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Gastric Cancer Treatment (PDQ®)–Health

Professional Version
General Information About Gastric Cancer

Incidence and Mortality

Estimated new cases and deaths from gastric cancer in the United States in 2024:[1]

• New cases: 26,890.

• Deaths: 10,880.

Epidemiology

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Management of adenocarcinoma histology, which accounts for 90% to 95% of all gastric
malignancies, is discussed in this summary. Changing epidemiological patterns in the United
States regarding the anatomical location of esophagogastric cancers show a trend of
decreased occurrence of distal or noncardia gastric cancers.[2] However, in people aged 25 to
39 years, there has been an increase in the incidence of noncardia gastric cancers from 0.27
cases per 100,000 individuals (1977–1981) to 0.45 cases per 100,000 individuals (2002–2006).[2]
Additional studies are needed to confirm the observed increases in noncardia gastric cancers
in this specific age group.

In contrast to the overall stable trend for noncardia gastric cancers, earlier studies
demonstrated an increased incidence of adenocarcinomas of the gastric cardia of 4% to 10%
per year from the mid-1970s to the late 1980s.[3] Similarly, the incidence of gastroesophageal
junction adenocarcinomas increased sharply, from 1.22 cases per 100,000 individuals (1973–
1978) to 2.00 cases per 100,000 individuals (1985–1990).[4] Since that time, the incidence has
remained steady at 1.94 cases per 100,000 individuals (2003–2008).[4] More recent data
demonstrate that the incidence of gastric cardia cancers has been relatively stable, although an
increase has been observed, from 2.4 cases per 100,000 individuals (1977–1981) to 2.9 cases
per 100,000 individuals (2001–2006) in the White population.[2] The reasons for these
temporal changes in incidence are unclear.

Risk Factors

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In the United States, gastric cancer ranks 14th in incidence among the major types of cancer.
While the precise etiology is unknown, acknowledged risk factors for gastric cancer include the
following:[5-7]

• Helicobacter pylori gastric infection.

• Advanced age.
• Male sex.
• Diet low in fruits and vegetables.
• Diet high in salted, smoked, or preserved foods.
• Chronic atrophic gastritis.
• Intestinal metaplasia.
• Pernicious anemia.
• Gastric adenomatous polyps.
• Family history of gastric cancer.
• Cigarette smoking.
• Ménétrier disease (giant hypertrophic gastritis).
• Epstein-Barr virus infection.
• Familial syndromes (including familial adenomatous polyposis).

Prognosis and Survival

The prognosis of patients with gastric cancer is related to tumor extent and includes both
nodal involvement and direct tumor extension beyond the gastric wall.[8,9] Tumor grade may
also provide some prognostic information.[10]

In localized distal gastric cancer, more than 50% of patients can be cured. However, early-stage
disease accounts for only 10% to 20% of all cases diagnosed in the United States. The
remaining patients present with metastatic disease in either regional or distant sites. The 5-
year overall survival rate in these patients ranges from almost no survival for patients with
disseminated disease to almost 50% survival for patients with localized distal gastric cancers
confined to resectable regional disease. Even with apparent localized disease, the 5-year
survival rate of patients with proximal gastric cancer is only 10% to 15%. Although the
treatment of patients with disseminated gastric cancer may result in palliation of symptoms
and some prolongation of survival, long remissions are uncommon.

Gastrointestinal stromal tumors occur most commonly in the stomach. For more information,
see Gastrointestinal Stromal Tumors Treatment.
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References
1. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024.
Available online. Last accessed June 21, 2024.
2. Anderson WF, Camargo MC, Fraumeni JF, et al.: Age-specific trends in incidence of
noncardia gastric cancer in US adults. JAMA 303 (17): 1723-8, 2010. [PUBMED Abstract]
3. Blot WJ, Devesa SS, Kneller RW, et al.: Rising incidence of adenocarcinoma of the
esophagus and gastric cardia. JAMA 265 (10): 1287-9, 1991. [PUBMED Abstract]
4. Buas MF, Vaughan TL: Epidemiology and risk factors for gastroesophageal junction
tumors: understanding the rising incidence of this disease. Semin Radiat Oncol 23 (1): 3-9,
2013. [PUBMED Abstract]
5. Kurtz RC, Sherlock P: The diagnosis of gastric cancer. Semin Oncol 12 (1): 11-8,
1985. [PUBMED Abstract]
6. Scheiman JM, Cutler AF: Helicobacter pylori and gastric cancer. Am J Med 106 (2): 222-6,
1999. [PUBMED Abstract]
7. Fenoglio-Preiser CM, Noffsinger AE, Belli J, et al.: Pathologic and phenotypic features of
gastric cancer. Semin Oncol 23 (3): 292-306, 1996. [PUBMED Abstract]
8. Siewert JR, Böttcher K, Stein HJ, et al.: Relevant prognostic factors in gastric cancer: ten-
year results of the German Gastric Cancer Study. Ann Surg 228 (4): 449-61,
1998. [PUBMED Abstract]
9. Nakamura K, Ueyama T, Yao T, et al.: Pathology and prognosis of gastric carcinoma.
Findings in 10,000 patients who underwent primary gastrectomy. Cancer 70 (5): 1030-7,
1992. [PUBMED Abstract]
10. Adachi Y, Yasuda K, Inomata M, et al.: Pathology and prognosis of gastric carcinoma: well
versus poorly differentiated type. Cancer 89 (7): 1418-24, 2000. [PUBMED Abstract]

Cellular Classification of Gastric Cancer

The two major types of gastric adenocarcinoma are the following:

• Intestinal.
• Diffuse.

Intestinal adenocarcinomas are well differentiated, and the cells tend to arrange themselves in
tubular or glandular structures. The terms tubular, papillary, and mucinous are assigned to the
various types of intestinal adenocarcinomas. Rarely, adenosquamous cancers can occur.

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Diffuse adenocarcinomas are undifferentiated or poorly differentiated, and they lack a gland
formation. Clinically, diffuse adenocarcinomas can give rise to infiltration of the gastric wall
(i.e., linitis plastica).

Some tumors can have mixed features of intestinal and diffuse types.

Stage Information for Gastric Cancer

AJCC Prognostic Stage Groups and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node,
metastasis) classification to define gastric cancer.[1]

Pathological (pTNM)

a
Table 1. Definitions of pTNM Stage 0

Stage TNM Description

0 Tis, N0, M0 Tis = Carcinoma in situ: intraepithelial tumor without

invasion of the lamina propria, high-grade dysplasia.

N0 = No regional lymph node metastasis.

M0 = No distant metastasis.

T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.

a
Reprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC
Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.

a
Table 2. Definitions of pTNM Stages IA and IB

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Stage TNM Description

IA T1, N0, M0 T1 = Tumor invades lamina propria, muscularis mucosae, or

submucosa.

–T1a = Tumor invades lamina propria or muscularis mucosae.

–T1b = Tumor invades submucosa.

N0 = No regional lymph node metastasis.

M0 = No distant metastasis.

IB T1, N1, M0 T1 = Tumor invades lamina propria, muscularis mucosae, or

submucosa.

–T1a = Tumor invades lamina propria or muscularis mucosae.

–T1b = Tumor invades submucosa.

N1 = Metastases in 1 or 2 regional lymph nodes.

M0 = No distant metastasis.

b
T2, N0, M0 T2 = Tumor invades muscularis propria.

T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.

a
Reprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC
Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.

b
A tumor may penetrate the muscularis propria with extension into the gastrocolic or
gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral
peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation
of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be
classified T4.

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Stage TNM Description

N0 = No regional lymph node metastasis.

M0 = No distant metastasis.

T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.

a
Reprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC
Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.

b
A tumor may penetrate the muscularis propria with extension into the gastrocolic or
gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral
peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation
of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be
classified T4.

a
Table 3. Definitions of pTNM Stages IIA and IIB

Stage TNM Description

IIA T1, N2, M0 T1 = Tumor invades lamina propria, muscularis mucosae, or

submucosa.

–T1a = Tumor invades lamina propria or muscularis mucosae.

