Seminar

Gastric cancer
Elizabeth C Smyth, Magnus Nilsson, Heike I Grabsch, Nicole CT van Grieken, Florian Lordick

Gastric cancer is the fifth most common cancer and the third most common cause of cancer death globally. Risk Lancet 2020; 396: 635–48
factors for the condition include Helicobacter pylori infection, age, high salt intake, and diets low in fruit and vegetables. Department of Oncology,
Gastric cancer is diagnosed histologically after endoscopic biopsy and staged using CT, endoscopic ultrasound, PET, Cambridge University
Hospitals National Health
and laparoscopy. It is a molecularly and phenotypically highly heterogeneous disease. The main treatment for early
Service Foundation Trust,
gastric cancer is endoscopic resection. Non-early operable gastric cancer is treated with surgery, which should include Hill’s Road, Cambridge, UK
D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial (E C Smyth MD); Division of
branches). Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers. Surgery, Department of Clinical
Science, Intervention and
Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine
Technology, Karolinska
doublet in the first line; median survival is less than 1 year. Targeted therapies licensed to treat gastric cancer include Institute, Stockholm, Sweden
trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or (M Nilsson PhD); Department of
pembrolizumab (anti-PD-1 third line). Upper Abdominal Diseases,
Karolinska University Hospital,
Stockholm, Sweden
Epidemiology and risk factors damage at the time of eradication. According to current (M Nilsson); Department of
Gastric cancer is a globally important disease. With over recommendations, eradi­cation of H pylori should be done Pathology, GROW School for
1 million estimated new cases annually, gastric cancer is in the following risk populations: pan-gastritis and corpus- Oncology and Developmental
Biology, Maastricht University
the fifth most diagnosed malignancy worldwide. Due to predominant gastritis, first-degree relatives of patients Medical Center+, Maastricht,
its frequently advanced stage at diagnosis, mortality from with gastric cancer, and previous gastric neoplasia.11–14 Risk Netherlands (H I Grabsch PhD);
gastric cancer is high, making it the third most com­ factors beyond H pylori for non-cardia gastric cancer are Pathology and Data Analytics,
mon cause of cancer-related deaths, with 784 000 deaths older age, low socio-economic status, cigarette smoking, Leeds Institute of Medical
Research at St James’s,
globally in 2018.1 Hotspots of inci­dence and mortality for alcohol consumption, familial predis­ position, previous University of Leeds, Leeds, UK
gastric cancer exist in East Asia, Eastern Europe, and gastric surgery, pernicious anaemia, and living in a (H I Grabsch); Department of
South America (figure 1). The incidence of gastric cancer population at high risk.15–17 Salted food intake might Pathology, Amsterdam
is two times higher in males than in females.1 A steady increase the risk of H pylori infection and could also act University Medical Centre,
Cancer Center Amsterdam,
decline in the incidence and mortality rates of this cancer synergistically to promote the develop­ ment of gastric VU University, Amsterdam,
have been observed over the past century. However, cancer. Therefore, dietary modification involving less salt Netherlands
despite declining incidence rates in most countries, and salted food intake is one possible strategy to prevent (N C T van Grieken PhD);
clinicians can expect to see more gastric cancer cases in gastric cancer. Gastric cancer risk might be decreased and University Cancer Center
Leipzig, Leipzig University
the future due to ageing populations. Improved living with a high intake of fruit and vegetables.18 In contrast to Medical Center, Leipzig,
conditions associated with economic development have distal gastric cancer, a positive association between gastro- Germany (F Lordick MD)
contributed to the reduction in the prevalence of oesophageal reflux disease and proximal (cardia type) Correspondence to:
Helicobacter pylori, the major cause of gastric cancer.3 In gastric cancer has been shown.19,20 Dr Elizabeth C Smyth,
high incidence areas such as Japan and Korea, screening Department of Oncology,
Cambridge University Hospitals
programmes have also led to substantial reductions Genetics of gastric cancer National Health Service
in gastric cancer associated mortality.4–6 An observed Approximately 10% of all gastric cancer cases show familial Foundation Trust, Hill’s Road,
increase in the incidence in younger people from aggregation and 1–3% of patients with gastric cancer have Cambridge CB2 0QQ, UK
high-income countries suggests a change in disease risk germline mutations.21 Hereditary forms of gastric cancer elizabeth.smyth2@nhs.net

and epidemiology of gastric cancer. Attention to ongoing
transitions in gastric cancer epidemiology is therefore
relevant to future cancer control and clinical practice.7
H pylori infection is the most well described risk factor
for non-cardia gastric cancer. Chronic infection of the
gastric mucosa leads to stepwise progression from
atrophic gastritis and intestinal metaplasia.8 The majority
of the population infected with H pylori remain asymp­
tomatic. Gastric cancer due to H pylori infection is
associated with bacterial virulence, genetic polymorphism
of hosts, and environmental factors. Most H pylori strains
possess a cytotoxin-associated gene A (CagA) pathogen­
icity island, encoding a 120–140 kDa CagA protein,
an oncoprotein that affects the expression of cellular
signalling proteins.9,10 Treatment of H pylori can reduce the
risk of transformation to gastric cancer, but the magnitude
of risk reduction depends on the degree of pre-existing
can be subdivided into three groups:21–23 hereditary diffuse
type gastric cancer (HDGC; autosomal dominant; <1% all
gastric cancer); familial intestinal gastric cancer (autosomal
dominant); and gastric adeno­ carcinoma with proximal
polyposis of the stomach (autosomal dominant).
Search strategy and selection criteria
We searched PubMed and abstracts from international
conferences (American Society of Clinical Oncology, European
Society of Medical Oncology [ESMO], and ESMO World
Congress on Gastrointestinal Cancer) between Nov 26, 2019,
and May 29, 2020, with the search terms “gastric cancer”,
“gastroesophageal cancer”, “surgery”, “genetics”,
“chemotherapy”, “targeted therapy”, and “immunotherapy”.
We only searched for articles and abstracts published in English.

