Clinical Review & Education

JAMA Surgery | Review

Surgical Management of Gastric Cancer

A Review
George Z. Li, MD; Gerard M. Doherty, MD; Jiping Wang, MD, PhD

IMPORTANCE Surgery plays a critical role in the management of all stages of gastric cancer.

OBSERVATIONS For patients with early gastric cancer and low risk of lymph node metastasis,
endoscopic therapy or surgery alone is potentially curative. Novel techniques, such as
sentinel lymph node biopsy, may allow for greater use of stomach-sparing procedures that
could improve quality of life without compromising oncologic outcomes; however,
experience with these techniques is rare outside of East Asia, and studies of long-term
outcomes are still ongoing. Patients with later-stage localized gastric cancer benefit from
more extensive lymphadenectomy and multimodality therapy, as they are at risk for nodal
and distant metastases. There have been recent advances in chemotherapy that have led
to improved survival, but the optimal sequencing of multimodality therapy is still being
investigated. Better systemic therapy may also increase the role of surgery for patients
with oligometastatic disease. There are ongoing studies examining the efficacy of
Author Affiliations: Department of
peritoneal-directed therapies in both patients with low-volume peritoneal disease and Surgery, Brigham and Women’s
patients at high risk of peritoneal recurrence. Hospital, Boston, Massachusetts
(Li, Doherty, Wang); Center for
CONCLUSIONS AND RELEVANCE The management of gastric cancer continues to evolve. Gastrointestinal Oncology,
Surgeons should be aware of novel surgical approaches currently under investigation as Dana-Farber Cancer Institute, Boston,
Massachusetts (Wang).
well as how surgery fits into the contemporary multidisciplinary approach to this disease.
Corresponding Author: Jiping Wang,
MD, PhD, Department of Surgery,
JAMA Surg. doi:10.1001/jamasurg.2022.0182 Brigham and Women’s Hospital,
Published online March 23, 2022. 75 Francis St, Boston, MA 02115
(jwang39@bwh.harvard.edu).

T
he incidence of gastric cancer has decreased worldwide
since the 1970s owing to factors such as improved
refrigeration1 and effective therapy against Helicobacter
pylori.2 However, prognosis for patients with gastric cancer has only
modestly improved during this time, probably because patients of-
ten present with advanced disease. In the US, up to 65% of pa-
tients present with stage III or IV disease, and even in countries like
Japan with robust screening programs, half of patients still present
with advanced disease.3 As a result, gastric cancer remains the third
most common cause of cancer mortality worldwide,4 and in the US,
there are still 27 000 new cases and 11 000 deaths each year.5 Treat-
ment of gastric cancer requires a multidisciplinary approach and
continues to evolve. Here, we review the contemporary surgical
management of all stages of gastric cancer.
Early Gastric Cancer
Early gastric cancer (EGC) is defined as a tumor limited to the
mucosa or submucosa (clinical T1) regardless of lymph node status.6
The risk of lymph node involvement dictates the subsequent man-
agement of EGCs.
Endoscopic Therapy
Gastric cT1a tumors that are less than 2 cm in diameter, lack ulcer-
ation with differentiated histology, have no lymphovascular inva-
sion, and lack clinical evidence of locoregional lymph node involve-
ment have a low 1% to 5% risk of lymph node metastasis.7,8 Patients
with these tumors are thus candidates for curative-intent endo-
scopic therapy with either endoscopic mucosal resection or endo-
scopic submucosal dissection.9,10 Although a propensity score–
matched analysis of data from the National Cancer Database found
that gastrectomy was associated with superior survival compared
with endoscopic resection for cT1a tumors, it is unclear what pro-
portion of these tumors met the other criteria for endoscopic
resection.8 Furthermore, other Eastern and Western series have re-
ported excellent long-term outcomes after endoscopic resection in
appropriately selected patients,9,10 and currently the Japanese Gas-
tric Cancer Association,11 European Society of Medical Oncology,12
and National Comprehensive Cancer Network (NCCN)13 all recom-
mend endoscopic therapy as initial therapy for EGC meeting the pre-
viously mentioned criteria. All patients with gastric cancer should
undergo H pylori testing and eradication therapy if test results are
positive, but this is especially important for patients with EGC who
are undergoing endoscopic resection, as H pylori eradication de-
creases the risk of developing metachronous gastric cancers.14
In contrast, gastric cT1b tumors have nodal metastasis rates of
18% to 32%,8,15 and a radical gastrectomy (ie, one that includes a
formal lymphadenectomy) should be considered for patients with
these tumors. Patients who undergo noncurative endoscopic re-
section, ie, those with positive margins, lymphovascular invasion,
or poorly differentiated histology on final pathology, also have a 14%