–T1b = Tumor invades submucosa.

N2 = Metastases in 3 to 6 regional lymph nodes.

M0 = No distant metastasis.

b
T2, N1, M0 T2 = Tumor invades muscularis propria.

N1 = Metastases in 1 or 2 regional lymph nodes.

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Stage TNM Description

M0 = No distant metastasis.

T3, N0, M0 T3 = Tumor penetrates the subserosal connective tissue without

c,d
invasion of the visceral peritoneum or adjacent structures.

N0 = No regional lymph node metastasis.

M0 = No distant metastasis.

IIB T1, N3a, M0 T1 = Tumor invades lamina propria, muscularis mucosae, or

submucosa.

–T1a = Tumor invades lamina propria or muscularis mucosae.

–T1b = Tumor invades submucosa.

N3a = Metastasis in 7 to 15 regional lymph nodes.

M0 = No distant metastasis.

b
T2, N2, M0 T2 = Tumor invades muscularis propria.

N2 = Metastases in 3 to 6 regional lymph nodes.

M0 = No distant metastasis.

T3, N1, M0 T3 = Tumor penetrates the subserosal connective tissue without

c,d
invasion of the visceral peritoneum or adjacent structures.

N1 = Metastasis in 1or 2 regional lymph nodes.

M0 = No distant metastasis.

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Stage TNM Description

T4a, N0, M0 T4a = Tumor invades serosa (visceral peritoneum).

N0 = No regional lymph node metastasis.

M0 = No distant metastasis.

T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.

a
Reprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC
Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.

b
A tumor may penetrate the muscularis propria with extension into the gastrocolic or
gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral
peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation
of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be
classified T4.

c
The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm,
pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.

d
Intramural extension to the duodenum or esophagus is not considered invasion of an adjacent
structure, but is classified using the depth of the greatest invasion in any of these sites.

a
Table 4. Definitions of pTNM Stages IIIA, IIIB, and IIIC

Stage TNM Description

b
IIIA T2, N3a, T2 = Tumor invades muscularis propria.
M0

N3a = Metastasis in 7 to 15 regional lymph nodes.

M0 = No distant metastasis.

T3, N2, M0 T3 = Tumor penetrates the subserosal connective tissue

without invasion
c,d of the visceral peritoneum or adjacent
structures.

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Stage TNM Description

N2 = Metastasis in 3 to 6 regional lymph nodes.

M0 = No distant metastasis.

T4a, N1, T4a = Tumor invades serosa (visceral peritoneum).

M0

N1 = Metastasis in 1or 2 regional lymph nodes.

M0 = No distant metastasis.

T4a, N2, T4a = Tumor invades serosa (visceral peritoneum).

M0

N2 = Metastasis in 3 to 6 regional lymph nodes.

M0 = No distant metastasis.

c,d
T4b, N0, T4b = Tumor invades adjacent structures/organs.
M0

N0 = No regional lymph node metastasis.

M0 = No distant metastasis.

IIIB T1, N3b, T1 = Tumor invades lamina propria, muscularis mucosae, or

M0 submucosa.

N3b = Metastases in 16 or more regional lymph nodes.

M0 = No distant metastasis.

b
T2, N3b, T2 = Tumor invades muscularis propria.
M0

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Stage TNM Description

N3b = Metastases in 16 or more regional lymph nodes.

M0 = No distant metastasis.

T3, N3a, T3 = Tumor penetrates the subserosal connective tissue

M0 without invasion
c,d
of the visceral peritoneum or adjacent
structures.

N3a = Metastasis in 7 to 15 regional lymph nodes.

M0 = No distant metastasis.

T4a, N3a, T4a = Tumor invades serosa (visceral peritoneum).

M0

N3a = Metastasis in 7 to 15 regional lymph nodes.

M0 = No distant metastasis.

c,d
T4b, N1, T4b = Tumor invades adjacent structures/organs.
M0

N1 = Metastasis in 1or 2 regional lymph nodes.

M0 = No distant metastasis.

c,d
T4b, N2, T4b = Tumor invades adjacent structures/organs.
M0

N2 = Metastasis in 3 to 6 regional lymph nodes.

M0 = No distant metastasis.

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Stage TNM Description

IIIC T3, N3b, T3 = Tumor penetrates the subserosal connective tissue

M0 without invasion
cd
of the visceral peritoneum or adjacent
structures.

N3b = Metastasis in 16 or more regional lymph nodes.

M0 = No distant metastasis.

T4a, N3b, T4a = Tumor invades serosa (visceral peritoneum).

M0

N3b = Metastasis in 16 or more regional lymph nodes.

M0 = No distant metastasis.

c,d
T4b, N3a, T4b = Tumor invades adjacent structures/organs.
M0

N3a = Metastasis in 7 to 15 regional lymph nodes.

M0 = No distant metastasis.

c,d
T4b, N3b, T4b = Tumor invades adjacent structures/organs.
M0

N3b = Metastasis in 16 or more regional lymph nodes.

M0 = No distant metastasis.

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Stage TNM Description

T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.

a
Reprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC
Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.

b
A tumor may penetrate the muscularis propria with extension into the gastrocolic or
gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral
peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation
of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be
classified T4.

c
The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm,
pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.

d
Intramural extension to the duodenum or esophagus is not considered invasion of an adjacent
structure, but is classified using the depth of the greatest invasion in any of these sites.

a
Table 5. Definitions of pTNM Stage IV

Stage TNM Description

IV Any T, Any N, TX = Primary tumor cannot be assessed.

M1

T0 = No evidence of primary tumor.

Tis = Carcinoma in situ: intraepithelial tumor without

invasion of the lamina propria, high-grade dysplasia.

T1 = Tumor invades lamina propria, muscularis mucosae, or

submucosa.

–T1a = Tumor invades lamina propria or muscularis

mucosae.

–T1b = Tumor invades submucosa.

b
T2 = Tumor invades muscularis propria.

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Stage TNM Description

T3 = Tumor penetrates the subserosal connective tissue

without invasion
c,d
of the visceral peritoneum or adjacent
structures.

T4 = Tumor invades c,d

the serosa (visceral peritoneum) or
adjacent structures.

–T4a = Tumor invades serosa (visceral peritoneum).

–T4b = Tumor invades adjacent structures/organs.

NX = Regional lymph node(s) cannot be assessed.

N0 = No regional lymph node metastasis.

N1 = Metastases in 1 or 2 regional lymph nodes.

N2 = Metastases in 3 to 6 regional lymph nodes.

N3 = Metastases in ≥7 regional lymph nodes.

–N3a = Metastases in 7 to 15 regional lymph nodes.

–N3b = Metastases in 16 or more regional lymph nodes.

M1 = Distant metastasis.

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Stage TNM Description

T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.

a
Reprinted with permission from AJCC: Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC
Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 203–20.

b
A tumor may penetrate the muscularis propria with extension into the gastrocolic or
gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral
peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation
of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be
classified T4.

c
The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm,
pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.

d
Intramural extension to the duodenum or esophagus is not considered invasion of an adjacent
structure, but is classified using the depth of the greatest invasion in any of these sites.

References
1. Stomach. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th
ed. Springer; 2017, pp. 203–20.

Treatment Option Overview

Radical surgery represents the standard form of therapy that has curative intent. However, the
incidences of local failure in the tumor bed and regional lymph nodes, and distant failures via
hematogenous or peritoneal routes, remain high.[1] As such, comprehensive staging and
evaluation with a multidisciplinary team to determine roles of neoadjuvant, perioperative, and
adjuvant combination chemotherapy, surgery, and external-beam radiation therapies should
be considered.