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 Seminar
ASR world per 100 000
≥11·1
7·3–11·1
5·0–7·3
3·8–5·0
<3·8
Not applicable
No data
Figure 1: Gastric cancer age standardised incidence in males and females around the world2
Data from GLOBOCAN 2018, reproduced from reference 2, by permission of WHO/IARC. ASR=age-standardised rate.
30–40% of patients with HDGC carry mutations in the
CDH1 gene which encodes E-cadherin. Patients meeting
screening criteria for CDH1 testing should be referred to a
clinical geneticist and patients with identified pathogenic
CDH1 mutations should be managed at expert centres.
Prophylactic total gastrectomy is recommended for
individuals with pathogenic CDH1 mutations.24 In three
HDGC families, a germline mutation in CTNNA1 was
found, which encodes for αE-catenin.25 Potential other
candidate genes for HDGC include PALB2, the insulin
receptor, F-Box Protein 24 (FBXO24), and DOT1-like
histone H3K79 methyltransferase (DOT1-L) genes.26,27
However, in approxi­mately 70% of patients with HDGC,
the underlying genetic alteration is currently unknown.
Gastric adeno­carcinoma with proximal polyposis of the
stomach has been shown to be associated with point
mutations in the APC promotor 1B gene.28 Furthermore,
gastric cancer more frequently occurs in other hereditary
diseases such as familial adenomatous polyposis (APC),
Lynch syndrome (MLH1, MLH2, PMS2, and MSH6),
Cowden syndrome (PTEN), juvenile polyposis (BMPR1A
and SMAD4), Li-Fraumeni syndrome (TP53), MUTYH-
asso­ciated adenomatous polyposis (MUTYH) and Peutz-
Jeghers syn­drome (STK11).29
Histological classification systems
The macroscopic appearance of early gastric cancers is
described as protruded (type I), superficial (type II), or
excavated (type III).30,31 Type II lesions are further
subdivided into elevated, flat, or depressed. The macro­
scopic appearance of advanced early gastric cancers
is commonly classified according to Borrmann32 into
four types: polypoid without ulceration and broad base
(type I), ulcerated with elevated borders and sharp
margins (type II), ulcerated with diffuse infiltration at
the base (type III), and diffusely infiltrative thickening of
636 www.thelancet.com Vol 396 August 29, 2020
the wall (type IV). The Borrmann type appears to be
an independent prognostic factor and patients with
type IV gastric cancer having the poorest survival.33
Early and advanced stage gastric cancer are both char­
acterised by extensive morphological diversity resulting in
a still growing number of classification systems. The most
commonly used classifications outside Japan, are those
from Nakamura and colleagues,34 Laurén,35 and WHO.36
The Nakamura classification distinguishes the differ­
entiated type from the undif­ferentiated type, and forms an
essential part of the indication criteria for endoscopic
resection of early gastric cancer.34,37 The Laurén classifi­
cation distinguishes intestinal type, diffuse type, and
indeter­ minate or unclas­ sifiable type.35 Since Laurén’s
original publication, a large number of special types of
gastric cancer have been identified which do not fit
into the Laurén types. The WHO classification of gastric
adenocarcinoma has been criticised for its complexity
distinguishing many subtypes (tubular, parietal cell,
papillary, micropapillary, mucoepidermoid, mucinous,
poorly cohesive, signet ring cell, medullary carcinoma with
lymphoid stroma, hepatoid, and Paneth cell type), some of
which are very rare.8 There is con­flicting evidence about
the ability of the histopathological phenotype to predict
patient prog­nosis or response to therapy. This conflicting
evidence is most likely related to the variation in the
histopathological classification, an issue that has been
addressed for gastric cancer with signet ring cells in a
consensus statement by expert pathologists.38
Genomic classification systems
Several different molecular gastric cancers classification
systems have been proposed in the past decade often
attempting to relate molecular features to histological
phenotypes and clinical features.39,40 In 2014, results from
the most comprehensive integrated genome-wide analyses
 Seminar

of DNA copy number alterations, mutations, mRNA,
miRNA, and protein patterns done by The Cancer Genome
Atlas (TCGA) research network was published and four
molecularly distinct gastric cancer subtypes were proposed:
Epstein-Barr virus-positive (EBV+), microsatellite instable
(MSI), genomically stable, and chromosomal unstable
(CIN).41 MSI, CIN, and EBV+ had previously been iden­
tified as distinct subtypes, but had never been character­
ised in such molecular detail before.42–48 Showing some
overlap with TCGA, in an analysis based on mRNA
expression profiling done by the Asian Cancer Research
Group, gastric cancers were classified as MSI, microsatellite
stable (MSS) or epithelial mesenchymal transition, MSS
with TP53 intact, or MSS with TP53 loss.49 TP53 mutation
or overexpression by immunohistochemistry has been
proposed as a sur­rogate for the presence of CIN. Although
molecular characteristics (either specific gene alterations or
broader molecular subtypes) rather than morphological
features might guide future treat­ ment development,
Laurén’s classification is still the most com­monly used for
subgroup analyses in clinical trials. The proposed molecular
classifications overlap substantially with existing molecular
and morphological classifications as illustrated in figure 2.
These molecular analyses have increased our knowl­
edge regarding gastric cancer biology; however, the
clinical importance (prognosis and response to therapy)
of these subgroups is currently only strongly supported
for the MSI or EBV+ gastric cancers subtypes.50–53
Additional molecular subgroup testing is not yet done in
routine clinical practice as clinical decisions are currently
not based on molecular subtypes. However, mismatch
repair deficiency and HER2 are routinely tested as these
are strongly predictive biomarkers for drug therapy.
New developments in gastric cancer pathology
Digital image analysis
implications of being able to accurately classify different
types of gastric cancer, predict driver mutations, micro­
satellite instability status, and other features using deep
learning technology on low-cost H&E stained slides could
potentially be enormous.
Liquid biopsies
Liquid biopsies including the detection of cell-free
circulating tumour DNA (ctDNA), circulating tumour cells,
exosomes, and tumour educated platelets have the poten­
tial to transform cancer diagnosis, disease monitoring,
response prediction, and identification of recurrent disease.
Furthermore, liquid biopsies could provide a more repre­
sentative view of heterogeneous tumours, such as gastric
cancer, compared with tissue biopsies. So far, results from
ctDNA, rather than other forms of liquid biopsy, have been
most promising in patients with gastric cancer. However,
with the currently used gene panels, the ctDNA detection
rate in patients with early stage gastric cancer is low.
Nevertheless, if ctDNA is detectable before gastrectomy,
a decrease in ctDNA after chemotherapy appears to be
associated with response to neoadjuvant treatment and
if detected after gastrectomy, is associated with disease
recurrence and poor survival.67,68 Therefore, ctDNA
detection in patients with gastric cancer might be a new
clinically useful marker for minimal residual disease
monitoring, which could potentially guide new adjuvant
treatment strategies. As intratumour heterogeneity in
gastric cancer might influence detection of HER2 ampli­
fication in tumour tissue,69 circulating tumour cells or
ctDNA analyses could have added value for detecting HER2
amplification70,71 or revealing patterns of resistance to
trastuzumab.72 Although promising, further validation of
these studies is needed before clinical implementation.
Unkno

