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

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

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.

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.

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)

Table 1. Definitions of pTNM Stage 0a
StageTNMDescription
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted 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.
0Tis, N0, M0Tis = Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria, high-grade dysplasia.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 2. Definitions of pTNM Stages IA and IBa
StageTNMDescription
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted 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.
bA 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.
IAT1, N0, M0T1 = 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.
IBT1, N1, M0T1 = 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.
T2, N0, M0T2 = Tumor invades muscularis propria.b
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 3. Definitions of pTNM Stages IIA and IIBa
StageTNMDescription
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted 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.
bA 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.
cThe adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
dIntramural 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.
IIAT1, N2, M0T1 = 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.
T2, N1, M0T2 = Tumor invades muscularis propria.b
N1 = Metastases in 1 or 2 regional lymph nodes.
M0 = No distant metastasis.
T3, N0, M0T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIBT1, N3a, M0T1 = 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.
T2, N2, M0 T2 = Tumor invades muscularis propria.b
N2 = Metastases in 3 to 6 regional lymph nodes.
M0 = No distant metastasis.
T3, N1, M0T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
N1 = Metastasis in 1or 2 regional lymph nodes.
M0 = No distant metastasis.
T4a, N0, M0T4a = Tumor invades serosa (visceral peritoneum).
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 4. Definitions of pTNM Stages IIIA, IIIB, and IIICa
StageTNMDescription
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted 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.
bA 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.
cThe adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
dIntramural 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.
IIIAT2, N3a, M0T2 = Tumor invades muscularis propria.b
N3a = Metastasis in 7 to 15 regional lymph nodes.
M0 = No distant metastasis.
T3, N2, M0T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
N2 = Metastasis in 3 to 6 regional lymph nodes.
M0 = No distant metastasis.
T4a, N1, M0T4a = Tumor invades serosa (visceral peritoneum).
N1 = Metastasis in 1or 2 regional lymph nodes.
M0 = No distant metastasis.
T4a, N2, M0 T4a = Tumor invades serosa (visceral peritoneum).
N2 = Metastasis in 3 to 6 regional lymph nodes.
M0 = No distant metastasis.
T4b, N0, M0T4b = Tumor invades adjacent structures/organs.c,d
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIIBT1, N3b, M0T1 = Tumor invades lamina propria, muscularis mucosae, or submucosa.
N3b = Metastases in 16 or more regional lymph nodes.
M0 = No distant metastasis.
T2, N3b, M0 T2 = Tumor invades muscularis propria.b
N3b = Metastases in 16 or more regional lymph nodes.
M0 = No distant metastasis.
T3, N3a, M0T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
N3a = Metastasis in 7 to 15 regional lymph nodes.
M0 = No distant metastasis.
T4a, N3a, M0T4a = Tumor invades serosa (visceral peritoneum).
N3a = Metastasis in 7 to 15 regional lymph nodes.
M0 = No distant metastasis.
T4b, N1, M0T4b = Tumor invades adjacent structures/organs.c,d
N1 = Metastasis in 1or 2 regional lymph nodes.
M0 = No distant metastasis.
T4b, N2, M0T4b = Tumor invades adjacent structures/organs.c,d
N2 = Metastasis in 3 to 6 regional lymph nodes.
M0 = No distant metastasis.
IIICT3, N3b, M0T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.cd
N3b = Metastasis in 16 or more regional lymph nodes.
M0 = No distant metastasis.
T4a, N3b, M0T4a = Tumor invades serosa (visceral peritoneum).
N3b = Metastasis in 16 or more regional lymph nodes.
M0 = No distant metastasis.
T4b, N3a, M0T4b = Tumor invades adjacent structures/organs.c,d
N3a = Metastasis in 7 to 15 regional lymph nodes.
M0 = No distant metastasis.
T4b, N3b, M0T4b = Tumor invades adjacent structures/organs.c,d
N3b = Metastasis in 16 or more regional lymph nodes.
M0 = No distant metastasis.
Table 5. Definitions of pTNM Stage IVa
StageTNMDescription
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological.
aReprinted 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.
bA 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.
cThe adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
dIntramural 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.
IVAny T, Any N, M1TX = Primary tumor cannot be assessed.
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.
T2 = Tumor invades muscularis propria.b
T3 = Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.c,d
T4 = Tumor invades the serosa (visceral peritoneum) or adjacent structures.c,d
–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.
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]

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 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

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 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, 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).
    • 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]
  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).
    • 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 (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).
    • 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 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 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.
    1. Palliative chemotherapy with or without immunotherapy.
      • Chemotherapy with immunotherapy: fluorouracil (5-FU) or capecitabine combined with oxaliplatin and nivolumab.
    2. 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]
    3. Doublet regimens.
      • A taxane (docetaxel or paclitaxel) and either cisplatin or carboplatin.
      • 5-FU and cisplatin.
      • Capecitabine and oxaliplatin.[8]
    4. 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]).
    1. Immunotherapy with chemotherapy.
  3. Second-line palliative systemic therapy.
    1. Palliative chemotherapy.
    2. Ramucirumab with or without chemotherapy.
    3. Pembrolizumab for patients with dMMR or MSI-high (MSI-H) tumors.
    4. 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.
    1. 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).
  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)
  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):

  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]
    • 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, 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 (60 mg/m2 every 3 weeks) or irinotecan (150 mg/m2 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).
    • 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 were randomly assigned to receive paclitaxel (80 mg/m2) 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 (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 mg/m2 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 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.

References
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  12. Murad AM, Santiago FF, Petroianu A, et al.: Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72 (1): 37-41, 1993. [PUBMED Abstract]
  13. Pyrhönen S, Kuitunen T, Nyandoto P, et al.: Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71 (3): 587-91, 1995. [PUBMED Abstract]
  14. Glimelius B, Ekström K, Hoffman K, et al.: Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8 (2): 163-8, 1997. [PUBMED Abstract]
  15. Wagner AD, Grothe W, Haerting J, et al.: Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 24 (18): 2903-9, 2006. [PUBMED Abstract]
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  17. Ajani JA, Moiseyenko VM, Tjulandin S, et al.: Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group. J Clin Oncol 25 (22): 3205-9, 2007. [PUBMED Abstract]
  18. Ilson DH: Docetaxel, cisplatin, and fluorouracil in gastric cancer: does the punishment fit the crime? J Clin Oncol 25 (22): 3188-90, 2007. [PUBMED Abstract]
  19. Ilson DH, Saltz L, Enzinger P, et al.: Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 17 (10): 3270-5, 1999. [PUBMED Abstract]
  20. Beretta E, Di Bartolomeo M, Buzzoni R, et al.: Irinotecan, fluorouracil and folinic acid (FOLFIRI) as effective treatment combination for patients with advanced gastric cancer in poor clinical condition. Tumori 92 (5): 379-83, 2006 Sep-Oct. [PUBMED Abstract]
  21. Pozzo C, Barone C, Szanto J, et al.: Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study. Ann Oncol 15 (12): 1773-81, 2004. [PUBMED Abstract]
  22. Bouché O, Raoul JL, Bonnetain F, et al.: Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol 22 (21): 4319-28, 2004. [PUBMED Abstract]
  23. Ajani JA, Baker J, Pisters PW, et al.: CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma: results of a phase II study. Cancer 94 (3): 641-6, 2002. [PUBMED Abstract]
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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:

  • 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.

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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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