Investigators in Europe evaluated the role of perioperative chemotherapy without radiation

therapy.[2] Initially, in a randomized phase III trial (MRC-ST02 [NCT00002615]), patients with
stage II or higher adenocarcinoma of the stomach or of the lower third of the esophagus were
assigned to receive three cycles of epirubicin, cisplatin, and continuous infusion fluorouracil (5-
FU) (ECF) before and after surgery or to receive surgery alone. Compared with the surgery
group, the perioperative chemotherapy group had a significantly higher overall survival (OS)
(hazard ratio [HR]death, 0.75; 95% confidence interval [CI], 0.60–0.93; P = .009).[2][Level of
evidence A1]

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In addition, in the randomized phase III AIO-FLOT4 trial (NCT01216644), patients with
resectable disease that was stage T2 or higher and/or node positive received either
perioperative epirubicin, cisplatin, and 5-FU or capecitabine (ECF/ECX) (three cycles before and
after surgery) or perioperative docetaxel, oxaliplatin, and 5-FU/leucovorin (FLOT) (four 2-week
cycles before and after surgery). OS was significantly increased from 35 months with ECF/ECX
to 50 months with FLOT (HR, 0.77; 95% CI, 0.63–0.94; P = .012).[3]

In a phase III Intergroup trial (SWOG-9008 [NCT01197118]), 559 patients with completely
resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal
junction were randomly assigned to receive either surgery alone or surgery plus postoperative
chemotherapy (5-FU and leucovorin) and concurrent radiation therapy (45 Gy). With a median
follow-up of more than 10 years, a significant survival benefit was reported for patients who
received adjuvant combined modality therapy.[4][Level of evidence A1] Median OS was 35
months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone
arm (P = .0046). Median relapse-free survival was 27 months in the chemoradiation arm
compared with 19 months in the surgery-alone arm (P < .001).

Gastroesophageal junction cancers may be treated like esophageal cancers and are best
managed under the care of a multidisciplinary team. For more information, see Esophageal
Cancer Treatment.

Capecitabine and Fluorouracil Dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like
capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline
pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation
of pyrimidines and fluoropyrimidines in the body.[5,6] Patients with the DPYD*2A variant who
receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes
fatal. Many other DPYD variants have been identified, with a range of clinical effects.[5-7]
Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the
patient's DPYD genotype and number of functioning DPYD alleles.[8-10] DPYD genetic testing
costs less than $200, but insurance coverage varies due to a lack of national guidelines.[11] In
addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent
situations. This controversial issue requires further evaluation.[12]

References
1. Gunderson LL, Sosin H: Adenocarcinoma of the stomach: areas of failure in a re-operation
series (second or symptomatic look) clinicopathologic correlation and implications for
adjuvant therapy. Int J Radiat Oncol Biol Phys 8 (1): 1-11, 1982. [PUBMED Abstract]
2. Cunningham D, Allum WH, Stenning SP, et al.: Perioperative chemotherapy versus surgery
alone for resectable gastroesophageal cancer. N Engl J Med 355 (1): 11-20, 2006. [PUBMED
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10/23/24, 10:52 PM Gastric Cancer Treatment (PDQ®) - NCI

Abstract]
3. Al-Batran SE, Homann N, Pauligk C, et al.: Perioperative chemotherapy with fluorouracil
plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus
cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal
junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393 (10184):
1948-1957, 2019. [PUBMED Abstract]
4. Smalley SR, Benedetti JK, Haller DG, 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 30 (19): 2327-33, 2012. [PUBMED Abstract]
5. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related
Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and
Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
6. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy
and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
7. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased
risk of severe toxicity and related treatment modifications during fluoropyrimidine
chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
8. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation
Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and
Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216,
2018. [PUBMED Abstract]
9. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose
individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety
analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
10. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to
guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative
study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
11. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to
Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer
21 (3): e189-e195, 2022. [PUBMED Abstract]
12. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin
Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]

Treatment of Stage 0 Gastric Cancer

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Treatment Options for Stage 0 Gastric Cancer

Treatment options for stage 0 gastric cancer include the following:

1. Surgery.
2. Endoscopic mucosal resection (EMR).

Surgery
Stage 0 is gastric cancer confined to mucosa. Experience in Japan, where stage 0 is diagnosed
frequently, indicates that more than 90% of patients treated by gastrectomy with
lymphadenectomy will survive beyond 5 years. An American series confirmed these results.[1]

Endoscopic mucosal resection (EMR)

EMR has been studied in Japan and throughout Asia in patients with early-stage tumors with
good-risk features (Tis or T1a, diameter ≤2 cm, predominantly differentiated type, without
ulcerative findings) that have a lower risk of nodal metastasis. Intramucosal tumors have a
lower risk of nodal metastasis than submucosal tumors.[2] Careful patient selection by the
above criteria, treatment with an experienced endoscopist, and close surveillance should be
considered.

Evidence (EMR):

1. A prospective trial of EMR included 445 patients with intramucosal carcinoma (a total of
479 tumors) treated in Tokyo between 1987 and 1998. Complete resection was
recommended for patients with evidence of submucosal invasion, blood vessel
involvement, and/or positive margins.[3][Level of evidence C2]
• Of the 405 patients with intramucosal disease, 278 underwent complete resection,
with 2% local recurrence treated with curative intent and 100% disease-free
survival at a median follow-up of 38 months.
• In those with resections that were incomplete or not evaluable, 18 of 127 patients
had a local recurrence and underwent curative surgery.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now
enrolling patients. The search can be narrowed by location of the trial, type of treatment, name
of the drug, and other criteria. General information about clinical trials is also available.

References
1. Green PH, O'Toole KM, Slonim D, et al.: Increasing incidence and excellent survival of
patients with early gastric cancer: experience in a United States medical center. Am J Med
https://www.cancer.gov/types/stomach/hp/stomach-treatment-pdq 17/41
10/23/24, 10:52 PM Gastric Cancer Treatment (PDQ®) - NCI

85 (5): 658-61, 1988. [PUBMED Abstract]

2. Japanese Gastric Cancer Association: Japanese gastric cancer treatment guidelines 2014
(ver. 4). Gastric Cancer 20 (1): 1-19, 2017. [PUBMED Abstract]
3. Ono H, Kondo H, Gotoda T, et al.: Endoscopic mucosal resection for treatment of early
gastric cancer. Gut 48 (2): 225-9, 2001. [PUBMED Abstract]

Treatment of Stage I Gastric Cancer

Treatment Options for Stage I Gastric Cancer

Treatment options for stage I gastric cancer include the following:

1. Surgical resection with one of the following procedures:

• Distal subtotal gastrectomy (if the lesion is not in the fundus or at the
cardioesophageal junction).
• Proximal subtotal gastrectomy or total gastrectomy, both with distal
esophagectomy (if the lesion involves the cardia). These tumors often involve the
submucosal lymphatics of the esophagus.
• Total gastrectomy (if the tumor involves the stomach diffusely or arises in the body
of the stomach and extends to within 6 cm of the cardia or distal antrum).

Regional lymphadenectomy is recommended with all of the above procedures.

Splenectomy is not routinely performed.[1]

2. Endoscopic mucosal resection (EMR) for select patients with stage IA gastric cancer.
3. Postoperative chemoradiation therapy or perioperative chemotherapy for patients with
node-positive (T1 N1) and muscle-invasive (T2 N0) disease.[2,3]
4. Neoadjuvant chemoradiation (under clinical evaluation).[4]

Surgical resection
Surgical resection including regional lymphadenectomy is the treatment of choice for patients
with stage I gastric cancer.[1] If the lesion is not in the cardioesophageal junction and does not
diffusely involve the stomach, subtotal gastrectomy is the procedure of choice, because it has
been demonstrated to provide equivalent survival when compared with total gastrectomy and
is associated with decreased morbidity.[5][Level of evidence A1] When the lesion involves the
cardia, proximal subtotal gastrectomy or total gastrectomy (including a sufficient length of
esophagus) may be performed with curative intent. If the lesion diffusely involves the stomach,
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total gastrectomy is required. At a minimum, surgical resection includes greater and lesser
curvature perigastric regional lymph nodes. In patients with stage I gastric cancer, perigastric
lymph nodes may contain cancer.

Endoscopic mucosal resection (EMR)

EMR has been studied in Japan and throughout Asia in patients with early-stage tumors with
good-risk features (Tis or T1a, diameter ≤2 cm, predominantly differentiated type, without
ulcerative findings) that have a lower risk of nodal metastasis. Intramucosal tumors have a
lower risk of nodal metastasis than submucosal tumors.[6] Careful patient selection by the
above criteria, treatment with an experienced endoscopist, and close surveillance should be
considered.