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CIN

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has shown potential to rapidly detect adenocarcinoma in

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gastric biopsies and resection specimens with relatively

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high sensitivity and specificity, supporting future diag­ V+

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so

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nostic pathology workflow as well as translational research

Ot

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by accurately segmenting gastric cancer regions for further Tubula

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EBV+ al or
analysis.54–57 Traditionally, histological gastric cancer classi­ Intestin
papilla
ry
fication has been based on features of the epithelial tumour CIN

component. However, there are other histological features

in the tumour microenvironment, such as tumour infil­
use

trating lymphocytes or the proportion of intratumoural

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stroma, which are emerging as potential clinically useful

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prognostic or predictive factors.58–61 These features can be

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assessed using multi­plexed immunofluorescence staining

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combined with automatic image analysis to quantitatively

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charac­terise the biomarker of interest and evaluate its

clinical importance.62–65 Studies have shown that deep
learning algorithms applied to H&E stained slides can Figure 2: Graphical depiction of overlapping classifications
predict microsatellite instability in gastric cancer54 as well CIN=chromosomal unstable. GS=genomically unstable. MSI=microsatellite
as specific mutations in other cancers.66 The practical instable. EBV+=Epstein-Barr virus positive.

www.thelancet.com Vol 396 August 29, 2020 637

 Seminar
Symptoms and diagnosis
The most common symptoms associated with gastric
cancer are indigestion (dyspepsia), anorexia (poor
appetite) or early satiety, weight loss, and abdominal
pain. Dysphagia or regurgitation might occur in proximal
gastric cancer or cancers located at the gastroesophageal
junction. Anaemia might be present in bleeding cancers.
If symptoms are present at the time of diagnosis, the
disease is often advanced and incurable.
Gastric cancer is diagnosed by endoscopic examination
during which the tumour localisation within the
stomach and its macroscopic type are determined and
biopsies are taken for histological confirmation. Clinical
staging determines whether the treatment approach
will be curative or palliative. All patients should be
staged according to the latest edition of the Union for
International Cancer Control and American Joint
Committee on Cancer and reviewed at an experienced
multidisciplinary tumour board before determining a
treatment pathway.73,74 CT of the abdomen and chest
provides information on the presence of metastases in
the liver, lung, or peritoneum. Endoscopic ultrasound
could be helpful for identifying superficial that do not
penetrate further than the submucosa (T1) or muscularis
propria (T2) from advanced cancers (T3–T4). Endoscopic
ultrasound is able to discriminate between T1 and
T2 cancers with a sensitivity and specificity of 0·85
(95% CI 0·78–0·91) for T1 and 0·90 (0·85–0·93)
for T2.75 Early T-stage, along with tumour size, differen­
tiation, and the presence of ulceration might be helpful
to identify patients suitable for endoscopic resection.
PET-CT might be helpful in detecting CT-occult
metastases but is less sensitive in mucinous or diffuse
type cancers.76 Peritoneal relapse is common in patients
with resected gastric cancer, especially in patients with
diffuse type cancers. Explo­rative laparoscopy to detect
peritoneal metastases is recommended for patients with
gastric cancer at stage 1B or higher for whom surgical
resection is planned.73 Patients with positive cytology on
peritoneal lavage have high rates of disease recurrence
following surgery, although conver­ sion to negative
cytology following chemotherapy could be associated
with better survival outcomes.77
Surgery for gastric cancer
Despite advances in understanding the biology of gastric
cancer, surgical or endoscopic resection is still a
mandatory backbone in treatment with curative intent.
In the past decades, gastric cancer surgery has been
dominated by two main themes: a discussion of the
optimal extent of lymphadenectomy; and the rapid
digital technology dev­elopment of screen-based inter­
vention techniques that have led to minimally invasive
inter­ventions such as endoscopic mucosal resections for
early gastric cancer and laparoscopic and robotic
gastrectomy techniques for early and locally advanced
gastric cancer.
638 www.thelancet.com Vol 396 August 29, 2020
Endoscopic resection
Endoscopic resection is now established as upfront
management for most early gastric cancer cases and can
be considered as a definitive treatment unless substantial
risk factors for lymph node metastases are present.78–80
The strongest risk factor for lymph node metastasis is the
presence of lymphovascular invasion. Other risk factors
include submucosal invasion (T1b), poor differentiation,
ulceration, and large tumour size.78 There are currently
two main endoscopic resection techniques: endoscopic
mucosal resection (EMR) and endoscopic submucosal
dissection (ESD). EMR is robust and technically repro­
ducible with a short learning curve, whereas ESD is
technically more demanding and therefore has a much
longer learning curve during which there could be
morbidity. However, ESD usually results in en-bloc
specimens, higher proportion of complete resections,
and fewer local recurrences.81,82 Asian and European
guidelines recommend ESD as the endoscopic resection
method of choice for early gastric cancer.76,79
Types of gastrectomy
For clinically staged T1 lymph node positive (N+) and
T2–T4a of any node status, and gastric cancer without
distant metastasis, the main treatment is surgical
resection with adequate lymphadenectomy and chemo­
therapy either before and after (perioperative), or just
after (adjuvant) resection. The purpose of the surgery is
to achieve a locally radical resection (eg, all resection
margins free from tumour and all relevant regional
lymph nodes removed). The main procedures used are
distal gastrectomy (resection of the distal two thirds of
the stomach and anastomosis of the proximal stomach
to the small bowel) or total gastrectomy with anastomosis
of the oesophagus to the small bowel. These procedures
involve resection of the pylorus leading to rapid bolus
passage to the small bowel, strongly contributing to
long-term problems with dumping syndrome and
weight loss.83,84
Pylorus function preserving procedures, such as
pylorus-preserving gastrectomy or proximal gastrectomy
with so-called double tract reconstruction, have been
introduced with promising reports of less dumping
symptoms and less weight loss, combined with accept­
able oncological outcomes for T1 cancers for which
endoscopic resection does not suffice.84–87 Care must be
taken to spare the hepatic and pyloric branches of the
vagal nerve, as well as the infrapyloric artery to preserve
pyloric function. These procedures might not generally
be feasible in non-Asian settings due to the low number
of patients diagnosed with early gastric cancer as a
certain case volume is needed to overcome the learning
curve. The mechanism of dumping symp­toms has been
shown to be mediated by the gastro­intestinal glucagon-
like peptide, and promising data suggest that blocking
this peptide could relieve dumping symptoms and
reduce weight loss after gastrectomy.88–90 Within the next