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 Clinical Review & Education Review
Table 1. Ongoing Randomized Clinical Trials in Gastric Cancer
Source study name and location Patients
SENORITA21; phase 3; South Korea cT1N0M0 gastric cancer ≤3 cma; target enrollment 580
CRITICS-II22; phase 2; the Stage IB-IIIC gastric cancer
Netherlands
TOPGEAR23; phase 3; Australia, Stage IB-IIIC gastric cancer; target
Europe, Canada enrollment 752
PILGRIM (HIPEC-01)24; phase 3; T3-4NxM0 gastric cancer (n = 648)
China
RENAISSANCE (AIO-FLOT5)25; M1 gastric cancer: retroperitoneal metastasis only or
phase 3; Germany 1 potentially resectable/controllable organ site met with or
without retroperitoneal metastasis; no disease progression
on FLOT ×4 cycles; target enrollment = 271
Abbreviations: AIO-FLOT5, Arbeitsgemeinschaft Internistische
Onkologie–Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel 5;
CRITICS-II, Chemoradiotherapy after Induction Chemotherapy in Cancer of
the Stomach II; CRT, chemoradiotherapy; DOC, docetaxel, oxaliplatin, and
capecitabine; ECF, epirubicin, cisplatin, and fluorouracil; FLOT, fluorouracil,
leucovorin, oxaliplatin, and docetaxel; HIPEC, hyperthermic intraperitoneal
chemotherapy; HIPEC-01, Phase III Clinical Trial in Evaluating the Role of
Hyperthermic Intraperitoneal Chemotherapy for Locally Advanced Gastric
rate of nodal metastases16 and should generally be referred for
radical gastrectomy if they are reasonable surgical candidates. In
addition, patients with EGC but clinical evidence of lymph node
metastases (cN >0) should be referred for multimodality therapy.
Sentinel Lymph Node Biopsy With
Function-Preserving Resection
Patients with cT1 to cT2N0M0 tumors who do not meet criteria for
endoscopic therapy or who have had noncurative endoscopic
therapy may be candidates for sentinel lymph node biopsy. Al-
though sentinel lymph node biopsy is well established for mela-
noma and breast cancer, its application to gastric cancer has been
limited primarily to centers in East Asia. Draining nodal basins are
mapped via submucosal injections of indocyanine green or radio-
active colloid. If any sentinel nodes are positive, then a radical gas-
trectomy is performed. If all sentinel nodes are negative, then a stom-
ach-preserving resection to negative margins is performed without
additional lymphadenectomy.17
Data on the accuracy of sentinel lymph node biopsy for gastric
cancer have been mixed. In an initial Japanese study, 440 patients
with cT1N0M0 gastric cancer underwent sentinel lymph node bi-
opsy followed immediately by D2 (extended systemic) lymphad-
enectomy. This study reported a high false-negative rate of 46%
(13 of 28 biopsy samples), with 7 of 13 patients (54%) having skip
metastases outside the sentinel lymph node basin.18 However, a sub-
sequent Japanese trial of 433 patients reported much better re-
sults, with a sentinel lymph node detection rate of 98%, an accu-
racy rate of 99%, and only 4 false-negatives.19 Part of the reason for
this discrepancy may be the steep procedural learning curve, as the
learning period was only 5 patients per center for the initial study
but 30 patients per center for the subsequent study. The resulting
operator dependence may also explain the highly heterogenous re-
sults found in prior meta-analyses of smaller series.20 Overall, the
data suggest that sentinel lymph node biopsy may be feasible in ex-
perienced hands, but that the steep learning curve may limit its wider
applicability at this time. To our knowledge, there are also no long-
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Surgical Management of Gastric Cancer
Groups Primary end point
SLNB + stomach-preserving 3-y Disease-free
resection; survival
standard gastrectomy
DOC + CRT + surgery; CRT + Event-free survival
surgery; DOC + surgery
ECF + CRT + surgery + ECF; Overall survival
ECF + surgery + ECF
Surgery + HIPEC + XELOX/SOX Overall survival
(n = 317);
surgery + XELOX/SOX (n = 331)
Surgery + FLOT; continue FLOT; Overall survival
alone
Cancer Patients After Radical Gastrectomy With D2 Lymphadenectomy;
SENORITA, Sentinel Node Oriented Tailored Approach; SLNB, sentinel lymph
node biopsy; SOX, S-1 and oxaliplatin; TOPGEAR, Trial of Preoperative
Therapy for Gastric and Esophagogastric Junction Adenocarcinoma;
XELOX, capecitabine and oxaliplatin.
a
T, tumor stage; N, nodal stage; M, metastasis stage from TNM staging system,
as per the American Joint Committee on Cancer, 8th Edition.
term survival data or direct comparisons with standard radical
gastrectomy yet, although the ongoing Sentinel Node Oriented
Tailored Approach (SENORITA) phase 3 randomized trial in South
Korea aims to address this (Table 1).21-25
For centers that perform sentinel lymph node biopsy, a nega-
tive biopsy is followed by a function-sparing gastric resection. This
may consist of either a gastric wedge resection or a segmental
gastric resection, in which the gastric body is resected, the vagal
nerve branches are preserved, and a gastrogastric anastomosis is
performed between the proximal and distal stomach.26 Segmental
gastric resections are performed primarily in East Asia, but long-
term quality of life for patients appears to be better than that of pa-
tients who undergo subtotal or total gastrectomy.27 Patients with
EGC who have had margin-negative endoscopic resection but tu-
mors with high-risk pathologic features may be candidates for sen-
tinel lymph node biopsy alone without additional gastric resection
if the sentinel nodes are negative. A small study28 from Japan en-
rolled 21 such patients and found a sentinel lymph node positivity
rate of 10% (2 of 21). Interestingly, both patients with positive nodes
opted against further surgery, and after a median follow-up of 61
months, all patients were alive without evidence of recurrence,
although 2 patients had undergone endoscopic therapy for meta-
chronous EGCs during follow-up.28
Other Localized Gastric Cancer
Patients with localized gastric cancer more advanced than EGC
(cT ⱖ2) or those with positive lymph nodes (cN >0) generally re-
quire multimodality therapy because they are at higher risk of both
nodal and distant metastases. This therapy consists of surgery,
chemotherapy, and possibly chemoradiotherapy.
Extent of Gastric Resection and Lymphadenectomy
Although EGC may be managed with stomach-sparing ap-
proaches, patients with more advanced localized gastric cancer
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usually require either a radical distal or total gastrectomy to obtain