Evidence (EMR):

1. A prospective trial of EMR included 445 patients with intramucosal carcinoma (a total of
479 tumors) treated in Tokyo between 1987 and 1998. Complete resection was
recommended for patients with evidence of submucosal invasion, blood vessel
involvement, and/or positive margins.[7][Level of evidence C2]
• Of the 405 patients with intramucosal disease, 278 underwent complete resection,
with 2% local recurrence treated with curative intent and 100% disease-free
survival at a median follow-up of 38 months.
• In those with resections that were incomplete or not evaluable, 18 of 127 patients
had a local recurrence and underwent curative surgery.

Postoperative chemoradiation therapy

In patients with node-positive (T1 N1) and muscle-invasive (T2 N0) disease, postoperative
chemoradiation therapy may be considered.

Evidence (postoperative chemoradiation therapy):

1. A prospective, multi-institution, phase III trial (SWOG-9008 [NCT01197118]) evaluated

postoperative combined chemoradiation therapy versus surgery alone in 559 patients
with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and
gastroesophageal junction. There was a significant survival benefit with adjuvant
combined modality therapy.[2][Level of evidence A1]
• With more than 10 years of follow-up, median survival was 35 months for the
adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm
(P = .0046).

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• Median relapse-free survival was 27 months in the chemoradiation arm compared

with 19 months in the surgery-alone arm (P < .001). Improvement was primarily
seen for locoregional recurrence risk (improvement from 47% for surgery vs. 29%
for chemoradiation).[2] However, only 36 patients in the trial had stage IB tumors
(18 patients in each arm).[8]

Because the prognosis is relatively favorable for patients with completely resected stage
IB disease, the effectiveness of adjuvant chemoradiation therapy for this group is less
clear.

Perioperative chemotherapy
Investigators in Europe evaluated the role of perioperative chemotherapy without radiation
therapy.[9]

Evidence (perioperative chemotherapy):

1. In the randomized phase III AIO-FLOT4 trial (NCT01216644), 716 patients with stage IB to
stage III resectable gastric or gastroesophageal adenocarcinoma were randomly assigned
to receive either perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil
(5-FU)/leucovorin (FLOT); or epirubicin, cisplatin, and 5-FU or capecitabine (ECF/ECX).[3]
[Level of evidence A1]
• Median overall survival was 50 months with FLOT and 35 months with ECF/ECX
(hazard ratio, 0.77; 95% confidence interval, 0.63–0.94; P = .012).
• Margin-free resection in the FLOT group was 85% versus 78% in the ECF/ECX group
(P = .0162).
• Toxicity rates were similar between groups (26% required hospitalizations in the
ECF/ECX group and 25% in the FLOT group). However, types of side effects differed,
with increased nausea, thromboembolic events, and anemia in the ECF/ECX group
versus higher rates of grade 3/4 infections, neutropenia, diarrhea, and neuropathy
in the FLOT group.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now
enrolling patients. The search can be narrowed by location of the trial, type of treatment, name
of the drug, and other criteria. General information about clinical trials is also available.

References
1. Brennan MF, Karpeh MS: Surgery for gastric cancer: the American view. Semin Oncol 23
(3): 352-9, 1996. [PUBMED Abstract]

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10/23/24, 10:52 PM Gastric Cancer Treatment (PDQ®) - NCI

2. Smalley SR, Benedetti JK, Haller DG, 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 30 (19): 2327-33, 2012. [PUBMED Abstract]
3. Al-Batran SE, Homann N, Pauligk C, et al.: Perioperative chemotherapy with fluorouracil
plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus
cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal
junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393 (10184):
1948-1957, 2019. [PUBMED Abstract]
4. Ajani JA, Winter K, Okawara GS, et al.: Phase II trial of preoperative chemoradiation in
patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality
therapy and pathologic response. J Clin Oncol 24 (24): 3953-8, 2006. [PUBMED Abstract]
5. Bozzetti F, Marubini E, Bonfanti G, et al.: Subtotal versus total gastrectomy for gastric
cancer: five-year survival rates in a multicenter randomized Italian trial. Italian
Gastrointestinal Tumor Study Group. Ann Surg 230 (2): 170-8, 1999. [PUBMED Abstract]
6. Japanese Gastric Cancer Association: Japanese gastric cancer treatment guidelines 2014
(ver. 4). Gastric Cancer 20 (1): 1-19, 2017. [PUBMED Abstract]
7. Ono H, Kondo H, Gotoda T, et al.: Endoscopic mucosal resection for treatment of early
gastric cancer. Gut 48 (2): 225-9, 2001. [PUBMED Abstract]
8. Kelsen DP: Postoperative adjuvant chemoradiation therapy for patients with resected
gastric cancer: intergroup 116. J Clin Oncol 18 (21 Suppl): 32S-4S, 2000. [PUBMED Abstract]
9. Cunningham D, Allum WH, Stenning SP, et al.: Perioperative chemotherapy versus surgery
alone for resectable gastroesophageal cancer. N Engl J Med 355 (1): 11-20, 2006. [PUBMED
Abstract]

Treatment of Stages II and III Gastric Cancer

Treatment Options for Stages II and III Gastric Cancer

Treatment options for stage II gastric cancer and stage III gastric cancer include the following:

1. Surgical resection (after discussion with a multidisciplinary team regarding the role of
perioperative and adjuvant therapy) may include one of the following procedures:
• Distal subtotal gastrectomy (if the lesion is not in the fundus or at the
cardioesophageal junction).
• Proximal subtotal gastrectomy or total gastrectomy (if the lesion involves the
cardia).
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• Total gastrectomy (if the tumor involves the stomach diffusely or arises in the body
of the stomach and extends to within 6 cm of the cardia).

Regional lymphadenectomy is recommended with all of the above procedures.

Splenectomy is not routinely performed.[1]
2. Perioperative chemotherapy.[2]
3. Postoperative (adjuvant) chemoradiation therapy.[3]
4. Postoperative (adjuvant) chemotherapy.
5. Neoadjuvant chemoradiation therapy (under clinical evaluation).[4]
6. Perioperative chemotherapy and immunotherapy regimens (under clinical evaluation).

No randomized trials of adjuvant chemoradiation versus perioperative chemotherapy have

been undertaken.

All newly diagnosed patients with stages II and III gastric cancer should consider clinical trials.

Surgical resection
Because of the high risk of locoregional and distant recurrence, perioperative and
postoperative therapy should be considered in addition to surgery.

Surgical resection with regional lymphadenectomy is the treatment of choice for patients with
stages II and III gastric cancer; all eligible patients undergo surgery.[1] If the lesion is not in the
cardioesophageal junction and does not diffusely involve the stomach, subtotal gastrectomy is
the procedure of choice. When the lesion involves the cardia, proximal subtotal gastrectomy or
total gastrectomy may be performed with curative intent. If the lesion diffusely involves the
stomach, total gastrectomy and appropriate lymph node resection may be required. The role
of extended lymph node (D2) dissection is uncertain [5] and in some series is associated with
increased morbidity.[6,7] As many as 15% of selected stage III patients can be cured by surgery
alone, particularly if lymph node involvement is minimal (<7 lymph nodes).