few years, anti-dumping pharmaceutical drugs could be
available to patients in clinical practice.
Lymphadenectomy
The optimal extent of lymphadenectomy has been
extensively discussed in the past decades. Japanese
registry data, mapping the likelihood of lymph node
metastasis from each primary tumour location to the
specific lymph node stations, has led to the definition of
specific levels of lymph node dissection.79 A D1 dissection
aims to clear only the lymph nodes with the highest risk
of involvement and thus all perigastric and left gastric
artery lymph nodes are removed. In a D2 dissection, all
D1 lymph nodes and lymph nodes along the common
hepatic, proper hepatic, and splenic artery, excluding the
splenic hilar nodes as well as those along the coeliac axis
are removed.79 In addition, a D3 dissection has been
described, which includes all D2 lymph node stations,
supplemented with well defined abdominal paraaortic
and hepatoduodenal lymph nodes.
East Asian observational studies as well as a randomised
trial from Taiwan have convincingly shown a better
survival with D2 gastrectomy than D1 gastrectomy.91,92
Three D1 versus D2 gastrectomy trials have been done in
Europe. Both the British and Dutch trials did not show
an initial survival benefit after D2 dissection, partly
explained by extremely high post­operative mortality after
D2 in these early trials.93,94 However, in the Dutch trial,
long-term follow-up showed less loco-regional recur­
rences and lower cancer-related mortality after D2.95 A
per-protocol analysis, where pathologically confirmed D1
and D2 dissections were compared, showed better
survival after D2 surgery.96 An Italian trial with very
low postoperative mortality, but hampered by non-
compliance regarding the lympha­ denectomy in both
groups, showed a statistically borderline significant
survival benefit in lymph node-positive patients after
D2 gastrectomy.97,98 A Japanese randomised trial showed
that routinely performed super-extended D3 lympha­
denectomy was of no benefit compared with D2 for
patients with regional disease.99 Currently, there is inter­
national consensus supporting that gastrectomy for non-
early gastric cancer should include a D2 lymphadenectomy
in patients who are medically fit and should be done in
specialised, high-volume centres.73,79,100
Enhanced recovery and minimally invasive surgery
In the past decades, great efforts have been undertaken to
reduce postoperative complications and expedite recovery
after surgery. Two main fields of development to this end
are: enhanced recovery programmes that are trying to
optimise perioperative care, standardise clinical path­
ways, and promote early postoperative mobilisation and
self care;101 and the development of minimally invasive
techniques of gastrectomy with the potential to cause less
entry wound trauma and through high resolution screen-
based surgery to improve operative field vision.
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Laparoscopic gastrectomy has evolved as an option to
conventional open gastrectomy. Trials from East Asia
for early gastric cancer with risk factors for lymph
node metastases, have shown that laparoscopic distal
gastrectomy is non-inferior with regard to overall survival
and has less wound complications compared with
open distal gastrectomy.102,103 Concerning locally advanced
(T2-T4a) gastric cancer, published short-term results from
the Korean KLASS-02 trial104 showed less morbidity, less
postoperative pain, and shorter length of stay after
laparoscopic compared with open distal gastrectomy.
Regarding survival, preliminary reports from KLASS-02
and the European STOMACH105 and LOGICA trials106
suggest non-inferiority with regard to survival for laparo­
scopic surgery. However, more data are still needed,
especially concerning total gastrectomy. Laparoscopic
gastrectomy done robot­ ically, with enhanced dexterity
and three-dimensional high-resolution vision, is gaining
popularity, but has so far not been shown to differ from
conventional laparos­ copic gastrectomy with regard to
outcomes. With the ongoing rate of technical evolution,
it’s likely that gastric cancer surgery in the future will
increasingly be minimally invasive and will probably take
advantage of the rapidly developing robotic and artificial
intelligence technologies.
Neoadjuvant and perioperative chemotherapy
Treatment with chemotherapy before surgery increases
the chance for curative resection, eliminates early micro­
scopic spread, and allows an in-vivo response assessment
of treatment. Based on the results of randomised con­
trolled trials, preoperative and peri­operative chemotherapy
became the standard for the management of patients with
locally advanced gastric cancer in the Western hemisphere
and in parts of the Asia–Pacific region (figure 3).107–111
The UK Medical Research Council’s MAGIC trial107
Operable gastric cancer
Staging
≥T2 any N+
Surgery Perioperative chemotherapy
FLOT preferred
Adjuvant chemotherapy Surgery
S-1, CapOx, or S-1 and docetaxel
Perioperative chemotherapy
If PS allows
Figure 3: Perioperative and adjuvant treatment algorithm
N+=node positive. FLOT=5-fluorouracil, folinic acid, oxaliplatin, and docetaxel.
CapeOx=capecitabine and oxaliplatin. PS=performance status. *S-1 is a
combination of tegafur, gimeracil, and oteracil.
 Seminar
showed an improve­ment in the 5-year survival rate from
23% to 36% for patients with resectable stage 2 and 3
gastric cancers treated with six cycles (three preoperative
and three postoperative) of ECF (epirubicin, cisplatin,
and 5-fluorouracil) chemo­ therapy compared with sur­
gery alone. The European Society for Medical Oncology
treatment guidelines73 for gastric cancer give a strong
recommendation for perioperative (preoperative and
postoperative) chemotherapy with a platinum or fluoro­
pyrimidine combination for patients with stage 1B or
greater resectable gastric cancer. The chemotherapy
duration during both the preoperative and postoperative
period is generally 2–3 months.73 Recently, the FLOT
regimen (5-fluorouracil, folinic acid, oxaliplatin, and
docetaxel) had better pathological response rates and
higher R0 resection rates compared with ECF or
epirubicin, 5-fluorouracil, and capecitabine (ECX) in
a randomised controlled trial.112 FLOT resulted in a better
overall survival (hazard ratio [HR] 0·77, 95% CI 0·63–0·94;
median overall survival 50 months [38·33 to not reached]
vs 35 months [27·35–46·26]). FLOT is now the recom­
mended standard of care for patients with locally advanced
gastric cancer who can tolerate a perioperative three
drug combination regimen (table). Despite this progress,
cure rates (approximately 40%) remain poor and novel
strategies are needed. One investigational approach is
tailoring perioperative treat­ ment according to radio­
logical or histopathological response. Previous studies on
PET-based response assessment as a correlate for early
metabolic changes in oesophago-gastric junction cancer
showed notable but non-definitive results.116,117 The post­
operative con­tinuation of chemotherapy in patients who
responded incompletely to the preoperatively given cycles
is also a matter of debate.118 Currently, the EORTC-1707
VESTIGE trial119 is investigating the role of adjuvant
immuno­ therapy with nivolumab and ipilimumab in
patients with a high risk for relapse, such as tumours
that have cancer cells found in lymph nodes at resection
following neoadjuvant chemotherapy, or patients who
have a margin positive (R1) resection (NCT03443856).
Preoperative or postoperative radiation therapy
The addition of postoperative radiotherapy to periop­erative
or adjuvant chemotherapy is currently not recom­mended.
Randomised controlled trials showed that the addition of
radiotherapy does not result in a better overall survival after
Setting Treatment
FLOT4-AIO 112
Perioperative; European ECX vs FLOT
ACTS-GC113 Adjuvant; Asia Surgery vs adjuvant S-1*
CLASSIC114 Adjuvant; Asia Surgery vs adjuvant CapeOx
JACCRO GC-07115 Adjuvant; Asia Adjuvant S-1 vs S-1 + docetaxel 3-year RFS; 50%
CapeOx=capecitabine and oxaliplatin. ECX=epirubicin, cisplatin, and capecitabine. FLOT=5-fluorouracil, leucovorin, oxaliplatin, and docetaxel. OS=overall survival.
RFS=relapse free survival. *S-1 is a combination of tegafur, gimeracil, and oteracil.
Table: Perioperative and adjuvant trials that define current practice
640 www.thelancet.com Vol 396 August 29, 2020
quality-assured gastrectomy with more than D1 or D2
lymphadenectomy.120,121 The results of the ARTIST trial
raised the hypothesis that the addition of radiotherapy to
adjuvant chemotherapy might benefit patients with lymph
node-positive disease, but the ARTIST-2 trial did not
confirm this observation.121,122 Results from ongoing trials
investigating preoperative radiotherapy plus periope­rative
chemo­therapy for patients with locally advanced gastric
cancer are awaited.123,124 Patients with less than D1+ or D2
lymphadenectomy or with R1 resection could benefit from
postoperative radiochemotherapy.125,126
Postoperative adjuvant chemotherapy
Several Japanese and South Korean have shown improve­
ments in overall survival using adjuvant chemotherapy.
Adjuvant chemotherapy is fluoropyrimidine based using
either monotherapy with S-1 (a combination of tegafur,
gimeracil, and oteracil) or combination treatment with
capecitabine and oxaliplatin or S-1 and docetaxel. Adjuvant
chemotherapy is the standard of care for Asian patients
(table).114,126 Of note, in these Asian landmark studies that
proved the efficacy of adjuvant chemotherapy, the patients
had received D2 lympha­denectomy. In contrast, studies on
adjuvant chemotherapy done in non-Asian patients did not
improve survival but patients received more variable
surgery that did not always include a D2 lymphadenec­
tomy. A large individual patient-level meta-analysis of
adjuvant chemotherapy in gastric cancer showed a
moderate 6% absolute benefit for 5-fluorouracil-based
chemo­ therapy compared with surgery alone (HR 0·82,
95% CI 0·76–0·90, p<0·001) in all subgroups tested.115
As adjuvant chemotherapy is also less well tolerated
than neoadjuvant chemotherapy, a peri­operative approach
is preferred outside of East Asia, so that more patients can
benefit from systemic treatment even if the postoperative
component of treatment cannot be delivered.73
Future perspectives of perioperative treatment
Trastuzumab combined with fluoropyrimidine and
platinum chemotherapy prolonged overall survival of
patients with HER2-positive inoperable gastric cancer.127
The value of anti-HER2-directed trastuzumab or
trastuzumab and pertuzumab in addition to perioperative
chemotherapy in patients with HER2-positive resectable
gastric cancer is currently under investigation in the
EORTC-1203 INNOVATION study (NCT02205047).128
Control group OS Experimental group OS Hazard ratio (95% CI)
Median OS; 35 months Median OS; 50 months 0·77 (0·63–0·94)
5-year OS; 61·1% 5-year OS; 71·7% 0·669 (0·54–0·83)
5-year OS; 69% 5-year OS; 78% 0·66 (0·51–0·85)
3-year RFS; 66% 0·632 (0·400–0·998)
 Seminar

