Current Oncology Reports (2019) 21:67

https://doi.org/10.1007/s11912-019-0820-4

GASTROINTESTINAL CANCERS (J MEYER, SECTION EDITOR)

Updates on Management of Gastric Cancer

Fabian M. Johnston 1 & Michael Beckman 2

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
Purpose of Review Gastric adenocarcinoma is the fifth most common and the third most lethal cancer worldwide. Surgery is the
only chance of cure, but recurrence is common, even with complete resection.
Recent Findings Advances in diagnosis and staging, genomic classification, surgical resection and treatment of peritoneal
disease, systemic chemotherapy and chemoradiation, and targeted and immune therapies have led to the current multidisciplinary
approach to gastric adenocarcinoma.
Summary Treatment of gastric cancer is rapidly evolving in an effort to combat this challenging disease.

Keywords Gastric cancer . Gastric adenocarcinoma . Siewert type III . FLOT . HIPEC . CYTO-CHIP

Introduction diagnosed in relatively advanced stage. Gastric cancer repre-

Globally, over 1 million new cases of gastric cancer were
diagnosed in 2018, making it the fifth most common cancer
in the world. Gastric cancer was estimated as responsible for
about 783,000 deaths worldwide in 2018, making it the third
most lethal cancer type [1]. Along with dietary factors such as
nitrites and salted foods, H. pylori infection is a known dom-
inant cause of gastric cancer. With improved food preservation
techniques and treatment of H. pylori, the rates of gastric
cancer have decreased. However, the proportion of more prox-
imal gastric cancers, which often lend a poor prognosis, is
increasing. Eastern Asian nations account for about half of
gastric cancer diagnoses worldwide, and with such high rates
of disease, aggressive screening programs have allowed for
frequent early diagnosis and improved outcomes. However, in
Western countries, where the incidence is relatively low,
screening is cost-prohibitive and gastric cancers are routinely
This article is part of the Topical Collection on Gastrointestinal Cancers
* Fabian M. Johnston
fjohnst4@jhmi.edu
1
Section of Gastrointestinal Surgical Oncology, Peritoneal Surface
Malignancy Program, Division of Surgical Oncology, Johns Hopkins
University, 600 N. Wolfe Street/Blalock 606, Baltimore, MD 21287,
USA
2
Department of Surgery, Johns Hopkins Hospital, 600 N. Wolfe
Street/Blalock 665, Baltimore, MD 21287, USA
sents a significant burden on society, and improvements in the
treatment of this disease are in need. Therapeutic advances are
underway, including better understanding of gastric cancer
genomics, advanced minimally invasive surgical techniques
and addressing peritoneal disease with cytoreductive surgery
and heated intraperitoneal chemotherapy (HIPEC), improved
systemic chemotherapy regimens, targeted therapies, and im-
mune therapy.
Pathogenesis and Classification
Gastric adenocarcinoma represents the vast majority of gastric
malignancies, and historically has been classified by histolo-
gy. The Lauren classification system divides gastric cancer
histologically into the poorly differentiated diffuse subtype
and the well differentiated intestinal subtype [2]. The World
Health Organization (WHO) system classifies gastric adeno-
carcinoma into five histologic subtypes [3]. Tubular is the
most common and often forms a fungating gastric luminal
mass. Papillary is also quite common and is notorious for
metastasizing to the liver. Mucinous adenocarcinoma consti-
tutes about 10% of gastric cancers and is composed of about
50% extracellular mucous on histology. Tubular, papillary,
and mucinous adenocarcinomas correspond to the Lauren in-
testinal subtype. Poorly cohesive carcinomas, including signet
ring cell carcinoma, are quite aggressive and often exhibit
lymphovascular invasion, and correspond to the diffuse
 67 Page 2 of 9
subtype of the Lauren classification. Mixed carcinomas are
composed of rare gastric cancer variants which are indetermi-
nate in the Lauren classification scheme.
Tumor location is of great significance to prognosis and
management guidance, particularly at the esophagogastric
junction (EGJ) [4]. The Siewert classification scheme divides
tumors involving the EGJ into three groups [5]. Siewert type I
tumors arise from areas of intestinal metaplasia of the esoph-
agus and invade the EGJ from above. Siewert type II tumors
arise from the EGJ itself. Siewert type III tumors arise from
the gastric mucosa and invade the EGJ and esophagus from
below. Siewert type III tumors have been shown to be rela-
tively aggressive, large lesions that portend poor outcomes
[4].
More recently with the advent of next-generation gene se-
quencing, gastric adenocarcinomas can be grouped into sub-
types with common mutations. In 2014, The Cancer Genome
Atlas (TCGA) Research Network reported genomic profiling
results of 295 primary gastric adenocarcinomas [6]. Four ge-
nomic subtypes were established in this system including tu-
mors exhibiting microsatellite instability (MSI+) (22%),
Epstein Barr Virus infection (EBV+) (9%), genomic stability
with low degree of aneuploidy (GS) (20%), and tumors
exhibiting chromosomal instability with high degree of aneu-
ploidy (CIN) (50%). The Asian Cancer Research Group
(ACRG) proposed a genomic classification system in 2015
that partially overlaps with that of the TCGA and also includes
four subtypes [7]. These include tumors with microsatellite
instability (MSI) (23%), tumors that are microsatellite stable
and TP53 mutation-negative (MSS/TP53−) (36%), tumors
that are microsatellite stable and TP53 mutation positive
(MSS/TP53+) (26%), and tumors that are microsatellite stable
and exhibit features of epithelial to mesenchymal transition
(MSS/EMT) (15%). These classification systems represent
the ongoing evolution of gastric cancer classification and still
require largescale validation.