Perioperative chemotherapy
Investigators in Europe evaluated the role of perioperative chemotherapy without radiation
therapy.[2]

Evidence (perioperative chemotherapy):

1. In the randomized phase III AIO-FLOT4 trial (NCT01216644), 716 patients with stage IB to
stage III resectable gastric or gastroesophageal adenocarcinoma were randomly assigned
to receive either perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil

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(5-FU)/leucovorin (FLOT) or epirubicin, cisplatin, and 5-FU or capecitabine (ECF/ECX).[8]

[Level of evidence A1]
• Median overall survival (OS) was 50 months with FLOT and 35 months with
ECF/ECX (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.63–0.94; P = .012).
• Margin-free resection in the FLOT group was 85% versus 78% in the ECF/ECX group
(P = .0162).
• Toxicity rates were similar between groups (26% required hospitalizations in the
ECF/ECX group and 25% in the FLOT group). However, types of side effects differed,
with increased nausea, thromboembolic events, and anemia in the ECF/ECX group
versus higher rates of grade 3/4 infections, neutropenia, diarrhea, and neuropathy
in the FLOT group.
2. In the randomized phase III MAGIC trial (NCT00002615), patients with stage II or higher
adenocarcinoma of the stomach or of the lower third of the esophagus were assigned to
receive three cycles of epirubicin, cisplatin, and continuous infusion 5-FU (ECF) before and
after surgery or to receive surgery alone.[2]
• Compared with the surgery group, the perioperative chemotherapy group had a
significantly higher likelihood of progression-free survival (HRprogression, 0.66; 95%
CI, 0.53–0.81; P < .001) and of OS (HRdeath, 0.75; 95% CI, 0.60–0.93; P = .009).
• The 5-year OS rate was 36.3% (95% CI, 29.5%‒43.0%) for the perioperative
chemotherapy group and 23% (95% CI, 16.6%‒29.4%) for the surgery group.[2]
[Level of evidence A1]

Postoperative (adjuvant) chemoradiation therapy

Postoperative chemoradiation therapy may be considered for patients with stages II and III
gastric cancer who have not received neoadjuvant therapy.

Evidence (postoperative [adjuvant] chemoradiation therapy):

1. A prospective, multi-institution, phase III trial (SWOG-9008 [NCT01197118]) evaluated

postoperative combined chemoradiation therapy compared with surgery alone in 559
patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the
stomach and gastroesophageal junction. Investigators reported a significant survival
benefit for patients who received adjuvant combined-modality therapy.[3][Level of
evidence A1]
• With more than 10 years of follow-up, median survival was 35 months for the
adjuvant chemoradiation therapy arm and 27 months for the surgery-alone arm (P
= .0046).

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• Median relapse-free survival was 27 months in the chemoradiation arm compared

with 19 months in the surgery-alone arm (P < .001). Improvement was primarily
seen for locoregional recurrence risk (improvement from 47% for surgery vs. 29%
for chemoradiation).[3] However, only 36 patients in the trial had stage IB tumors
(18 patients in each arm).[9]
2. Attempts to evaluate the role of more intensive chemotherapy regimens in combination
with radiation in the Cancer and Leukemia Group B study (CALGB-80101 [NCT00052910])
demonstrated no survival benefit. The 546 patients who had undergone curative
resection of stage IB to stage IV (M0) gastric or gastroesophageal junction
adenocarcinoma received postoperative 5-FU with leucovorin before and after radiation
or postoperative ECF before and after combined radiation therapy.[10]
• The 5-year OS rate was 44% in both arms.
3. In a phase III Dutch trial (CRITICS [NCT00407186]), 788 patients with stage IB to stage IVA
gastric/gastroesophageal junction adenocarcinoma received preoperative chemotherapy
and surgery, and then were randomly assigned to receive postoperative chemotherapy or
chemoradiotherapy.[11] Adjuvant chemoradiation did not improve survival in those who
received neoadjuvant chemotherapy.
• Median OS was 43 months in the chemotherapy arm and 37 months in the
chemoradiotherapy group (95% CI, 0.84–1.22; P = .90).

Postoperative (adjuvant) chemotherapy

Investigators in Europe evaluated the role of postoperative chemotherapy without radiation
therapy.[2]

Evidence (postoperative [adjuvant] chemotherapy):

1. Japanese investigators randomly assigned 1,059 patients with stage II or III gastric cancer
who had undergone a D2 gastrectomy to receive either 1 year of S-1, an oral
fluoropyrimidine not available in the United States, or follow-up after surgery alone.[12]
Patients were randomly assigned in a 1:1 fashion.
• The 3-year OS rate was 80.1% in the S-1 group and 70.1% in the surgery-only
group. The HRdeath in the S-1 group, as compared with the surgery-only group, was
0.68 (95% CI, 0.52–0.87; P = .003).[12][Level of evidence A1]

2. Investigators in Asia evaluated the role of capecitabine/oxaliplatin as adjuvant therapy

after gastric cancer resection. In the CLASSIC trial (NCT00411229), 37 centers in South
Korea, China, and Taiwan randomly assigned 1,035 patients with stages IIA, IIB, IIIA, or IIIB
gastric cancer who had undergone a curative D2 gastrectomy to receive either adjuvant

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chemotherapy (eight 3-week cycles of capecitabine plus oxaliplatin) or follow-up alone

after surgery.[13]
• The 3-year disease-free survival rate was 74% in the chemotherapy group and 59%
in the surgery-alone group (HR, 0.56; 95% CI, 0.44–0.72; P < .0001).
• The 3-year OS rate was 83% in the chemotherapy group and 78% in the surgery-
alone group (HR, 0.72; 95% CI, 0.52–1.00; P = .0493).[13][Level of evidence A1]
• Further follow-up is anticipated.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now
enrolling patients. The search can be narrowed by location of the trial, type of treatment, name
of the drug, and other criteria. General information about clinical trials is also available.

References
1. Brennan MF, Karpeh MS: Surgery for gastric cancer: the American view. Semin Oncol 23
(3): 352-9, 1996. [PUBMED Abstract]
2. Cunningham D, Allum WH, Stenning SP, et al.: Perioperative chemotherapy versus surgery
alone for resectable gastroesophageal cancer. N Engl J Med 355 (1): 11-20, 2006. [PUBMED
Abstract]
3. Smalley SR, Benedetti JK, Haller DG, 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 30 (19): 2327-33, 2012. [PUBMED Abstract]
4. Ajani JA, Winter K, Okawara GS, et al.: Phase II trial of preoperative chemoradiation in
patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality
therapy and pathologic response. J Clin Oncol 24 (24): 3953-8, 2006. [PUBMED Abstract]
5. Kitamura K, Yamaguchi T, Sawai K, et al.: Chronologic changes in the clinicopathologic
findings and survival of gastric cancer patients. J Clin Oncol 15 (12): 3471-80,
1997. [PUBMED Abstract]
6. Bonenkamp JJ, Songun I, Hermans J, et al.: Randomised comparison of morbidity after D1
and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 345 (8952): 745-8,
1995. [PUBMED Abstract]
7. Cuschieri A, Fayers P, Fielding J, et al.: Postoperative morbidity and mortality after D1 and
D2 resections for gastric cancer: preliminary results of the MRC randomised controlled
surgical trial.The Surgical Cooperative Group. Lancet 347 (9007): 995-9, 1996. [PUBMED
Abstract]
8. Al-Batran SE, Homann N, Pauligk C, et al.: Perioperative chemotherapy with fluorouracil
plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus
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10/23/24, 10:52 PM Gastric Cancer Treatment (PDQ®) - NCI

cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal

junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393 (10184):
1948-1957, 2019. [PUBMED Abstract]
9. Kelsen DP: Postoperative adjuvant chemoradiation therapy for patients with resected
gastric cancer: intergroup 116. J Clin Oncol 18 (21 Suppl): 32S-4S, 2000. [PUBMED Abstract]
10. Fuchs CS, Niedzwiecki D, Mamon HJ, et al.: Adjuvant Chemoradiotherapy With Epirubicin,
Cisplatin, and Fluorouracil Compared With Adjuvant Chemoradiotherapy With Fluorouracil
and Leucovorin After Curative Resection of Gastric Cancer: Results From CALGB 80101
(Alliance). J Clin Oncol 35 (32): 3671-3677, 2017. [PUBMED Abstract]
11. Cats A, Jansen EPM, van Grieken NCT, et al.: Chemotherapy versus chemoradiotherapy
after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an
international, open-label, randomised phase 3 trial. Lancet Oncol 19 (5): 616-628,
2018. [PUBMED Abstract]
12. Sakuramoto S, Sasako M, Yamaguchi T, et al.: Adjuvant chemotherapy for gastric cancer
with S-1, an oral fluoropyrimidine. N Engl J Med 357 (18): 1810-20, 2007. [PUBMED
Abstract]
13. Bang YJ, Kim YW, Yang HK, et al.: Adjuvant capecitabine and oxaliplatin for gastric cancer
after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet
379 (9813): 315-21, 2012. [PUBMED Abstract]

Treatment of Stage IV, Inoperable, and Recurrent Gastric

Cancer

Treatment Options for Stage IV, Inoperable, and Recurrent Gastric

Cancer
Treatment options for stage IV, inoperable, and recurrent gastric cancer, including patients
with medically or surgically unresectable disease, include a combination of cytotoxic therapies,
targeted therapies, immunotherapies, and palliative locoregional therapies.

