate for patients who received surgery alone with Thoracic Surgery, Sun Yat-sen University Cancer Center, China) for
postoperative upstaging? assistance with writing and revising the manuscript and preparing the
• How long should adjuvant immunotherapy last after surgery? data materials.
• Can the addition of immunotherapy into definitive chemoradiotherapy for one year or References
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Seminar

(GLOBOCAN) report, oesophageal cancer ranks as the recommendation.8–10

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Cell cycle Squamous cell maturation Wnt pathway

Cell cycle Chromatin remodelling DNA repair • Loss of CDKN2A

Healthy epithelium Barrett's oesophagus Oesophageal adenocarcinoma

Figure: Genomic changes during the development of oesophageal cancer

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