Analysis of TCGA genomic subtypes has identified poten-
tial therapeutic targets [8]. EBV+ gastric cancers show fea-
tures of PD-L1/2 overexpression and immune cell infiltration,
making them an attractive and promising target for immune
therapies. Also, PIK3CA is mutated in the majority of EBV+
gastric cancers, indicating PI3K pathway inhibition may
prove useful. MSI+ gastric cancers show overexpression of
PD-L1, as well as high frequency of targetable mutations in
PIK3CA, ERBB3, ERBB2, and EGFR tyrosine kinases. CIN
tumors, which show high rates of TP53 mutation, exhibited
frequent receptor tyrosine kinase amplification and elevated
phosphorylation, as well as amplification of the VEGFR li-
gand, VEGFA, representing several possible therapeutic tar-
gets. Finally, GS gastric cancers exhibit frequent mutations in
RHOA (Ras homolog gene family, member A) which modu-
lates apoptosis and cell motility, and CLDN18-ARHGAP6
fusion which likely prevents effective cellular cohesion. The
Curr Oncol Rep (2019) 21:67
identification of these possible tumor drivers may lead to de-
velopment of specific targeted therapies.
Diagnosis and Staging
The signs and symptoms associated with gastric cancer, if
present, may include weight loss, nausea, emesis, anorexia,
early satiety, dyspepsia, and epigastric pain. These symptoms
are vague, non-specific, and may not occur until late in disease
progression. Physical examination is largely unrevealing in
early disease. In late disease, there may be the presence of
an abdominal mass, characteristic Virchow’s node (left
supraclavicular lymphadenopathy), Sister Mary Joseph’s node
(umbilical nodule), or Blumer’s shelf (palpable tumor deposit
anterior to the rectum) on digital rectal examination. In many
Asian countries, where gastric cancer is quite prevalent,
screening systems are useful and effectively lead to early di-
agnoses. However, in Western nations, the relatively low in-
cidence of gastric cancer prohibits the use of screening pro-
grams and late diagnoses are common. In fact, greater than
half of the gastric cancer patients in the USA have regional or
distant metastases at the time of diagnosis [9].
Gastric cancer is most effectively diagnosed by upper en-
doscopy with a thorough evaluation of the gastric mucosa and
biopsy of suspicious lesions. Following diagnosis, staging is
critical to guide therapy. The most widely accepted staging
system is the American Joint Committee on Cancer and
International Union Against Cancer (AJCC/UICC) system
[10••]. It uses a traditional tumor/node/metastasis (TNM)
framework and was most recently updated in 2017 to the
eighth edition and includes several notable changes. The clas-
sification of esophagogastric junction (EGJ) tumors has been
adjusted. As of the eighth edition definition, tumors arising >
2 cm from the EGJ (Siewert type III) are considered gastric,
while tumors arising from within 2 cm distal to the EGJ are
classified as esophageal. Additional clinical staging (cTNM)
and post-neoadjuvant staging (ypTNM) systems are included
for prognostic purposes and to aid in establishing initial treat-
ment plans prior to surgery. Further subdivision of nodal stag-
ing is added based on Japanese and Korean data from the
International Gastric Cancer Association (IGCA) [11].
Pathologic N3 patients are now separated into pN3a (7–15
regional metastatic nodes) and pN3b (>15 regional metastatic
nodes) to better stratify survival.
There are several effective and complementary modalities
recommended for the staging of gastric cancer. Endoscopic
ultrasound (EUS) is an important diagnostic and staging mo-
dality as it can assess the depth of primary tumor invasion and
identify and biopsy any suspected nodal metastases. EUS as-
sessment of T stage in gastric cancer has been evaluated in
meta-analysis, showing greater than 85% sensitivity and spec-
ificity for distinguishing T1–2 tumors from T3–4 tumors [12].
Curr Oncol Rep (2019) 21:67
Sensitivity and specificity for N staging in gastric cancer were
found to be lower (83% and 67%, respectively) due to the
difficulty of identifying distant positive nodes [12]. This con-
trasts with esophageal and EGJ tumor diagnosis and staging,
in which nodal metastasis is common at early T stage. EUS
with fine needle aspiration biopsy has been shown to have
sensitivity and specificity for N staging in esophageal cancer
as high as 97% and 96%, respectively [13]. Computerized
tomography (CT) is widely used to evaluate for locoregional
spread of disease and distant metastases. However, CT is no-
toriously inadequate at detecting peritoneal disease. Similarly,
positron emission tomography (PET) underestimates gastric
cancer which often demonstrates FDG-avidity poorly, partic-
ularly diffuse-type gastric cancers. While each of their limita-
tions remain, utilization of PET/CT in combination may have
utility in gastric cancer staging as patients with more advanced
nodal and T stage disease have a higher likelihood of distant
metastasis [14].
Laparoscopy is a critical modality in the peritoneal staging
of gastric cancer. Performance of diagnostic laparoscopy al-
lows for visualization of the peritoneal surface, biopsy of sus-
picious lesions, and evaluation for microscopic disease by
cytology from peritoneal washings. Diagnostic laparoscopy
is recommended for T1b (invading submucosa) lesions and
above unless palliative gastrectomy is already planned [15••].
The diagnosis of the peritoneal disease is a finding of utmost
importance as it represents a divergence point in treatment
paths. The presence of peritoneal disease predicts abysmal
prognosis by peritoneal recurrence [16]. While the surgical
treatment of gastric cancer peritoneal carcinomatosis is being
explored, the current guidelines recommend systemic therapy
in the setting of active peritoneal disease to avoid performance
of a futile operation. Following systemic therapy, if repeat
staging work up and diagnostic laparoscopy show clearance
of peritoneal disease, curative surgery may then be
considered.