A retrospective analysis129 from a French National registry
suggested no benefit for perioperative chemo­therapy in
patients with resectable signet ring cell type gastric
cancer.129 This observation was not confirmed in a subse­
quent prospective randomised controlled trial comparing
perioperative chemotherapy with primary surgery and
adjuvant chemotherapy in patients with resectable signet
ring cell type gastric cancer.130 Therefore, the current
recom­­mendation of perioperative chemo­ therapy for
resectable locally advanced gastric cancer should be
applied to all patients irrespective of histological subtype.
Retrospective analyses and large clinical trials suggest
that DNA-mismatch repair deficient or MSI resectable
gastric cancers have a favourable prognosis compared
with mismatch repair proficient or microsatellite stable
gastric cancer, but the benefit from perioperative or
adjuvant chemotherapy has been topic of debate.50,131
Despite pooled data sets, due to the low incidence of MSI
considered equivalent in terms of efficacy; however,
they have differing spectra of side-effects. Cisplatin is
associated with more thromboembolic disease and renal
dysfunc­tion, whereas oxaliplatin is associated with
higher rates of neuropathy and diarrhoea.146,147 Infused
and oral fluoropyrimidines are considered equivalent
in efficacy; however, capecitabine is associated with
higher rates of hand-foot syndrome.146 Irinotecan could
also be used in combination with fluoropyrimidines for
patients in whom platinum is contraindicated.148 For
older patients (aged >65 years), oxaliplatin might be
more effective and has a superior safety profile.149 The
GO-2 trial150 showed that in older, frail patients with
metastatic gastric cancer, a reduced dose oxaliplatin
and fluoropyrimidine chemo­therapy was equivalent to
standard dose chemo­therapy in terms of progression
immunotherapy with or
without chemotherapy