Table 2. Japanese Gastric Cancer Association Lymph Node Stationsa
both an adequate nodal dissection and microscopically negative
(R0) margins. A proximal gastrectomy can also be performed for Stations Definition

tumors near the gastroesophageal junction,11 but many centers pre- 1-6 Perigastric along the greater and lesser curvatures

fer a total gastrectomy in this scenario owing to lower rates of bile 7 Left gastric artery

reflux and anastomotic strictures.29 The NCCN no longer specifies 8a, 8p Common hepatic artery
a minimum margin length,13 but the Japanese Gastric Cancer Asso- 8a: Anterior
ciation recommends aiming for gross margins of at least 3 cm for T1 8p: Posterior
to T2 tumors and at least 5 cm for T3 to T4 tumors to improve the 9 Celiac artery
chances of an R0 resection, which is ultimately the goal.11 Euro- 10 Splenic hilum
pean Society of Medical Oncology guidelines recommend a proxi- 11p, 11d Splenic artery
mal margin of at least 5 cm, or 8 cm for diffuse-type gastric cancer, 11p: Proximal
if considering less than a total gastrectomy.12 11d: distal
The extent of lymphadenectomy has been heavily debated,30 12a, 12b, 12p Porta hepatis
as East Asian surgeons have historically performed more radical 12a: Proper hepatic artery
lymphadenectomies than Western surgeons (Table 2). Several 12b: Common bile duct
subsequent randomized trials have been conducted in Europe 12p: Portal vein
comparing outcomes after D1 and D2 lymphadenectomy. The 13 Posterior to pancreatic head
Medical Research Council trial in the UK found a higher rate of 14v Superior mesenteric vein
postoperative morbidity and mortality and equivalent 5-year over-
15 Middle colic vein
all survival with D2 lymphadenectomy,31 with the worse peri-
16a1, 16a2, Para-aortic
operative outcomes probably attributable to a high rate of distal 16b1
pancreatectomy and splenectomy.32 Similarly, the Dutch Gastric 16a1: Hiatus
Cancer Group Trial also found a higher rate of postoperative mor- 16a2: Between celiac artery and left renal vein
bidity and mortality in the D2 group and equivalent 5-year overall 16b1: Between left renal vein and inferior mesenteric
survival.33 However, after 15 years of follow-up, the D2 group had artery

significantly lower locoregional recurrence rates and gastric Total gastrectomy11

cancer–specific mortality. Although the 15-year overall survival was D1 Stations 1-7