Patients with metastatic gastric adenocarcinoma should consider undergoing testing for HER2
amplification, defective mismatch repair (dMMR) (immunohistochemistry [IHC] staining), or
microsatellite instability (MSI) (polymerase chain reaction), along with programmed death
ligand 1 (PD-L1) combined positive score (CPS score in the United States).

1. First-line palliative systemic therapy for patients with HER2-negative tumors.

a. Palliative chemotherapy with or without immunotherapy.
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• Chemotherapy with immunotherapy: fluorouracil (5-FU) or capecitabine

combined with oxaliplatin and nivolumab.
b. Triplet regimens.
• 5-FU combined with either epirubicin and cisplatin, etoposide and
leucovorin, doxorubicin and methotrexate, leucovorin and irinotecan, or
docetaxel and cisplatin or oxaliplatin.[1-7]

c. Doublet regimens.
• A taxane (docetaxel or paclitaxel) and either cisplatin or carboplatin.
• 5-FU and cisplatin.
• Capecitabine and oxaliplatin.[8]
d. Single agents.
• 5-FU or capecitabine.[9,10]
• A taxane (either docetaxel or paclitaxel).
2. First-line palliative systemic therapy for patients with HER2-positive tumors (3+ on IHC or
2+ on IHC with a positive fluorescence in situ hybridization [FISH]).
a. Immunotherapy with chemotherapy.
• Nivolumab with chemotherapy.
• Trastuzumab with chemotherapy.
3. Second-line palliative systemic therapy.
a. Palliative chemotherapy.
b. Ramucirumab with or without chemotherapy.
c. Pembrolizumab for patients with dMMR or MSI-high (MSI-H) tumors.
d. Trastuzumab deruxtecan for patients with HER2-positive tumors (3+ on IHC or 2+
on IHC with a positive FISH).

4. Third-line palliative systemic therapy.

a. Trifluridine and tipiracil.

5. Endoluminal laser therapy, endoluminal stent placement, or gastrojejunostomy may be

helpful to patients with gastric obstruction.[11]
6. Palliative radiation therapy may alleviate bleeding, pain, and obstruction.
7. Palliative resection is reserved for patients with continued bleeding or obstruction.
8. Regorafenib with nivolumab (under clinical evaluation).
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9. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (under clinical

evaluation).

Treatment with poly (ADP-ribose) polymerase (PARP) inhibitors and hepatocyte growth factor
inhibitors have not shown efficacy at this time, but combination studies are under way.

First-line palliative systemic therapy for patients with HER2-negative tumors

Palliative chemotherapy with or without immunotherapy

Standard chemotherapy versus best supportive care for patients with metastatic gastric cancer
has been tested in several clinical trials, and there is general agreement that patients who
receive chemotherapy live for several months longer on average than patients who receive
supportive care.[12-14][Level of evidence A1] During the last 20 years, multiple randomized
studies evaluating different treatment regimens (monotherapy vs. combination [doublet and
triplet] chemotherapy) have been performed in patients with metastatic gastric cancer with no
clear consensus as to the best management approach. A meta-analysis of these studies
demonstrated a hazard ratio (HR) of 0.83 for overall survival (OS) (95% confidence interval [CI],
0.74–0.93) in favor of combination chemotherapy.[15] The addition of immune checkpoint
inhibitors to oxaliplatin-based chemotherapy has shown further OS benefit.

Evidence (palliative chemotherapy):

1. Of all the combination regimens, epirubicin, cisplatin, and 5-FU (ECF) is often considered
the reference standard in the United States and Europe. In one European trial, 274
patients with metastatic esophagogastric cancer were randomly assigned to receive either
ECF or 5-FU, doxorubicin, and methotrexate (FAMTX).[16]
• The group who received ECF had a significantly longer median survival (8.9 vs. 5.7
months, P = .0009) than the FAMTX group.[16][Level of evidence A1]

2. In a second trial that compared ECF with mitomycin, cisplatin, and 5-FU (MCF), there was
no statistically significant difference in median survival (9.4 vs. 8.7 months, P = .315).[2]
[Level of evidence A1]
3. Oxaliplatin and capecitabine are often substituted for cisplatin and 5-FU within the ECF
regimen on the basis of results from the REAL-2 trial (ISRCTN51678883).[8] This
randomized trial of 1,002 patients with advanced esophageal, gastroesophageal junction,
or gastric cancer utilized a 2 × 2 design.
• The trial demonstrated noninferior median OS in patients treated with
capecitabine rather than 5-FU (HRdeath, 0.86; 95% CI, 0.82–0.99) and in patients
treated with oxaliplatin in place of cisplatin (HRdeath, 0.92; 95% CI, 0.80–1.10)

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4. An international collaboration of investigators randomly assigned 445 patients with

metastatic gastric cancer to receive docetaxel, cisplatin, and 5-FU (DCF) or cisplatin and 5-
FU (CF).[17] Time-to-treatment progression (TTP) was the primary end point.
• Patients who received DCF experienced a significantly longer TTP (5.6 months; 95%
CI, 4.9–5.9; vs. 3.7 months; 95% CI, 3.4–4.5; HR, 1.47; 95% CI, 1.19–1.82; log-rank P <
.001; risk reduction, 32%).
• The median OS was significantly longer for patients who received DCF compared
with patients who received CF (9.2 months; 95% CI, 8.4–10.6; vs. 8.6 months; 95%
CI, 7.2–9.5; HR, 1.29; 95% CI, 1.0–1.6; log-rank P = .02; risk reduction, 23%).[17]
[Level of evidence A1]
• The toxicity rates were high in both arms.[18]
• Febrile neutropenia was more common in patients who received DCF (29% vs.
12%), and the death rate on the study was 10.4% for patients on the DCF arm and
9.4% for patients on the CF arm.

5. Whether the CF regimen should be considered as an index regimen for the treatment of
patients with metastatic gastric cancer is the subject of debate.[18] The results of a study
that randomly assigned 245 patients with metastatic gastric cancer to receive CF, FAMTX,
or etoposide, leucovorin, and 5-FU (ELF) demonstrated no significant difference in
response rate, progression-free survival, or OS between the arms.[3]
• Grades 3 and 4 neutropenia occurred in 35% to 43% of patients on all arms, but
severe nausea and vomiting was more common in patients in the CF arm and
occurred in 26% of those patients.[3][Level of evidence B3]

Phase II studies that evaluated irinotecan-based or oxaliplatin-based regimens demonstrated

similar response rates and TTP to those reported in trials using ECF or CF, but the former may
be less toxic.[19-24] There are conflicting data regarding relative efficacy of any one regimen.