Multidisciplinary Treatment
Surgery
Complete surgical resection remains the only opportunity
for cure in gastric cancer. No prospective data exists to
guide resection margin goals, but retrospective evidence
indicates that 2–6 cm gross margins decrease the likeli-
hood of microscopically positive margins. Currently,
NCCN guidelines recommend 4 cm gross margins
[15••]. Classic operations for gastric cancer include total
gastrectomy and subtotal gastrectomy, and indications for
each depend on tumor location. For purposes of thorough
oncologic resection and staging of gastric cancer, lymph-
adenectomy is performed along with gastrectomy,
Page 3 of 9 67
although the extent of lymphadenectomy remains a point
of contention. D1 (perigastric lymph node stations only),
D2 (perigastric and celiac axis lymph node stations), and
D3 (perigastric, celiac axis, and para-aortic lymph node
stations) lymphadenectomies have been compared by ran-
domized trials over the years since standardized gastric
cancer lymphadenectomy was first described by the
Japanese Research Society for Gastric Cancer (JRSGC)
in 1973 [17]. Recently, the Dutch Gastric Cancer Trial
(DGCT) reported data spanning 15 years and showed
disease-specific survival improvement in patients receiv-
ing D2 vs. D1 lymphadenectomy, but no improvement in
overall survival [18]. A recent Cochrane systematic re-
view showed that D2 lymphadenectomy was associated
with a significantly better disease-specific survival com-
pared to D1 lymphadenectomy (HR 0.81, 95% CI 0.71 to
0.92), but D2 lymphadenectomy was also associated with
a higher postoperative mortality rate (RR 2.02, 95% CI
1.34 to 3.04). There was no significant difference in
disease-free survival or overall survival between D1 and
D2 lymphadenectomy [19]. The Japan Clinical Oncology
Group (JCOG) trial 9501 compared D2 and D3 lymphad-
enectomy [20]. While overall complication rate was sig-
nificantly higher in the D3 lymphadenectomy group, there
was no significant difference in 5-year recurrence-free
survival and overall survival with the additional dissection
of para-aortic lymph nodes. According to data from the
Surveillance, Epidemiology, and End-Results (SEER) da-
tabase, patients with advanced gastric cancer who had >
15 lymph nodes excised during gastrectomy exhibited im-
proved survival [21]. While D2 lymphadenectomy is not
mandated with gastrectomy for gastric cancer in Western
countries, it is recommended. Ultimately, the NCCN
guidelines currently recommend procurement of a mini-
mum of 15 lymph nodes to optimize oncologic outcomes
in gastric cancer [15••].
As technology and surgeon affinity for minimally invasive
techniques progress, laparoscopic and robotic gastrectomy for
gastric cancer has emerged. The first laparoscopic gastrecto-
my was reported in 1994 and the first robotic gastrectomy in
2003 [22, 23]. The advantages of minimally invasive gastrec-
tomy may include decreased blood loss, reduced morbidity,
faster return of bowel function, and shorter hospital stay.
Mortality and lymph node procurement appear comparable
[24]. Oncologic outcomes appear to be equivalent between
open and minimally invasive techniques at present; however,
prospective data remains to be shown.
Endoscopic mucosal resection (EMR) and endoscopic sub-
mucosal dissection (ESD) have shown utility in Eastern coun-
tries where many patients are diagnosed with early disease
[25]. In the USA, where screening programs are not available
to detect such early gastric cancers, there are fewer opportu-
nities for endoscopic resection, and Asian studies of safety and
 67 Page 4 of 9
efficacy may not be applicable. While no prospective data is
yet available, meta-analyses of retrospective data have com-
pared EMR to ESD and found ESD to be superior in terms of
higher en bloc resection rate, higher rate of microscopically
negative margins, and lower local recurrence rate [26, 27].
This oncologic resection advantage came at the cost of higher
perforation rate in the ESD group (4% vs. 1%). In the setting
of very early stage gastric cancer, endoscopic resection may
be appropriate, but recommendations are for performance by
experienced endoscopists at a high volume centers [15••].
Peritoneal spread of gastric adenocarcinoma portends a
poor prognosis. Surgery has classically been avoided in
the setting of active peritoneal disease as recurrence rates
are prohibitive. However, palliative options including che-
moradiation, systemic therapies, and best supportive care
have poor survival statistics. A 2017 Cochrane meta-
analysis reviewed trials comparing palliative chemothera-
py to best supportive care in patients with advanced gas-
tric cancer [28]. Best supportive care was shown to have a
median overall survival of 4.3 months. Palliative chemo-
therapy did show a 6.7-month improvement in median
overall survival, but still this reached only 11 months.
To address macroscopic peritoneal disease or positive
peritoneal washings in patients with otherwise absent dis-
tant metastasis, cytoreductive surgery, and heated intra-
peritoneal chemotherapy is an option that is being ex-
plored. Some retrospective studies have provided proof
of principle to directly addressing peritoneal disease in
gastric cancer. Several studies have linked completeness
of peritoneal disease resection to outcomes. Hall et al.
found that completely resected patients and those with
microscopically positive margins had a median survival
time of 11.2 months compared to 3.3 months for patients
left with grossly residual disease [29]. Glehen et al. pre-
sented retrospective multi-institutional French data in
2010 analyzing advanced gastric cancer patients who
underwent cytoreductive surgery with heated intraperito-
neal chemotherapy or post-operative intraperitoneal che-
motherapy [30]. This study revealed the heterogeneity of
morbidity and mortality among institutions, but the single
independent prognostic indicator revealed was complete-
ness of cytoreduction. A meta-analysis of retrospective
and prospective studies underpinned the variation in prac-
tice among institutions and studies [31]. In 2018, data
from the CYTO-CHIP study was reported [32••]. Among
19 French centers from 1989 to 2014, 277 consecutive
gastric cancer patients with peritoneal carcinomatosis
were included. This propensity score analysis compared
patients undergoing complete cytoreductive surgery plus
heated intraperitoneal chemotherapy (CRS-HIPEC) to pa-
tients undergoing cytoreductive surgery alone (CRSa).
CRS-HIPEC showed a dramatic median overall survival
advantage of 18.8 months compared to 12.1 months for
Curr Oncol Rep (2019) 21:67
CRSa, and 11 months for chemotherapy alone as previ-
ously reported in the 2017 Cochrane meta-analysis [28].
Desiderio et al. reported in their 2017 meta-analysis of
randomized and high-quality non-randomized trials that
HIPEC may provide the most benefit as peritoneal carcinoma-
tosis prophylaxis in high-risk patients or in patients without
macroscopic peritoneal disease but positive cytology.