not statistically significantly different between groups (D1 group,
21% vs D2 group, 29%; P = .34), the survival curves were still con-
tinuing to separate in favor of the D2 group.34 Overall, these data
suggest that D2 lymphadenectomy may improve locoregional
control and perhaps long-term patient survival compared with D1
lymphadenectomy, but only if performed with low rates of peri-
operative morbidity and mortality.
Evidence of improved locoregional control with D2 lymphad-
enectomy also comes indirectly from adjuvant chemoradiotherapy
trials. An analysis that compared patients from the Dutch lymph-
adenectomy trial, all of whom received surgery alone, with those
from 3 Dutch phase I and II adjuvant chemoradiotherapy trials
found that chemoradiotherapy was associated with significantly
lower local recurrence rates for patients who had undergone a D1
lymphadenectomy but not for those who had undergone a D2
lymphadenectomy,35 suggesting that the D1 subgroup benefited
from chemoradiotherapy because they had suboptimal locore-
gional control. In line with these data, the NCCN and European
Society of Medical Oncology guidelines both currently recom-
mend a D2 lymphadenectomy if it can be performed at an experi-
enced high-volume center.12,13 A minimum of 16 nodes should
be removed in order to accurately obtain an N stage,36 but the num-
ber of nodes is not used to assess the extent of lymphadenectomy.37
Patients undergoing less than a D2 lymphadenectomy should be con-
sidered for postoperative chemoradiotherapy. Pancreatectomy or
splenectomy should not be performed unless there is direct tumor
involvement or extensive hilar lymphadenopathy, as these proce-
dures are likely the main contributors to morbidity and mortality.13
An even more extensive D3 lymphadenectomy, which includes para-
aortic nodes, does not seem to improve oncologic outcomes com-
D2 D1 + stations 8a, 9, 10, 11p, 11d, 12a
D3 D2 + stations 16a2, 16b1
Distal gastrectomy11
D1 Stations 1-7 except gastric cardia and short gastric artery
nodes (2, 4sa)
D2 D1 + stations 8a, 9, 11p, 12a
D3 D2 + stations 16a2 (optional), 16b1
a
Table adapted with permission from the Japanese Gastric Cancer
Association.30
pared with a D2 lymphadenectomy based on the Japan Clinical
Oncology Group 9501 trial.38
Minimally Invasive Gastrectomy
Compared with open gastrectomy, minimally invasive gastrec-
tomy for cancer may be associated with equivalent or improved
short- and long-term outcomes. The Korean Laparoendoscopic Gas-
trointestinal Surgery Study 01 (KLASS-01), Korean Laparoendo-
scopic Gastrointestinal Surgery Study 02 (KLASS-02), and Chinese
Laparoscopic Gastrointestinal Surgery Study 01 (CLASS-01) ran-
domized trials from South Korea and China showed that laparo-
scopic distal gastrectomy for gastric cancer had lower complica-
tion rates, equivalent lymph node harvests, and equivalent long-
term survival compared with open distal gastrectomy,39-41 and
a retrospective series from the US comparing 87 matched laparo-
scopic and open gastrectomy operations for gastric cancer found that
laparoscopy was associated with equivalent lymph node harvest,
lower complication rates, and shorter length of stay.42 However, the
Laparoscopic vs Open Gastrectomy for Gastric Cancer (LOGICA) trial
from the Netherlands found that laparoscopic gastrectomy was not

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 Clinical Review & Education Review Surgical Management of Gastric Cancer

Table 3. Perioperative Chemotherapy and Chemoradiotherapy Trials for Gastric Cancer

Source study name and
location Patients Groups Results, HR (95% CI)
Perioperative chemotherapy
MAGIC50 2006; UK cT ≥2 or cN >0; gastric/GEJ ECF + surgery + ECF (n = 250); Improved OS for perioperative ECF:
(n = 503)a surgery (n = 253) 0.75 (0.6-0.93)
FLOT4-AIO51; cT ≥2 or cN >0; FLOT + surgery + FLOT (n = 356); Improved OS for perioperative FLOT:
Germany gastric/GEJ (n = 716) ECF + surgery + ECF (n = 360) 0.77 (90.63-0.94); median OS 35 mo vs 50 mo
Perioperative chemotherapy + CRT
CRITICS52; Stage IB-IVA; gastric/GEJ ECX/EOX + surgery + CRT (n = 395); OS not different 1.01 (0.84-1.22);
the Netherlands (n = 788) ECX/EOX + surgery + ECX/EOX median OS 37 mo vs 43 mo
(n = 393)
Abbreviations: CRITICS, Chemoradiotherapy After Induction Chemotherapy junction; HR, hazard ratio; MAGIC, Medical Research Council Adjuvant Gastric
in Cancer of the Stomach; CRT, chemoradiotherapy; ECF, epirubicin, cisplatin, Infusional Chemotherapy; OS, overall survival.
and fluorouracil; ECX, epirubicin, cisplatin, and capecitabine; EOX, epirubicin, a
T, tumor stage; N, nodal stage; M, metastasis stage from TNM staging system,
oxaliplatin, and capecitabine; FLOT, fluorouracil, leucovorin, oxaliplatin, and as per the American Joint Committee on Cancer, 8th Edition.
docetaxel; FLOT4-AIO, Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel
4—Arbeitsgemeinschaft Internistische Onkologie; GEJ, gastroesophageal