First-line palliative systemic therapy for patients with HER2-positive tumors

(3+ on IHC or 2+ on IHC with a positive FISH)

Immunotherapy with chemotherapy

Nivolumab with chemotherapy

Nivolumab may be considered in combination with chemotherapy for patients with advanced
or metastatic gastric cancer regardless of PD-L1 CPS status.[25]

Evidence (nivolumab with chemotherapy):

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1. In a randomized, open-label, international, phase III study (CheckMate-649

[NCT02872116]), patients with HER2-negative gastric or gastroesophageal junction
adenocarcinomas were randomly assigned 1:1:1 to receive either nivolumab with
chemotherapy (nivolumab 360 mg with capecitabine and oxaliplatin every 3 weeks or
nivolumab 240 mg with leucovorin, 5-FU, and oxaliplatin [FOLFOX] every 2 weeks),
chemotherapy alone (capecitabine and oxaliplatin every 3 weeks or FOLFOX every 2
weeks), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks × 4 (followed by
maintenance nivolumab). The trial randomly assigned 1,581 patients (including 955 with
PD-L1 CPS ≥5) to the chemotherapy-plus-nivolumab arm (n = 789; n = 473 with PD-L1 CPS
≥5) or the chemotherapy-alone arm (n = 792; n = 482 with PD-L1 CPS ≥5).[25]
• For all patients (regardless of PD-L1 status), the median OS was 14.0 months (95%
CI, 12.6–15.0) in the nivolumab-plus-chemotherapy arm compared with 11.3
months (95 % CI, 10.6–12.3) in the chemotherapy-alone arm (HR, 0.77; 99.3% CI,
0.64–0.92; P < .0001).
• Patients with tumors with PD-L1 CPS greater than 5 had a median OS of 14.4
months (95% CI, 13.1–16.2) in the nivolumab-plus-chemotherapy arm compared
with 11.1 months (95% CI, 10.0−12.1) in the chemotherapy-alone arm (HR, 0.71;
98.4% CI, 0.59–0.86; P = .0001).
• Grades 3 and 4 adverse events occurred in 462 patients in the combination arm
and in 341 patients in the chemotherapy-alone arm.[25][Level of evidence A1]
Trastuzumab with chemotherapy
Trastuzumab may be combined with pembrolizumab and chemotherapy (5-FU and cisplatin or
oxaliplatin with capecitabine) as treatment for patients with HER2-positive metastatic gastric
adenocarcinoma. For patients who do not tolerate pembrolizumab, trastuzumab may be
combined with cisplatin and 5-FU or capecitabine. HER2 testing is recommended for patients
with metastatic disease.[26]

Evidence (trastuzumab and pembrolizumab with chemotherapy):

1. The double-blind, placebo-controlled, phase III, international KEYNOTE-811 trial

(NCT03615326) studied dual pembrolizumab, trastuzumab, and chemotherapy (either 5-
FU with cisplatin or capecitabine with oxaliplatin). A total of 434 patients with metastatic
HER2-positive gastric adenocarcinoma were randomly assigned in a 1:1 ratio to receive
either chemotherapy and trastuzumab (6 mg/kg every 3 weeks) with or without
pembrolizumab (200 mg intravenously [IV] every 3 weeks).
• The objective response rate at the first interim analysis was 74.4% (95% CI, 66.2%–
81.6%) for patients in the pembrolizumab arm and 51.9% (95% CI, 43.0%–60.7%)
for patients in the placebo arm.[26][Level of evidence B3]

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• Adverse events grade 3 or higher were observed in 57.1% of patients in the

pembrolizumab arm (including 33.6% of patients with immune-related reactions)
and 57.4% of patients in the placebo arm.

Evidence (trastuzumab):

1. In the open-label, international, phase III Trastuzumab for Gastric Cancer trial (ToGA
[NCT01041404]), patients with HER2-positive metastatic, inoperable locally advanced, or
recurrent gastric or gastroesophageal junction cancer were randomly assigned to receive
chemotherapy with or without the anti-HER2 monoclonal antibody trastuzumab.[27] HER2
positivity was defined as either 3+ by IHC or a HER2 to CEP17 ratio of 2 or more using
FISH. Tumors from 3,665 patients were tested for HER2; of the patients, 810 were positive
(22%) and 594 met eligibility criteria for randomization. Chemotherapy consisted of
cisplatin plus 5-FU or capecitabine chosen at the investigator’s discretion. The study
treatment was administered every 3 weeks for six cycles, and trastuzumab was continued
every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent.
Crossover to trastuzumab at disease progression was not permitted.
• The median OS was 13.8 months (95% CI, 12–16) in patients assigned to
trastuzumab and 11.1 months (95% CI, 10–13) in patients assigned to
chemotherapy alone (HR, 0.74; 95% CI, 0.60–0.91; P = .0046).[27][Level of evidence
A1]
• There was no significant difference in rates of any adverse event, and cardiotoxic
effects were equally rare in both arms.
Pembrolizumab with chemotherapy
The combination of pembrolizumab and chemotherapy has not shown superiority over
chemotherapy alone.

Evidence (pembrolizumab with chemotherapy):

1. A phase III, partially blinded, randomized, international study (KEYNOTE-062

[NCT02494583]) of 763 patients with previously untreated advanced gastric cancer with a
PD-L1 CPS of one or greater randomly assigned patients 1:1:1 to receive either
pembrolizumab 200 mg IV every 3 weeks, pembrolizumab with chemotherapy (cisplatin
with 5-FU or capecitabine), or chemotherapy alone.[28]
• The final results did not show superiority of pembrolizumab or pembrolizumab
with chemotherapy over chemotherapy alone.
• However, when selected for a PD-L1 CPS of ten or greater, median OS was 17.4
months (95% CI, 9.1−23.1) in the pembrolizumab-alone arm compared with 10.8
months (95% CI, 8.5−13.8) in the chemotherapy-alone arm (HR, 0.69; 95% CI,
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0.49−0.97). The prespecified statistical analysis plan did not test this difference
further.

Second-line palliative systemic therapy

There is no standard treatment option for patients who develop disease progression after first-
line palliative chemotherapy. Accepted regimens include paclitaxel with or without
ramucirumab, docetaxel, and irinotecan with or without 5-FU/leucovorin. Pembrolizumab is
approved for the treatment of patients with dMMR or MSI-H tumors, and trastuzumab
deruxtecan is approved for patients with HER2-positive gastric cancer.

Palliative chemotherapy
Evidence (palliative chemotherapy):

1. Investigators in Korea randomly assigned patients with advanced gastric cancer who had
previously received one or two chemotherapy regimens that involved both a
fluoropyrimidine and a platinum agent to receive either salvage chemotherapy or best
supportive care in a 2:1 fashion.[29] Salvage chemotherapy consisted of either docetaxel
2 2
(60 mg/m every 3 weeks) or irinotecan (150 mg/m every 2 weeks) and was left to the
discretion of the treating physicians. Of the 202 patients enrolled, 133 received salvage
chemotherapy and 69 received best supportive care.
• The median OS was 5.3 months in the group that received salvage chemotherapy
and 3.8 months in the group that received best supportive care (HR, 0.657; P =
.007).
• There was no difference in median OS between docetaxel and irinotecan (5.2
months vs. 6.5 months, P = .116).[29][Level of evidence A1]
Ramucirumab with or without chemotherapy
Ramucirumab is a fully humanized monoclonal antibody directed against the vascular
endothelial growth factor receptor-2.

Evidence (ramucirumab):

1. The international, phase III, placebo-controlled, REGARD trial (NCT00917384) included 355
patients with stage IV gastric or gastroesophageal junction cancer who had progressed on
a first-line 5-FU‒ or platinum-containing regimen. Patients were randomly assigned in a
2:1 fashion to receive either ramucirumab or placebo.[30]
• Patients who were assigned to ramucirumab had a significantly improved median
OS of 5.2 months compared with a median OS of 3.8 months in patients who were
assigned to the placebo (HR, 0.776; P = .047).