Prophylactic HIPEC in advanced gastric cancer patients with-
out carcinomatosis afforded a statistically significant risk re-
duction in overall survival at 3 years (RR = 0.71, P = 0.03)
and 5 years (RR = 0.82, P = 0.01). Patients with macroscopic
peritoneal carcinomatosis showed only a slight improvement
in median survival with HIPEC over the control group
(11.1 months vs. 7.06 months). However, at the 3-year end-
point, no survival advantage was seen (RR = 0.99, P = 0.85
[33].
Internationally, there are 13 ongoing prospective ran-
domized phases II–III clinical trials evaluating the use of
HIPEC in gastric cancer including studies based out of
China, the Netherlands, Germany, Korea, France, and
the USA. The groups running active trials out of the
USA currently include MD Anderson Cancer Center,
Montefiore Medical Center, and the National Institutes
of Health, and each of these phase II trials exhibit varia-
tion on the theme of HIPEC in the setting of gastric can-
cer. MD Anderson is currently running two trials. Both
use cisplatin and mitomycin C as the intra-operative che-
motherapeutic agents. One trial is designed to assess over-
all survival from the date of diagnosis and safety of the
treatment in patients with stage IV stomach or gastro-
esophageal cancer and positive cytology or carcinomato-
sis after cytoreduction, gastrectomy, and HIPEC. Their
other trial is meant to assess overall survival and safety
for patients with positive cytology or peritoneal carcino-
matosis receiving HIPEC administered by laparoscopy.
The Montefiore group’s trial utilizes Mitomycin C and is
designed primarily to assess the technical parameters of
utilizing HIPEC for peritoneal disease. Secondary analy-
ses include progression-free survival, overall survival, and
patient-reported outcomes. The NIH group’s trial utilizes
mitomycin C and cisplatin in HIPEC for patients with
stage IV gastric cancer and positive peritoneal cytology.
They aim to evaluate overall survival, intraperitoneal
progression-free survival, extraperitoneal disease-free sur-
vival, and morbidity. Ultimately, further prospective ran-
domized trials will be important in delineating the role of
cytoreductive surgery and heated intraperitoneal chemo-
therapy in advanced gastric cancer. Critical selection of
patients that are likely to receive a complete
cytoreduction, and performance at a high-volume center
by an experienced surgeon may help to optimize the ben-
efit of this potentially morbid procedure in gastric cancer
patients who are at high risk for disease-specific mortality.
Curr Oncol Rep (2019) 21:67
Chemotherapy
Recurrence is common following surgical resection for gastric
cancer, even with negative margins in early stage disease.
Since the British Medical Research Council’s landmark
MAGIC Trial in 2006, perioperative chemotherapy has been
a valuable therapeutic modality for gastric adenocarcinoma
[34]. The MAGIC Trial compared neoadjuvant epirubicin,
cisplatin, and 5-fluorouracil (ECF) to surgery alone in patients
with stage II/III gastric or esophageal cancer. While a minority
of patients completed the full course of neoadjuvant therapy,
the systemic treatment arm still showed improved
progression-free and overall survival.
Recently, reported in 2017, the FLOT4-AIO Phase 3 trial
compared perioperative ECF or ECX (EC + capecitabine) to
another perioperative systemic therapy regimen, FLOT (5-
fluorouracil, leucovorin, oxaliplatin, and docetaxel). Not only
did patients receiving FLOT exhibit improved progression-
free and overall survival, but also showed more frequent path-
ologic complete regression, and were more likely to complete
all intended therapies [35••]. While FLOT has shown excel-
lent efficacy compared to other regimens, it does exhibit a
significant side effect profile. Therefore, in patients with poor
performance status, FOLFOX is recommended instead for
improved tolerance [15••].
Chemoradiotherapy
Historical studies have assessed the efficacy of combination
chemoradiotherapy versus radiation or chemotherapy, demon-
strating that chemoradiation provided a survival advantage
over either modality alone [36, 37]. In patients with complete-
ly resected esophagogastric junction or gastric cancer who
have not received neoadjuvant therapy, postoperative chemo-
radiation is the standard of care [15••]. This was established by
the American Intergroup trial SWOG9008/INT-0116 which
compared surgery plus postoperative chemotherapy (5-FU
and leucovorin) + radiation therapy to surgery alone [38].
Recent studies have sought to identify superior chemotherapy
versus chemoradiotherapy regimens.
The CRITICS trial, reported in 2018, compared gastric
cancer patients receiving perioperative chemotherapy (chemo-
therapy group) versus preoperative chemotherapy and post-
operative chemoradiation (chemoradiotherapy group) [39].
Authors found no significant difference in overall survival
between the adjuvant chemotherapy and chemoradiotherapy
groups. The study did show that patients exhibited poor post-
operative treatment adherence and suggested that future stud-
ies may do well to optimize preoperative therapy.
Currently underway, the TOPGEAR randomized phase III
trial seeks to evaluate the efficacy of preoperative chemoradi-
ation in patients with resectable gastric cancer receiving peri-
operative ECF. The interim analysis assessed the safety and
Page 5 of 9 67
feasibility of preoperative chemoradiation with favorable re-
sults. There was no statistical difference in patients proceeding
to surgery, or occurrence of grade 3 or higher surgical, toxic-
ity, or hematologic complications [40].
The ARTIST trial, reported in 2018, compared patients
with completely D2-resected gastric cancer receiving capecit-
abine plus cisplatin versus capecitabine plus cisplatin with
concurrent capecitabline radiotherapy [41]. Overall, disease-
free survival was not significantly different between groups.