associated with any differences in postoperative complications,
lymph node yield, R0 resection rates, or 1-year survival compared
with open gastrectomy.43
A key disadvantage of laparoscopic gastrectomy is its steep
learning curve, as studies from South Korea have estimated a learn-
ing curve of 20 to 40 cases for laparoscopic distal gastrectomy
procedures44 and up to 100 cases for laparoscopic total gastrec-
tomy procedures.45 However, since 2016, robotic gastrectomy has
emerged as an alternative minimally invasive approach. Robotic gas-
trectomy is significantly more expensive and associated with lon-
ger operative times, whereas complication rates and lymph node
harvests are either equivalent or only marginally better based on large
studies from South Korea and China.46,47 However, despite no de-
finitive evidence of technical superiority, robotic surgery can be easier
to perform owing to improved ergonomics, increased degrees of in-
strument freedom, and stable optical views. As such, reported learn-
ing curves for robotic gastrectomy are lower than those for laparo-
scopic gastrectomy,48,49 although most surgeons in these studies
were already experienced in laparoscopic gastrectomy before learn-
ing robotic gastrectomy. Long-term outcomes data after robotic
gastrectomy also remain limited.
Neoadjuvant/Perioperative Therapy
Patients with cT2 or higher tumors or clinically positive lymph nodes
should undergo multimodality therapy based on multiple large ran-
domized trials (Table 3).50-52 The Medical Research Council Adju-
vant Gastric Infusional Chemotherapy (MAGIC) trial showed that peri-
operative (neoadjuvant plus adjuvant) chemotherapy with
epirubicin, cisplatin, and fluorouracil (ECF) improved both progres-
sion-free and overall survival compared with surgery alone for pa-
tients with localized (cT ⱖ2 or cN >0) gastric or distal esophageal
adenocarcinomas.50 Subsequently, the Fluorouracil, Leucovorin, Ox-
aliplatin, and Docetaxel 4—Arbeitsgemeinschaft Internistische
Onkologie (FLOT4-AIO) trial showed that perioperative fluoroura-
cil, leucovorin, oxaliplatin, and docetaxel (FLOT) was superior to peri-
operative ECF in these patients.51 Ongoing trials are investigating
other perioperative regimens, including the addition of trastuzumab
for patients with ERBB2 (formerly HER2 or HER2/neu)–positive
tumors.53 Immune checkpoint inhibitors have also emerged as an
option for mismatch repair-deficient tumors that express pro-
grammed death-ligand 1, but its use currently remains limited to pa-
tients with unresectable or metastatic disease.54 Use of chemora-
diotherapy in the neoadjuvant setting is also under investigation with
the ongoing Chemoradiotherapy after Induction Chemotherapy in
Cancer of the Stomach II (CRITICS-II)22 and Trial of Preoperative
Therapy for Gastric and Esophagogastric Junction Adenocarci-
noma (TOPGEAR)23 trials (Table 1), with the hypothesis being that
chemoradiotherapy may be better tolerated preoperatively and also
help down-stage tumors.55
Adjuvant Therapy
Patients who undergo upfront resection without neoadjuvant che-
motherapy and are subsequently found to have gastric cancer cat-
egories pT3 to pT4 or pN greater than 0 should receive adjuvant che-
motherapy. The Capecitabine and Oxaliplatin Adjuvant Study in
Stomach Cancer (CLASSIC) trial conducted in China, Taiwan, and South
Korea56,57 andtheAdjuvantChemotherapyTrialofTS-1forGastricCan-
cer (ACTS-GC) trial from Japan58 showed that adjuvant capecitabine
and oxaliplatin (CAPOX) or S-1 (an oral agent used for gastric cancer),
respectively, significantly improved disease-free and overall survival
compared with postoperative surveillance alone (Table 4).59-61
Adjuvant chemoradiotherapy plus chemotherapy is superior to
surveillance alone based on the Intergroup 0116 (INT 0116) trial,59 but
whether chemoradiotherapy adds additional benefit to adjuvant che-
motherapy is controversial. The Adjuvant Chemoradiation Therapy in
Stomach Cancer (ARTIST) trial from South Korea randomized 458 pa-
tients who had undergone gastrectomy with D2 lymphadenectomy
to either adjuvant chemotherapy or adjuvant chemotherapy plus che-
moradiotherapy. Although the investigators found no difference in
either disease-free or overall survival between the groups,60 pa-
tients with positive lymph nodes interestingly had a significantly
improved disease-free survival with the addition of chemoradio-
therapy in an unplanned subgroup analysis. Unfortunately, the
ARTIST-2 trial, which only enrolled patients with node-positive dis-
ease, was inadequately powered to validate this finding.61 A retro-
spective analysis of data from the National Cancer Database found that
the addition of chemoradiotherapy was associated with higher 5-year
overall survival in patients with both positive lymph nodes and lym-
phovascular invasion, but not in patients with positive lymph nodes
without lymphovascular invasion, suggesting that select subsets of
patients probably benefit from chemoradiotherapy more than
others.62 The Chemoradiotherapy after Induction Chemotherapy in