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• Rates of hypertension were higher in the ramucirumab group than in the placebo
group.[30][Level of evidence A1]

Ramucirumab is an acceptable treatment in patients with cisplatin- or 5-FU‒refractory,

stage IV, gastric cancer.
2. In the international, double-blinded, phase III RAINBOW trial (NCT01170663), 665 patients
2
were randomly assigned to receive paclitaxel (80 mg/m ) on days 1, 8, and 15 every 28
days with either ramucirumab (8 mg/kg) added on days 1 and 15 or a placebo added on
days 1 and 15.[31]
• Patients who were assigned to ramucirumab had a significant improvement in
median OS of 9.6 months compared with a median OS of 7.4 months in patients
who were assigned to a placebo (HR, 0.807; P = .017).
• Grade 3 or higher neutropenia, fatigue, hypertension, and abdominal pain were
more common in the ramucirumab group.[31][Level of evidence A1]

The combination of paclitaxel and ramucirumab is an acceptable second-line

chemotherapy regimen in patients with stage IV gastric or gastroesophageal junction
cancer.
Pembrolizumab for patients with dMMR or MSI-H tumors
Evidence (pembrolizumab for patients with dMMR or MSI-H tumors):

1. In a phase II study of pembrolizumab 200 mg IV every 3 weeks in patients with colon

cancer with or without dMMR, and noncolorectal cancer with dMMR, the immune-related
objective response rate was 71% (5 of 7 patients). On the basis of these data,
pembrolizumab was approved for patients with dMMR solid tumors that have progressed
after previous treatment and who have no satisfactory alternative treatment options.[32]
Trastuzumab deruxtecan for patients with HER2-positive tumors (3+ on IHC or 2+ on
IHC with a positive FISH)
Trastuzumab deruxtecan is an antibody-drug conjugate combining an anti-HER2 antibody with
a topoisomerase I inhibitor via a cleavable tetrapeptide-based linker. The U.S. Food and Drug
Administration (FDA) approved trastuzumab deruxtecan for patients with locally advanced or
metastatic gastric or gastroesophageal junction cancer that is HER2-positive who have
previously received a trastuzumab-based regimen.

Evidence (trastuzumab deruxtecan for patients with HER2-positive tumors):

1. The international, open-label, randomized, phase II DESTINY-Gastric01 trial

(NCT03329690) included 187 patients from Japan and South Korea with HER2-positive
advanced gastric cancer that had progressed after at least two previous therapies
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(including trastuzumab). Patients were randomly assigned in a 2:1 ratio to receive either
trastuzumab deruxtecan (6.4 mg/kg every 3 weeks) or the physician’s choice of
chemotherapy. The primary study end point was objective response.[33]
• The objective response rate was 51% for patients who received trastuzumab
deruxtecan and 14% for patients who received chemotherapy (P < .001).
• The OS was 12.5 months for patients who received trastuzumab deruxtecan and
8.4 months for patients who received chemotherapy (HR, 0.59; 95% CI, 0.39–0.88, P
= .02).[33][Level of evidence A1]
• Common side effects of trastuzumab deruxtecan included neutropenia (grade 3–4
in 51% of patients, with six patients developing neutropenic fever) and anemia
(grade 3–4 in 38% of patients). Twelve patients (10%) developed drug-related
interstitial lung disease.

Third-line palliative systemic therapy

Trifluridine and tipiracil

Trifluridine and tipiracil is an oral cytotoxic therapy approved by the FDA for third-line
treatment of patients with metastatic gastric or gastroesophageal junction cancer.

Evidence (trifluridine and tipiracil):

1. A randomized, double-blinded, placebo-controlled, international, phase III trial (TAGS

[NCT02500043]) included 507 patients with metastatic gastric or gastroesophageal
junction adenocarcinoma who had progressive disease after receiving two previous
regimens, including a fluoropyrimidine, a platinum agent, and a taxane and/or irinotecan.
Patients were randomly assigned in a 2:1 ratio to receive either trifluridine and tipiracil (35
2
mg/m twice a day on days 1−5 and 8−12 every 28 days) or placebo.[34]
• The median OS was 5.7 months (95% CI, 4.8−6.2) in patients who received
trifluridine and tipiracil, compared with 3.6 months (95% CI, 3.1−4.1) in patients
who received placebo (HR, 0.69; 95% CI, 0.57−0.85; P = .00058).
• The objective response rate was 4% (disease control rate, 44%) in the trifluridine
and tipiracil arm, compared with 2% (disease control rate, 14%) in the placebo arm.
• Grade 3 or higher adverse events occurred in 80% of patients treated with
trifluridine and tipiracil, compared with 58% of patients who received placebo.
Immunotherapy

Pembrolizumab
While pembrolizumab was previously evaluated as third-line treatment for patients with gastric
and gastroesophageal junction cancers and a PD-L1 CPS of one or greater, this approval was
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withdrawn after updates to first-line therapy using combination chemotherapy and

programmed death 1 (PD-1) inhibitors.
Nivolumab
Nivolumab has been approved by the Japanese Ministry of Health, Labor, and Welfare for
treatment of advanced gastric cancer, regardless of PD-L1 CPS status.

Evidence (nivolumab):

1. A randomized, double-blinded, placebo-controlled, phase III trial (ONO-4538-12

[ATTRACTION-2] [NCT02267343]) enrolled 493 patients with refractory
gastroesophageal/gastric cancer from Japan, South Korea, and Taiwan.[35] Patients were
randomly assigned 2:1 to receive either nivolumab (3 mg/kg every 2 weeks) or placebo.
• The median OS was 5.26 months (95% CI, 4.60–6.37) in the nivolumab group
compared with 4.14 months (95% CI, 3.42–4.86) in the placebo group.
• Serious treatment-related adverse events occurred in 10% of the patients.[35]
[Level of evidence A1]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now
enrolling patients. The search can be narrowed by location of the trial, type of treatment, name
of the drug, and other criteria. General information about clinical trials is also available.

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34. Shitara K, Doi T, Dvorkin M, et al.: Trifluridine/tipiracil versus placebo in patients with
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35. Kang YK, Boku N, Satoh T, et al.: Nivolumab in patients with advanced gastric or gastro-
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Latest Updates to This Summary (01/26/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new
information becomes available. This section describes the latest changes made to this
summary as of the date above.

General Information About Gastric Cancer

Updated statistics with estimated new cases and deaths for 2024 (cited American Cancer
Society as reference 1).

Treatment Option Overview

Added Capecitabine and Fluorouracil Dosing as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is
editorially independent of NCI. The summary reflects an independent review of the literature
and does not represent a policy statement of NCI or NIH. More information about summary
policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be
found on the About This PDQ Summary and PDQ® Cancer Information for Health
Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-
reviewed, evidence-based information about the treatment of gastric cancer. It is intended as a
resource to inform and assist clinicians in the care of their patients. It does not provide formal
guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment
Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The
summary reflects an independent review of the literature and does not represent a policy
statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article
should:

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• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members
evaluate the strength of the evidence in the published articles and determine how the article
should be included in the summary.

The lead reviewers for Gastric Cancer Treatment are:

• Amit Chowdhry, MD, PhD (University of Rochester Medical Center)

• Valerie Lee, MD (Johns Hopkins University)
• Leon Pappas, MD, PhD (Dana-Farber Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov
through the NCI website's Email Us. Do not contact the individual Board Members with
questions or comments about the summaries. Board members will not respond to individual
inquiries.

Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence
designation. These designations are intended to help readers assess the strength of the
evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment
Editorial Board uses a formal evidence ranking system in developing its level-of-evidence
designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as
text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented
in its entirety and is regularly updated. However, an author would be permitted to write a
sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention
states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Gastric Cancer Treatment. Bethesda, MD:
National Cancer Institute. Updated <MM/DD/YYYY>. Available at:
https://www.cancer.gov/types/stomach/hp/stomach-treatment-pdq. Accessed <MM/DD/YYYY>.
[PMID: 26389209]

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Images in this summary are used with permission of the author(s), artist, and/or publisher for
use within the PDQ summaries only. Permission to use images outside the context of PDQ
information must be obtained from the owner(s) and cannot be granted by the National
Cancer Institute. Information about using the illustrations in this summary, along with many
other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific
images.

Disclaimer
Based on the strength of the available evidence, treatment options may be described as either
“standard” or “under clinical evaluation.” These classifications should not be used as a basis for
insurance reimbursement determinations. More information on insurance coverage is
available on Cancer.gov on the Managing Cancer Care page.

Contact Us
More information about contacting us or receiving help with the Cancer.gov website can be
found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov
through the website’s Email Us.

Updated: January 26, 2024

If you would like to reproduce some or all of this content, see Reuse of NCI Information for guidance
about copyright and permissions. In the case of permitted digital reproduction, please credit the
National Cancer Institute as the source and link to the original NCI product using the original
product's title; e.g., “Gastric Cancer Treatment (PDQ®)–Health Professional Version was originally
published by the National Cancer Institute.”

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