in gastric cancer, the number of analysed MSI gastric Pembrolizumab in

First-line targeted or

PD-L1 CPS ≥10 patients

cancers is still limited. Therefore, the debate whether Trastuzumab + CF/X in
perioperative chemotherapy should be given or not in HER2 3+/2+ FISH positive
patients with resectable MSI gastric cancer is ongoing. Pembrolizumab in PD-L1 CPS
>1 patient
Each case should be discussed in the multi­disciplinary
tumour board and an individualised decision for each
patient depending on patient and tumour characteristics Oxaliplatin + S-1 (Asian patients)
is needed.51,132 Cisplatin + S-1 (Asian patients)
First-line chemotherapy

Cisplatin + 5-FU or capecitabine

Chemotherapy for patients with advanced (RAINFALL)
combinations

gastric cancer FOLFOX (from phase 2

randomised)
Chemotherapy improves survival and quality of life for
Docetaxel + cisplatin + 5FU (V325)
patients with locally advanced unresectable or metastatic
gastric cancer.133–135 Patients with gastric cancer who are Cisplatin + 5FU (V325)
treated with combination chemotherapy have a median
Best supportive care
overall survival of around 1 year (patients in Asia tend to
have modestly longer survival) compared with 3–4 months
when treated with supportive care alone (figure 4).134–138 Paclitaxel–ramucirumab
Therefore, chemotherapy should be offered to patients (RAINBOW)
Second-line chemotherapy with
or without ramucirumab

with adequate performance status and organ function.73,139,140 Paclitaxel (RAINBOW)

Chemotherapy drugs that are active in gastric cancer Ramucirumab monotherapy
(REGARD)
include fluoropyrimidines (5-fluorouracil, capecitabine,
S-1, and trifluridine–tipiracil), platinums, taxanes, and Irinotecan (Korean trial)
irinotecan. S-1 is an oral fluoropyrimidine comprised of Docetaxel (COUGAR-02)
tegafur (an oral 5-fluorouracil prodrug), gimeracil (a Best supportive care
dihydro­pyrimidine dehydrogenase inhibitor), and oteracil (UK and Korean trials)
(an inhibitor of orotate phosphoribosyltransferase).141,142
S-1 is more frequently used in Asia as it is less well
Third-line chemotherapy

Trifluridine–tipiracil (TAGS)
tolerated in non-Asian populations because of pharma­
or immunotherapy

cogenomic differences in S-1 meta­bolism.143,144 TAS118, a Nivolumab (ATTRACTION-2)

combination of S1 plus leucovorin has also showed
Best supportive care (TAGS)
promise in Asian patients.145 There are no validated
Best supportive care
biomarkers to guide chemotherapy selection in advanced (ATTRACTION-2)
gastric cancer. 0 5 10 15 20
Overall survival (months)
First-line chemotherapy
Figure 4: Overall survival (months) in randomised trials of chemotherapy, targeted therapy, and immunotherapy
For the initial treatment of patients with metastatic in first line, second line, and chemorefractory gastric cancer
gastric cancer, a platinum–fluoropyrimidine doublet is CPS=combined proportion score. CF/X=cisplatin and 5FU or capecitabine. FISH=fluorescent in situ hybridisation.
preferred (figure 5).73,139,140 Cisplatin and oxaliplatin are 5FU=5 fluorouracil. FOLFOX=5-fluorouracil, folinic acid, and oxaliplatin.