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 Surgical Management of Gastric Cancer
Table 4. Adjuvant Chemotherapy and Chemoradiotherapy Trials for Gastric Cancer
Source study name and location Patients
Adjuvant chemotherapy
CLASSIC56; China, Taiwan, Stage II-IIIB;
South Korea resected/D2;
gastric (n = 1035)
ACTS-GC58; Japan Stage II-III; resected/D2;
gastric (n = 1034)
Adjuvant CRT plus chemotherapy
INT 011659; US Resected; gastric/GEJ
(n = 556)
ARTIST60; South Korea Resected/D2;
gastric (n = 458)
ARTIST-261; South Korea Stage II-III; pN>0;
resected/D2 gastric (n = 546)b
Abbreviations: ACTS-GC, Adjuvant Chemotherapy Trial of TS-1 for Gastric
Cancer; ARTIST, Adjuvant Chemoradiation Therapy in Stomach Cancer;
ARTIST-2, Adjuvant Chemoradiation Therapy in Stomach Cancer 2;
CAPOX, capecitabine and oxaliplatin; CLASSIC, Capecitabine and Oxaliplatin
Adjuvant Study in Stomach Cancer; CRT, chemoradiotherapy; DFS, disease-free
survival; 5-FU, 5-fluorouracil; GEJ, gastroesophageal junction; HR, hazard ratio;
INT 0116, Intergroup 0116; LV, leucovorin; OS, overall survival; SOX, S-1 and
Cancer of the Stomach (CRITICS) trial from the Netherlands also did
not find a survival difference between patients randomly assigned to
postoperative chemotherapy and those randomly assigned to post-
operative chemoradiotherapy, although only half of all patients could
complete their assigned postoperative treatment.52
As discussed previously, the addition of chemoradiotherapy
to chemotherapy may be associated with lower rates of local recur-
rence in the subgroup of patients who receive less than a D2
lymphadenectomy.35 Local recurrence rates also seem to be lower
with chemoradiotherapy in patients who underwent microscopi-
cally margin-positive R1 resections in retrospective studies.35,63
As such, the NCCN currently recommends adjuvant chemoradio-
therapy for patients who underwent less than a D2 lymphadenec-
tomy and/or an R1 or grossly margin-positive (R2) gastrectomy.13
Metastatic Gastric Cancer
The traditional paradigm that stage IV gastric cancer is not a surgi-
cal disease has been replaced by a more nuanced patient-specific
approach. However, systemic therapy remains the backbone of
treatment for these patients and most surgical approaches dis-
cussed here remain investigational. Indeed, expansion of surgical
indications for metastatic disease is being driven by advances in
systemic therapy.
Resectable Metastatic Disease
There is growing evidence that select patients with metastatic gas-
tric cancer can have long-term survival with modern chemotherapy
followed by aggressive surgery if all residual gross disease is poten-
tially resectable. The phase 2 Arbeitsgemeinschaft Internistische
Onkologie—Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel 3
(AIO-FLOT3) trial included 60 patients with limited metastatic dis-
ease (defined as either retroperitoneal nodes alone or 1 metastatic
organ site with or without retroperitoneal nodes) who received peri-
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Review Clinical Review & Education
Groups Results, HR (95% CI)
CAPOX (n = 520); Improved DFS for adjuvant CAPOX;
observation (n = 515) 0.56 (0.44-0.72);
3-y DFS 74% vs 59%
S-1 (n = 515); Improved OS for adjuvant S-1 0.67
observation (n = 519) (0.54-0.83);
5-y OS 72% vs 61%
CRT + 5-FU/LV (n = 281); Improved OS with CRT 1.35 (1.09-1.66)a;
observation (n = 275) median OS 36 mo vs 27 mo
XP + CRT (n = 230); XP (n = 228) OS not different;
1.13 (0.78-1.65)
SOX + CRT (n = 183); SOX (n = 181); DFS not different between SOX and
S-1 (n = 182) SOX + CRT; 0.97 (0.66-1.42);
3-y DFS 73% SOX + CRT vs 74% SOX vs
65% S-1
oxaliplatin; XP, capecitabine and cisplatin.
a
HR is reported for the control group; other studies reported HR for the
treatment group.
b
T, tumor stage; N, nodal stage; M, metastasis stage from TNM staging system,
as per the American Joint Committee on Cancer, 8th Edition.
operative FLOT plus surgery if R0 resection of the primary tumor and
macroscopically complete resection of metastatic lesions were fea-
sible. Median overall survival for this group was 22.9 months, with pa-
tients who proceeded to surgery (36 of 60 [60%]) having a higher
median overall survival than patients who were unable to and re-
ceived FLOT alone (31 months vs 16 months).64 The follow-up phase
3 RENAISSANCE (AIO-FLOT5) trial is currently enrolling patients with
limited metastatic disease as defined in AIO-FLOT3. Patients with-
out progression after 4 cycles of FLOT are randomized to additional