However, in the subgroup of patients with lymph node metas-
tasis, the chemoradiotherapy group did show statistically im-
proved disease-free survival. Now, the ARTIST 2 trial is cur-
rently ongoing and seeks to compare disease-free survival in
node-positive, stage II or III gastric cancer patients who have
undergone gastrectomy with D2 lymphadenectomy, and have
received chemotherapy and chemoradiation. Patients were
randomized to three different adjuvant therapy groups: oral
S-1 for 12 months vs. S-1 and oxaliplatin (SOX) for 6 months
or SOX plus chemoradiation (SOXRT). The interim safety
analysis revealed no significant concerns in 2018, and the trial
is underway. [42]
Controversy remains as to the most appropriate therapy for
very proximal gastric cancers (Siewert type III lesions) at the
EGJ. As discussed previously, the perioperative FLOT che-
motherapy regimen has shown excellent efficacy in gastric
adenocarcinoma [35••]. The CROSS chemoradiation regimen
has shown benefit in esophageal and EGJ cancers [43]. The
CROSS group’s randomized prospective trial included pa-
tients with squamous cell carcinoma or adenocarcinoma of
the esophagus or EGJ and compared treatment with neoadju-
vant chemoradiation (radiation, carboplatin, paclitaxel) then
surgery versus surgery alone. The chemoradiation + surgery
arm outperformed the surgery alone arm with improved R0
resection rate, 29% complete pathologic response rate, and
improved median overall survival of 49.4 months compared
to 24 months. The German ESOPEC trial is ongoing and is
designed as a prospective study to compare FLOT chemother-
apy versus CROSS chemoradiation in EGJ cancers [44]. This
comparison is complex considering the inclusion of squamous
esophageal cancers but should provide insight into this chal-
lenging treatment question.
Targeted and Immune Therapies
First-line therapy for metastatic gastric cancer generally com-
bines a fluorinated pyrimidine (5-fluorouracil) with platinum-
based therapy. While there have been some changes over the
decades to delivery of these drugs, such as oral regimens (cap-
ecitabine), the treatment regimens have remained relatively
constant. Gastric cancer prognosis has improved only very
gradually as clinical trials help to provide evidence for optimal
combination and sequence of the suboptimal available treat-
ment modalities. This highlights the need for new therapies,
 67 Page 6 of 9
which have now entered the therapeutic arena in the form of
targeted and immune therapies.
Targeted Therapy
With genetic profiling of cancers and discovery of tumor
markers, the opportunity to tailor effective drug regimens to
individuals is becoming a reality. Targeted therapies in the
form of monoclonal antibodies and small molecule inhibitors
have become available and have recently become important
aspects of multimodal therapy for gastric cancer.
A member of the human epidermal growth factor receptor
family of proteins, HER2 is well known to participate in driv-
ing certain breast cancers and is often exploited as a treatment
target. It has been shown that 15–37% of gastric cancers also
exhibit elevated HER2 expression [45]. The randomized
phase III ToGA trial compared the combination of anti-
HER2 monoclonal antibody trastuzumab + chemotherapy to
chemotherapy alone in patients with advanced gastric cancer
[46]. The trastuzumab + chemotherapy group showed im-
proved disease-free survival as well as overall survival.
Ultimately, the NCCN guidelines recommend HER2 testing
at diagnosis of gastric cancer, if metastasis is suspected, to
help guide initial therapeutic planning [15••].
Another human epidermal growth factor receptor family
targeting agent which has shown promise is nimotuzumab,
the anti-EGFR monoclonal antibody [47]. While no survival
improvement was shown in the phase II trial assessing the
addition of nimotuzumab to irinotecan in advanced gastric
cancer, there did appear to be potential improvement in re-
sponse rate, progression-free, and overall survival in an
EGFR-overexpressed subset of patients. It is not surprising
that targeted therapies should specifically benefit the subsets
of patients expressing the targets.
The vascular endothelial growth factor receptor (VEGFR)
family of proteins has proven to be a useful target in gastric
cancer with ramucirumab, the anti-VEGFR2 monoclonal an-
tibody, showing efficacy in two recent phase III trials. The
REGARD trial compared ramucirumab monotherapy to pla-
cebo in advanced gastric cancer patients and showed an in-
crease in median survival time [48]. The RAINBOW trial
assessed the addition of ramucirumab to paclitaxel in ad-
vanced gastric cancer patients and showed a significant in-
crease in progression-free and overall survival compared to
paclitaxel alone [49].
Immune Checkpoint Inhibition
Over a relatively brief timespan, immunotherapy has emerged
as the so-called fourth pillar of oncologic therapies. A vast
array of tumor types have shown susceptibility to treatments
aimed at blocking cancer immune evasion mechanisms in-
cluding targets such as CTLA4 and PD-1/PD-L1.
Curr Oncol Rep (2019) 21:67
Nivolumab is a monoclonal antibody against PD-1. After
promising initial studies, the ATTRACTION-2 trial was per-
formed, comparing nivolumab to placebo in patients with ad-
vanced gastric cancer or esophagogastric junction cancer who
had failed at least two chemotherapy regimens. Overall sur-
vival was significantly improved with nivolumab, leading to
its approval as third-line treatment [50].
Ipilimumab (anti-CTLA4 monoclonal antibody),
pembrolizumab (anti-PD-1 monoclonal antibody), and
avelumab (anti-PD-L1 monoclonal antibody) are other im-
mune therapies which have shown efficacy in other cancer
types. Ongoing research is exploring their uses in gastric can-
cer [51–55].
Conclusion
The management of gastric cancer is a challenge requiring a
multidisciplinary approach for optimal treatment. With next-
generation genomic analysis, new gastric cancer classification
systems may help to facilitate the appropriate use of targeted
therapies in a precise and efficient manner. The employment
of improved chemoradiotherapy regimens not only show sur-
vival gains, but also may facilitate the judicious use of aggres-
sive surgical techniques for cure of relatively late-stage dis-
ease which previously would have been treated with palliative
measures. Moving forward, the use of targeted therapies, im-
mune therapies, better chemoradiotherapy regimens, and per-
haps cytoreductive surgical techniques all appear to have
promising potential in the evolving treatment of gastric cancer.
Compliance with Ethical Standards
Conflict of Interest Fabian M. Johnston and Michael Beckman declare
they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.
Global cancer statistics 2018: GLOBOCAN estimates of incidence
and mortality worldwide for 36 cancers in 185 countries. CA
Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.
21492.