www.thelancet.com Vol 396 August 29, 2020 641

 Seminar
First-line treatment
HER2 testing
HER2-positive HER2-negative
Chemotherapy + trastuzumab Platinum doublet
Nutrition and palliative care
Second-line treatment Microsatellite unstable
Anti-PD-1
Ramucirumab Chemotherapy (taxane, Paclitaxel + ramucirumab
irinotecan)
Third-line treatment
Trifluridine-tipiracil Anti-PD-1
Figure 5: Treatment algorithm for advanced gastric cancer
free survival and was more acceptable to patients and
oncologists.
Doublet versus triplet chemotherapy
Triplet chemotherapy with cisplatin, 5-fluorouracil, and
docetaxel improved survival compared with cisplatin and
5-fluorouracil alone in a phase 3 randomised trial, but is
associated with high rates of serious neutropenia and
febrile neutropenia, even when prophylactic granulocyte
colony stimulating factor is used.138,151 In a recent phase 3
Japanese randomised trial,152 a triplet of docetaxel, cisplatin
and, S-1 did not improve survival compared with cisplatin
and S-1 alone. Due to the questionable benefit of triplet
chemotherapy compared with doublet treatment, and a
clear increase in toxicity when a three drug treatment is
used, taxane-based triplet chemotherapy might be re­served
for patients who are very fit or those with a high burden of
disease in whom a rapid response is desirable.73,139
Biologics in first-line advanced gastric cancer:
trastuzumab
Amplification of the HER2 (also known as ERBB2)
oncogene and overexpression of the HER2 protein
occur in approximately 17–20% of patients with gastric
cancers, and is more common in intestinal-type gastric
cancer and cancers located in the proximal stomach or
at the gastroesophageal junction.41,153 Patients with HER2
overexpressing gastric cancer benefit from treatment with
the anti-HER2 anti­body trastuzumab.127 In the randomised
controlled TOGA trial,128 patients treated with trastuzumab
642 www.thelancet.com Vol 396 August 29, 2020
plus cisplatin and fluoropyrimidine chemotherapy
had improved median overall survival compared with
patients treated with chemotherapy alone. In the
highly sensitive subgroup (HER2 immu­nohistochemistry
[IHC] score 3+ or HER2 IHC 2+, and fluorescent in situ
hybridisation [FISH]-positive), median overall survival
was 16 months for chemother­apy and trastuzumab treated
patients compared with 11·1 months in patients treated
with chemotherapy alone (HR 0·74, 95% CI 0·60–0·91,
p=0·0046; figure 5). Patients with HER2 overexpressing
(HER2 3+ IHC or HER2 IHC 2+ and FISH-positive)
gastric cancer should be treated with trastuzumab in
addition to first-line chemo­ therapy, fol­lowed by trastu­
zumab monotherapy as maintenance.73,139,140 Currently
there is no evidence to support trastuzumab beyond pro­
gression after first-line chemotherapy or before surgery in
patients with resectable gastric cancer.
HER2 overexpressing gastric cancer has several unique
characteristics including heterogeneity of HER2 expres­
sion and loss of dependence on HER2 signalling after
trastuzumab treatment.154,155 As a result, separate guide­
lines for HER2 testing in gastric cancer have been
developed.156 A minimum of 5 tumour containing biopsies
is required to confirm HER2 expression level and a
biopsy of primary and metastatic sites also increases the
detection of HER2 positive patients.156–158 Unlike breast
cancer, neither pertuzumab (first line) nor trastuzumab–
emtansine (second line) have been effective at improving
survival for patients who have HER2 overexpressing
gastric cancer.159,160 However, ongoing trials using anti-
HER2 therapy in second-line gastric cancer require
biopsies to show retained HER2 overexpression and new
anti-HER2 molecules such as trastuzumab–deruxtecan
show promise.161,162
Chemotherapy for previously treated advanced
gastric cancer
In the second-line setting, patients who are fit for
chemotherapy might be offered taxane or irinotecan
chemotherapy that improve survival compared with best
supportive care in randomised trials; however, the
benefit from second-line chemotherapy is limited.163–165
Median overall survival of patients treated with second-
line chemotherapy in clinical trials is approximately
6 months. The average benefit in overall survival in
clinical trials for second line chemotherapy is 6 weeks.
Patients with excellent performance status who have had
a sustained response to first-line chemotherapy derive
the most benefit from second-line treatment.166 In
countries where ramucirumab is funded, the combi­
nation of paclitaxel and ramucirumab is preferred as
second-line therapy due to improved survival (figure 5).167
For patients with gastric cancer whose disease has
progressed after second-line chemotherapy, trifluridine–
tipiracil (an oral nucleoside analog plus thymidine
phosphorylase inhibitor) improves overall survival
compared with best supportive care.168