FLOT or surgical resection of both primary and metastatic tumors fol-
lowed by postoperative FLOT (Table 1).25 A large retrospective co-
hort study from Japan, South Korea, and China, Conversion Therapy
for Stage IV Gastric Cancer 1 (CONVO-GC-1), also reported favorable
outcomes for 1206 patients with metastatic gastric cancer who un-
derwent chemotherapy followed by attempted R0 resection of all
disease. Despite a high proportion of patients with gross peritoneal
dissemination (n = 417), median overall survival was 36.7 (95% CI,
34.4-40.0) months for all patients and 56.6 (95% CI, 46.4-74.5)
months for patients for whom an R0 resection was achieved.65
Peritoneal Disease
The peritoneum is the second most common site of metastatic
spread after the liver.66 For select patients with isolated gross peri-
toneal metastases, cytoreductive surgery (CRS) with or without
hyperthermic intraperitoneal chemotherapy (HIPEC) is offered at
some centers, although this approach remains controversial. Re-
ported median overall survival after CRS with HIPEC ranges from
11 to 19 months, with completeness of cytoreduction being an im-
portant prognostic factor.67,68 The addition of HIPEC to CRS is as-
sociated with improved survival based on both a phase 3 trial from
China68 and a large prospective database study from France,67 but
CRS with or without HIPEC has never been, to our knowledge, com-
pared with systemic chemotherapy alone in a randomized trial. Most
HIPEC regimens contain mitomycin C at 40 °C to 43 °C, but proto-
cols vary by study and institution.
(Reprinted) JAMA Surgery Published online March 23, 2022 E5
 Clinical Review & Education Review
The management of patients with gastric cancer with occult or
minimal-volume peritoneal disease, such as those with positive cy-
tology only or radiographically occult peritoneal disease, is contro-
versial. These patients have a poor prognosis and poor outcomes with
either systemic therapy or gastrectomy alone,69 but rare long-term
survival has been reported in patients who convert to negative cy-
tology after neoadjuvant chemotherapy and subsequently undergo
curative-intent surgery.70,71 Peritoneal-directed therapy using HIPEC
without CRS is also being investigated for these patients. A phase II
study from the US reported a median overall survival of 30.2 months
in 19 patients with gastric cancer with minimal-volume peritoneal dis-
ease who received systemic chemotherapy followed by laparo-
scopic HIPEC. Seven of these patients (37%) converted to negative
cytology with no visible peritoneal disease, and 5 of these 7 patients
(71%) subsequently underwent curative-intent resection, all of whom
were alive without evidence of disease at 90-day follow-up.72
Interestingly, some studies have shown that surgery itself, in par-
ticular division of contaminated lymphatic channels, can lead to peri-
toneal tumor dissemination, and the chance of this occurring increases
with increasing T and N categories.73,74 In one study, 57 patients with
negative cytology and no detectable carcinoembryonic antigen or
cytokeratin 20 messenger RNA (molecular biomarkers for gastric can-
cer cells) in peritoneal washings pregastrectomy subsequently had
detectable carcinoembryonic antigen and/or cytokeratin 20 messen-
gerRNAinperitonealwashingspostgastrectomy.Twenty-fourofthese
patients (42%) had viable cancer cells that could be cultured in vitro,
and 4 of these 24 patients (17%) had viable cancer cells that could form
tumors in mice.74 Another study found similarly that gastrectomy and
lymphadenectomy, particularly for patients with positive nodes, could
lead to intraperitoneal tumor dissemination, but subsequent perito-
neal lavage reduced the number of cells to undetectable levels,
although no survival data were reported.73 These translational stud-
ies may provide rationale for the use of neoadjuvant chemoradio-
therapy to sterilize lymph node basins before surgery to decrease the
risk of iatrogenic tumor dissemination, but as discussed previously,
clinical data are still currently pending.
The PILGRIM HIPEC-01 trial is also currently ongoing in China
to test the hypothesis that adjuvant HIPEC may help eliminate post-
gastrectomy contamination and reduce peritoneal recurrence rates
for patients with high-risk resectable gastric cancers. Patients with
T3 to T4NxM0 disease undergoing curative-intent surgery were
randomly assigned to adjuvant chemotherapy alone (capecitabine