2. LAURÉN P. The two histological main types of gastric carcinoma:
diffuse and so-called intestinal-type carcinoma. Acta Pathol
Curr Oncol Rep (2019) 21:67
Microbiol Scand. 1965;64(1):31–49. https://doi.org/10.1111/apm.
1965.64.1.31.
3. WHO Classification of Tumours of the Digestive System. Fourth
Edition - WHO - OMS -. http://apps.who.int/bookorders/anglais/
detart1.jsp?codlan=1&codcol=70&codcch=4003. Accessed
February 26, 2019.
4. Curtis NJ, Noble F, Bailey IS, Kelly JJ, Byrne JP, Underwood TJ.
The relevance of the Siewert classification in the era of multimodal
therapy for adenocarcinoma of the gastro-oesophageal junction. J
Surg Oncol. 2014;109(3):202–7. https://doi.org/10.1002/jso.
23484.
5. Rüdiger Siewert J, Feith M, Werner M, Stein HJ. Adenocarcinoma
of the esophagogastric junction: results of surgical therapy based on
anatomical/topographic classification in 1,002 consecutive patients.
Ann Surg 2000;232(3):353–361. http://www.ncbi.nlm.nih.gov/
pubmed/10973385. Accessed March 6, 2019.
6. Bass AJ, Thorsson V, Shmulevich I, et al. Comprehensive molecu-
lar characterization of gastric adenocarcinoma. Nature.
2014;513(7517):202–9. https://doi.org/10.1038/nature13480.
7. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS,
et al. Molecular analysis of gastric cancer identifies subtypes asso-
ciated with distinct clinical outcomes. Nat Med. 2015;21(5):449–
56. https://doi.org/10.1038/nm.3850.
8. Fonkoua LK, Yee NS. Biomedicines molecular characterization of
gastric carcinoma: therapeutic implications for biomarkers and tar-
gets. doi:https://doi.org/10.3390/biomedicines6010032, 2018.
9. Leake P-A, Cardoso R, Seevaratnam R, Lourenco L, Helyer L,
Mahar A, et al. A systematic review of the accuracy and indications
for diagnostic laparoscopy prior to curative-intent resection of gas-
tric cancer. Gastric Cancer. 2012;15(S1):38–47. https://doi.org/10.
1007/s10120-011-0047-z.
10.•• Amin MB, Edge SB, American Joint Committee on Cancer. AJCC
Cancer Staging Manual. https://www.springer.com/us/book/
9783319406176. Accessed February 25, 2019. The 8th edition
AJCC Cancer Staging Manual for gastric cancer is integral
for clinical practice. It has been updated with evidence-based
clinical and post-neoadjuvant staging systems for facilitation of
initial treatment plan recommendations.
11. Shu P, Qin J, Shen K, Chen W, Liu F, Fang Y, et al. The IGCA
staging system is more accurate than AJCC7 system in stratifying
survival of patients with gastric cancer in stage III. BMC Cancer.
2017;17(1):238. https://doi.org/10.1186/s12885-017-3235-3.
12. Mocellin S, Pasquali S. Diagnostic accuracy of endoscopic ultraso-
nography (EUS) for the preoperative locoregional staging of prima-
ry gastric cancer. Cochrane Database Syst Rev. 2015;2:CD009944.
https://doi.org/10.1002/14651858.CD009944.pub2.
13. Puli S-R, Reddy J-B, Bechtold M-L, Antillon D, Ibdah J-A,
Antillon M-R. Staging accuracy of esophageal cancer by endoscop-
ic ultrasound: a meta-analysis and systematic review. World J
Gastroenterol 2008;14(10):1479–1490. http://www.ncbi.nlm.nih.
gov/pubmed/18330935. Accessed March 6, 2019.
14. Rosenbaum SJ, Stergar H, Antoch G, Veit P, Bockisch A, Kühl H.
Staging and follow-up of gastrointestinal tumors with PET/CT.
Abdom Imaging. 2006;31(1):25–35. https://doi.org/10.1007/
s00261-005-0031-3.
15.•• Lisa Gurski N, McMillian N, Lenora Pluchino MA, et al. NCCN
Guidelines Version 2.2018 Panel Members Gastric Cancer.; 2019.
https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf.
Accessed February 26, 2019. The NCCN Guidelines for gastric
cancer are comprehensive, evidence-based, and frequently
updated. They are compiled and published by a panel of
experts in the field.
Page 7 of 9 67
16. De Andrade JP, Mezhir JJ. The critical role of peritoneal cytology in
the staging of gastric cancer: an evidence-based review. J Surg
Oncol. 2014;110(3):291–7. https://doi.org/10.1002/jso.23632.
17. The general rules for The gastric cancer study in surgery. Jpn J
Surg. 1973;3(1):61–71. http://www.ncbi.nlm.nih.gov/pubmed/
4803902. Accessed February 26, 2019.
18. Songun I, Putter H, Kranenbarg EM-K, Sasako M, van de Velde CJ.
Surgical treatment of gastric cancer: 15-year follow-up results of the
randomised nationwide Dutch D1D2 trial. Lancet Oncol.
2010;11(5):439–49. https://doi.org/10.1016/S1470-2045(10)
70070-X.
19. Mocellin S, McCulloch P, Kazi H, Gama-Rodrigues JJ, Yuan Y,
Nitti D. Extent of lymph node dissection for adenocarcinoma of
the stomach. Cochrane Database Syst Rev. 2015;8:CD001964.
https://doi.org/10.1002/14651858.CD001964.pub4.
20. Fujimura T, Nakamura K, Oyama K, et al. Selective lymphadenec-
tomy of Para-aortic lymph nodes for advanced gastric cancer. Oncol
Rep 2009;22(3):509–514. http://www.ncbi.nlm.nih.gov/pubmed/
19639196. Accessed February 26, 2019.
21. Schwarz RE, Smith DD. Clinical impact of lymphadenectomy ex-
tent in resectable gastric cancer of advanced stage. Ann Surg Oncol.
2007;14(2):317–28. https://doi.org/10.1245/s10434-006-9218-2.