Anti-angiogenic therapy in advanced gastric
cancer
Anti-angiogenic therapy with ramucirumab (an anti-
vas­cular endothelial growth factor 2 receptor antibody)
has shown clinical use both as monotherapy and in
combination with paclitaxel for patients with gastric
cancer who have progressed after first-line chemo­
therapy. In the second line REGARD trial,169 ramucirumab
improved survival compared with best supportive care,
whereas in the RAINBOW trial167 the combination of
ramucirumab and paclitaxel improved survival compared
with paclitaxel alone.168,169 However, neither ramucirumab
nor bevacizumab (an anti-VEGF monoclonal anti­
body) improved survival when added to platinum or
fluoropyrimidine chemotherapy in patients with treat­
ment naive gastric cancer.136,170
Immunotherapy for patients with advanced
gastric cancer
Immune checkpoint blockade is now established as a
treatment for chemorefractory gastric cancer (cancer
which has progressed after two or more lines of
chemotherapy). The phase 3 randomised ATTRACTION-2
trial171 showed improved overall survival for Asian
patients treated with the anti-PD-1 monoclonal antibody
nivolumab compared with placebo plus best supportive
care.171 The phase 2 non-randomised KEYNOTE-059
trial172 showed similar overall survival for an interna­
tional chemorefractory gastric cancer patient population
treated with pembrolizumab, another PD-1 antibody.
In KEYNOTE 059, radiological response rates were
improved in patients who had tumours that expressed
PD-L1 protein on tumour and immune cells. Radiological
response rates and overall survival are also substantially
higher in patients with mismatch repair deficient or
microsatellite unstable cancers, and tumour agnostic
indications exist for treatment of MSI cancers with anti-
PD-1 therapy.172
However, immune checkpoint blockade has not been
successful until recently in earlier lines of therapy;
pembrolizumab did not improve survival compared with
paclitaxel in second line gastric cancer patients who
expressed PD-L1 at a low level (CPS ≥1).173 In the first
line KEYNOTE-062 trial, pembrolizumab showed non-
inferiority to chemotherapy in patients who had PD-L1-
positive (CPS ≥1) gastric cancer.174 However, response
rates to anti-PD-1 mono­ therapy were low and many
patients had early progression. In KEYNOTE-062,
overall sur­vival was improved com­pared with chemo­
therapy in pembrolizumab monotherapy treated patients
who had tumours with high expression of PD-L1
(CPS ≥10), although this finding was not statistically
significant (figure 5), and this group requires further
study in future. Despite encouraging early results for
the combination of chemotherapy and anti-PD-1 therapy,
the addition of pembrolizumab to chemotherapy did
not improve survival compared with chemotherapy
www.thelancet.com Vol 396 August 29, 2020 643
Seminar
alone in a randomised trial regardless of PD-L1 expres­
sion status.174,175 However, early reports from the
ATTRACTION-4176 and CHECKMATE 649177 trials sug­
gest that the combination of nivolumab with chemo­
therapy might be more effective than chemo­ therapy
alone. Other biomarkers including EBV and tumour
mutation burden are currently being evaluated.
Novel targets in gastric cancer
Novel targets that are under investigation in gastric cancer
include Claudin-18.2 (more commonly expressed in dif­
fuse type gastric cancer), inhibitors of the fibro­blast growth
receptor 2 pathway, and combinations of anti-angiogenic
therapies and immune checkpoint blockade.41,178–181
Palliative care for gastric cancer patients
Patients with advanced gastric cancer benefit from a
holistic approach to care, in addition to chemotherapy.
Nutritional advice should be provided to minimise
avoidable weight loss; dietary changes or supplementa­
tion could be recommended.182 Bleeding tumours could
be addressed with endoscopic coagulation, tranexamic
acid, radiotherapy, embolisation, or rarely surgery.183 The
REGATTA trial184 did not show improved survival for
palliative gastrectomy in addition to chemo­ therapy.
Radiotherapy might be helpful in palliating painful
metastases or dysphagia.185 Endoscopic stent placement
might also relieve dysphagia for patients with proximal
gastric cancer or relieve vomiting in patients with gastric
outlet obstruction. Early referral to palliative care services
can improve symptom control and quality of life;
palliative care should be considered an essential part of
the patient pathway and not mutually exclusive with
active treatment such as chemotherapy.186
Ongoing challenges and future directions
Challenges for gastric cancer are epidemiological and
therapeutic. The first aim must be to reduce the incidence
rate of gastric cancer through ongoing attention to
improved public health, implementation of endoscopic
screening programmes in high-risk areas, and develop­
ment of novel, less invasive tools for early detection.
A major challenge is to translate recent discoveries in
molecular biology to effective treatment for patients
with gastric cancer. Intratumoural, intrapatient, and
interpatient heterogeneity in gastric cancer remains a
crucial barrier to drug development for targeted therapies
and therefore more research is needed to understand
how these challenges can be overcome. Additionally,
most gastric cancers are not sensitive to immune
checkpoint inhibitor monotherapies and thus patients
with gastric cancer will probably require combination
therapy to improve responses to anti-PD-1 therapy or
other immune checkpoint inhibitors. Over the next few
years, trials that have the potential to change clinical
practice include the VESTIGE trial (NCT03443856;
adjuvant immunotherapy vs chemo­therapy), TOPGEAR
 Seminar
study (NCT01924819; chemoradiotherapy vs chemo­
therapy before surgery in operable gastric cancer),
INNOVATION study (NCT02205047; chemotherapy vs
chemotherapy plus anti-HER2 therapy in operable
gastric cancer), and SPOTLIGHT trial (NCT03504397;
chemotherapy vs chemotherapy plus claudiximab (anti-
Claudin18.2) in first line metastatic gastric cancer), as
well as future trials of the anti-HER2 antibody drug
conjugate trastuzumab dexrutecan and combinations of
anti-PD-1 therapy with anti-angiogenic tyrosine kinase
inhibitors.
Contributors
All authors contributed to the manuscript equally. All authors did the
literature search and review, wrote the manuscript, reviewed the
manuscript before publication, and provided replies to reviewers.
Declaration of interests
ECS reports personal fees from Astellas Pharma, Bristol-Myers Squibb
(BMS), Celgene, Five Prime Therapeutics, Merck, AstraZeneca,
and Servier Laboratories, outside the submitted work. NCTvG reports
personal fees from BMS and Merck Sharp & Dohme, outside the
submitted work. FL reports personal fees from Amgen, Astellas Pharma,
AstraZeneca, Bayer, Biontech, Eli Lilly, Elsevier, Excerpta Medica,
Imedex, Infomedica, Medscape, MedUpdate, Merck Serono, Merck
Sharp & Dohme, Oncovis, Promedicis, Roche, Springer Nature,
and StreamedUp!; and grants and personal fees from BMS, Iomedico,
and Zymeworks, outside the submitted work. HIG reports personal fees
from Merck Sharp & Dohme, outside the submitted work. MN declares
no competing interests.
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