and oxaliplatin [XELOX] or S-1 and oxaliplatin [SOX]) or adjuvant
HIPEC within a week of gastrectomy followed by adjuvant chemo-
therapy (Table 1). A preliminary report showed a favorable safety pro-
file for the HIPEC group,24 with outcomes data still maturing.
Palliation
Palliative gastrectomy for patients with metastatic gastric cancer
does not improve survival based on data from the REGATTA (Japan
Clinical Oncology Group 0705 and Korean Gastric Cancer Associa-
tion 01) trial,75 but can help relieve symptoms of bleeding or ob-
struction in select patients. Given the morbidity of gastrectomy and
the need to discontinue systemic therapy for a period of time, other
ARTICLE INFORMATION Published Online: March 23, 2022.
Accepted for Publication: December 19, 2021. doi:10.1001/jamasurg.2022.0182
E6 JAMA Surgery Published online March 23, 2022 (Reprinted)
© 2022 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a UFAM User on 04/13/2022
Surgical Management of Gastric Cancer
modalities, such as radiation and endoscopic interventions, can also
be considered. Radiation therapy is particularly effective in control-
ling tumor-related bleeding76 and should generally be attempted
before considering surgery for bleeding. Obstruction can be man-
aged with radiation, endoscopic procedures, or surgery. Radiation
appears to be less effective for obstruction than for bleeding.77 En-
doscopic stenting may be useful for patients with a short life expec-
tancy, as it is associated with better short-term outcomes but poorer
durability and higher reintervention rates than surgical palliation.78
Newer endoscopic bypass techniques with lumen-apposing stents
from the stomach to the jejunum are also being performed at some
centers, although there are few data regarding this approach. Among
surgical options, data are also limited but there does not appear to
be a significant difference in outcomes between palliative gastrec-
tomy and gastrojejunostomy bypass.79
Discussion
The surgical treatment of gastric cancer is constantly evolving as new
surgical techniques and systemic therapies are introduced, with sev-
eral ongoing clinical trials summarized in Table 1. For EGC, new ap-
proaches from East Asia, such as sentinel lymph node biopsy and
function-sparing gastric resections, may improve quality of life with-
out compromising oncologic outcomes. For more advanced but re-
sectable gastric cancers, contemporary survival rates still leave much
room for improvement, and novel multimodality approaches are ac-
tively being investigated. These include the use of neoadjuvant che-
moradiation to allow for higher rates of therapy delivery and steril-
ization of lymph node basins before surgery to prevent possible
iatrogenic tumor dissemination, the use of adjuvant HIPEC to re-
duce the risk of peritoneal recurrence, and the addition of targeted
therapy to systemic regimens. For metastatic gastric cancer, simi-
lar to the treatment evolution of other cancers, such as colorectal
cancer and gastrointestinal stromal tumors, improvements in sys-
temic therapies may now allow for more aggressive surgical man-
agement of metastatic lesions.
Limitations
This review had several limitations. First, we did not discuss heredi-
tary gastric cancer. Although surgery plays a major role in its manage-
ment, hereditary gastric cancer is a complex subject for which an en-
tirely separate review would be required to do it justice. Second, we
did not discuss molecular profiling in gastric cancer, which in the fu-
ture may have implications on the choice of perioperative therapies.
Conclusions
This narrative review discussed novel surgical approaches in the
treatment of gastric cancer. The management of gastric cancer con-
tinues to evolve. Surgeons should be aware of novel surgical op-
tions currently under investigation as well as how surgery fits into
the contemporary multidisciplinary approach to this disease.
Author Contributions: Dr Wang had full access to
all of the data in the study and takes responsibility
jamasurgery.com
 Surgical Management of Gastric Cancer
for the integrity of the data and the accuracy of
the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data:
Wang.
Drafting of the manuscript: Li, Wang.
Critical revision of the manuscript for important
intellectual content: All authors.
Administrative, technical, or material support:
Doherty, Wang.
Supervision: Doherty, Wang.
Conflict of Interest Disclosures: None reported.
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