22. Kitano S, Iso Y, Moriyama M, Sugimachi K. Laparoscopy-assisted
Billroth I gastrectomy. Surg Laparosc Endosc 1994;4(2):146–148.
http://www.ncbi.nlm.nih.gov/pubmed/8180768. Accessed
February 26, 2019.
23. Hashizume M, Sugimachi K. Robot-assisted gastric surgery. Surg
Clin North Am. 2003;83(6):1429–44. https://doi.org/10.1016/
S0039-6109(03)00158-0.
24. Huscher CGS, Mingoli A, Sgarzini G, Sansonetti A, di Paola M,
Recher A, Ponzano C Laparoscopic versus open subtotal gastrec-
tomy for distal gastric cancer: five-year results of a randomized
prospective trial. Ann Surg 2005;241(2):232–237. http://www.
ncbi.nlm.nih.gov/pubmed/15650632. Accessed February 28,
2019.
25. Soetikno R, Kaltenbach T, Yeh R, Gotoda T. Endoscopic mucosal
resection for early cancers of the upper gastrointestinal tract. J Clin
Oncol. 2005;23(20):4490–8. https://doi.org/10.1200/JCO.2005.19.
935.
26. Lian J, Chen S, Zhang Y, Qiu F. A meta-analysis of endoscopic
submucosal dissection and EMR for early gastric cancer.
Gastrointest Endosc. 2012;76(4):763–70. https://doi.org/10.1016/j.
gie.2012.06.014.
27. Facciorusso A, Antonino M, Di Maso M, Muscatiello N.
Endoscopic submucosal dissection vs endoscopic mucosal resec-
tion for early gastric cancer: a meta-analysis. World J Gastrointest
Endosc. 2014;6(11):555–63. https://doi.org/10.4253/wjge.v6.i11.
555.
28. Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for ad-
vanced gastric cancer. Cochrane Database Syst Rev. 2017;8.
https://doi.org/10.1002/14651858.CD004064.pub4.
29. Hall J, Loggie BW, Shen P, et al. Cytoreductive surgery with intra-
peritoneal hyperthermic chemotherapy for advanced gastric cancer.
J Gastrointest Surg. 2004;8(4):454–63. https://doi.org/10.1016/j.
gassur.2003.12.014.
30. Glehen O, Gilly FN, Arvieux C, et al. Peritoneal Carcinomatosis
from gastric cancer: a multi-institutional study of 159 patients treat-
ed by cytoreductive surgery combined with perioperative intraper-
itoneal chemotherapy. Ann Surg Oncol. 2010;17(9):2370–7.
https://doi.org/10.1245/s10434-010-1039-7.
31. Gill RS, Al-Adra DP, Nagendran J, et al. Treatment of gastric cancer
with peritoneal carcinomatosis by cytoreductive surgery and
 67 Page 8 of 9
HIPEC: a systematic review of survival, mortality, and morbidity. J
Surg Oncol. 2011;104(6):692–8. https://doi.org/10.1002/jso.22017.
32.•• Bonnot PE, Piessen G, Pocard M, Meunier B, Bereder JM, Abboud
K, et al. CYTO-CHIP: cytoreductive surgery versus cytoreductive
surgery and hyperthermic intraperitoneal chemotherapy for gastric
cancer with peritoneal metastasis: a propensity-score analysis from
BIG RENAPE and FREGAT working groups. J Clin Oncol.
2018;36(4_suppl):8–8. https://doi.org/10.1200/JCO.2018.36.4_
suppl.8. The CYTO-CHIP analysis data has only recently been
reported, and provides evidence of survival benefit of
cytoreductive surgery plus HIPEC in gastric cancer in patients
with evidence of peritoneal disease.
33. Desiderio J, Chao J, Melstrom L, Warner S, Tozzi F, Fong Y, et al.
The 30-year experience—a meta-analysis of randomised and high-
quality non-randomised studies of hyperthermic intraperitoneal
chemotherapy in the treatment of gastric cancer. Eur J Cancer.
2017;79:1–14. https://doi.org/10.1016/j.ejca.2017.03.030.
34. Cunningham D, Allum WH, Stenning SP, Thompson JN, van de
Velde C, Nicolson M, et al. Perioperative chemotherapy versus
surgery alone for resectable gastroesophageal cancer. N Engl J
Med. 2006;355(1):11–20. https://doi.org/10.1056/NEJMoa055531.
35.•• Al-Batran S-E, Homann N, Schmalenberg H, et al. Perioperative
chemotherapy with docetaxel, oxaliplatin, and fluorouracil/
leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil
or capecitabine (ECF/ECX) for resectable gastric or gastroesopha-
geal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter,
randomized phase 3 trial. J Clin Oncol. 2017;35(15_suppl):4004–4.
https://doi.org/10.1200/JCO.2017.35.15_suppl.4004 The FLOT
regimen recently showed improved survival over previous
chemotherapy regimens in the perioperative setting. This has
caused a dramatic change in the chemotherapeutic treatment of
gastric cancer over a brief period of time.
36. Moertel C, Reitemeier R, Childs D, Colby M, Holbrook M.
Combined 5-fluorouracil and SUPERVOLTAGE radiation therapy
of locally UNRESECTABLE gastrointestinal cancer. Lancet.
1969;294(7626):865–7. https://doi.org/10.1016/S0140-6736(69)
92326-5.
37. Gastrointestinal Tumor Study Group. A comparison of combination
chemotherapy and combined modality therapy for locally advanced
gastric carcinoma. Cancer. 1982;49(9):1771–7 http://www.ncbi.
nlm.nih.gov/pubmed/6176313. Accessed February 28, 2019.
38. Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC,
Ajani JA, et al. Updated analysis of SWOG-directed intergroup
study 0116: a phase III trial of adjuvant radiochemotherapy versus
observation after curative gastric cancer resection. J Clin Oncol.
2012;30(19):2327–33. https://doi.org/10.1200/JCO.2011.36.7136.
39. Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P,
Nordsmark M, et al. Chemotherapy versus chemoradiotherapy after
surgery and preoperative chemotherapy for resectable gastric can-
cer (CRITICS): an international, open-label, randomised phase 3
trial. Lancet Oncol. 2018;19(5):616–28. https://doi.org/10.1016/
S1470-2045(18)30132-3.
40. Leong T, Smithers BM, Haustermans K, Michael M, Gebski V,
Miller D, et al. TOPGEAR: a randomized, phase III trial of periop-
erative ECF chemotherapy with or without preoperative chemora-
diation for resectable gastric cancer: interim results from an inter-
national, intergroup trial of the AGITG, TROG, EORTC and
CCTG. Ann Surg Oncol. 2017;24(8):2252–8. https://doi.org/10.
1245/s10434-017-5830-6.
41. Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, et al. Phase III
trial comparing capecitabine plus cisplatin versus capecitabine plus
cisplatin with concurrent capecitabine radiotherapy in completely
Curr Oncol Rep (2019) 21:67
resected gastric cancer with D2 lymph node dissection: the ARTIST
trial. J Clin Oncol. 2012;30(3):268–73. https://doi.org/10.1200/
JCO.2011.39.1953.
42. Park SH, Lee SJ, Kim ST, Lee J, Park JO, Park YS, et al.
Multicenter phase III trial of adjuvant chemoradiotherapy in stom-
ach tumors 2 (ARTIST 2). J Clin Oncol. 2015;33(3_suppl:
TPS228–8. https://doi.org/10.1200/jco.2015.33.3_suppl.tps228.
43. van Hagen P, Hulshof MCCM, van Lanschot JJB, Steyerberg EW,
Henegouwen MIB, Wijnhoven BPL, et al. Preoperative chemora-
diotherapy for esophageal or junctional cancer. N Engl J Med.
2012;366(22):2074–84. https://doi.org/10.1056/NEJMoa1112088.
44. Hoeppner J, Lordick F, Brunner T, Glatz T, Bronsert P, Röthling N,
et al. ESOPEC: prospective randomized controlled multicenter
phase III trial comparing perioperative chemotherapy (FLOT pro-
tocol) to neoadjuvant chemoradiation (CROSS protocol) in patients
with adenocarcinoma of the esophagus (NCT02509286). BMC
Cancer. 2016;16(1):503. https://doi.org/10.1186/s12885-016-
2564-y.
45. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic
factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523–
9. https://doi.org/10.1093/annonc/mdn169.
46. Bang Y-J, Van Cutsem E, Feyereislova A, et al. Trastuzumab in
combination with chemotherapy versus chemotherapy alone for
treatment of HER2-positive advanced gastric or gastro-
oesophageal junction cancer (ToGA): a phase 3, open-label,
randomised controlled trial. Lancet (London, England).
2010;376(9742):687–97. https://doi.org/10.1016/S0140-6736(10)
61121-X.
47. Satoh T, Lee KH, Rha SY, Sasaki Y, Park SH, Komatsu Y, et al.
Randomized phase II trial of nimotuzumab plus irinotecan versus
irinotecan alone as second-line therapy for patients with advanced
gastric cancer. Gastric Cancer. 2015;18(4):824–32. https://doi.org/
10.1007/s10120-014-0420-9.
48. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R,
Goswami C, et al. Ramucirumab monotherapy for previously treat-
ed advanced gastric or gastro-oesophageal junction adenocarcino-
ma (REGARD): an international, randomised, multicentre, place-
bo-controlled, phase 3 trial. Lancet (London, England).
2014;383(9911):31–9. https://doi.org/10.1016/S0140-6736(13)
61719-5.
49. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus pacli-
taxel versus placebo plus paclitaxel in patients with previously treat-
ed advanced gastric or gastro-oesophageal junction adenocarcino-
ma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet
Oncol. 2014;15(11):1224–35. https://doi.org/10.1016/S1470-
2045(14)70420-6.
50. Kang Y-K, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, et al.
Nivolumab in patients with advanced gastric or gastro-
oesophageal junction cancer refractory to, or intolerant of, at least
two previous chemotherapy regimens (ONO-4538-12,
ATTRACTION-2): a randomised, double-blind, placebo-con-
trolled, phase 3 trial. Lancet (London, England).
2017;390(10111):2461–71. https://doi.org/10.1016/S0140-
6736(17)31827-5.
51. Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S,
et al. Pembrolizumab for patients with PD-L1-positive advanced
gastric cancer (KEYNOTE-012): a multicentre, open-label, phase
1b trial. Lancet Oncol. 2016;17(6):717–26. https://doi.org/10.1016/
S1470-2045(16)00175-3.
52. Bang Y-J, Cho JY, Kim YH, Kim JW, di Bartolomeo M, Ajani JA,
et al. Efficacy of sequential ipilimumab monotherapy versus best
supportive care for unresectable locally advanced/metastatic gastric
Curr Oncol Rep (2019) 21:67
or gastroesophageal junction cancer. Clin Cancer Res. 2017;23(19):
5671–8. https://doi.org/10.1158/1078-0432.CCR-17-0025.
53. Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P,
et al. CheckMate-032 study: efficacy and safety of Nivolumab and
Nivolumab plus Ipilimumab in patients with metastatic
Esophagogastric Cancer. J Clin Oncol. 2018;36(28):2836–44.
https://doi.org/10.1200/JCO.2017.76.6212.
54. Moehler M, Ryu M-H, Dvorkin M, Lee KW, Coşkun HŞ, Wong R,
et al. Maintenance avelumab versus continuation of first-line che-
motherapy in gastric cancer: JAVELIN gastric 100 study design.
Future Oncol. 2019;15(6):567–77. https://doi.org/10.2217/fon-
2018-0668.
Page 9 of 9 67
55. Bang Y-J, Ruiz EY, Van Cutsem E, et al. Phase III, randomised trial
of avelumab versus physician’s choice of chemotherapy as third-
line treatment of patients with advanced gastric or gastro-
oesophageal junction cancer: primary analysis of JAVELIN
Gastric 300. Ann Oncol. 2018;29(10):2052–60. https://doi.org/10.
1093/annonc/mdy264.
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