Gastric Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Gastric Cancer

Incidence and Mortality

Estimated new cases and deaths from gastric cancer in the United States in 2017:[1]

• New cases: 28,000.
• Deaths: 10,960.

Epidemiology

Management of adenocarcinoma histology, which accounts for 90% to 95% of all gastric malignancies, is discussed in this summary. There are changing epidemiologic patterns in the United States regarding the anatomic location of esophagogastric cancers, with a trend of decreased occurrence of distal or noncardia gastric cancers.[2] However, in persons 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, incidence has remained steady, with an incidence of 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 Caucasian 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 malignancies. While the precise etiology is unknown, acknowledged risk factors for gastric cancer include the following:[5,6,7]

• Helicobacter pylori gastric infection.
• Advanced age.
• Male gender.
• 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.
• Menetrier disease (giant hypertrophic gastritis).
• 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 overall survival rate in these patients at 5 years 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. (Refer to the PDQ summary on Gastrointestinal Stromal Tumors Treatment for more information.)

Related Summaries

Other PDQ summaries containing information related to gastric cancer include the following:

• Stomach (Gastric) Cancer Prevention.
• Stomach (Gastric) Cancer Screening.
• Unusual Cancers of Childhood (childhood cancer of the stomach).

References:

1. American Cancer Society: Cancer Facts and Figures 2017. Atlanta, Ga: American Cancer Society, 2017. Available online. Last accessed May 25, 2017.
2. Anderson WF, Camargo MC, Fraumeni JF Jr, et al.: Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA 303 (17): 1723-8, 2010.
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.
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.
5. Kurtz RC, Sherlock P: The diagnosis of gastric cancer. Semin Oncol 12 (1): 11-8, 1985.
6. Scheiman JM, Cutler AF: Helicobacter pylori and gastric cancer. Am J Med 106 (2): 222-6, 1999.
7. Fenoglio-Preiser CM, Noffsinger AE, Belli J, et al.: Pathologic and phenotypic features of gastric cancer. Semin Oncol 23 (3): 292-306, 1996.
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.
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.
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.

Cellular Classification of Gastric Cancer

There are two major types of gastric adenocarcinoma including 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

Definitions of TNM

The American Joint Committee on Cancer has designated staging by TNM classification to define gastric cancer.[1,2,3]

References:

1. Stomach. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, p 120.
2. Roder JD, Böttcher K, Busch R, et al.: Classification of regional lymph node metastasis from gastric carcinoma. German Gastric Cancer Study Group. Cancer 82 (4): 621-31, 1998.
3. Ichikura T, Tomimatsu S, Uefuji K, et al.: Evaluation of the New American Joint Committee on Cancer/International Union against cancer classification of lymph node metastasis from gastric carcinoma in comparison with the Japanese classification. Cancer 86 (4): 553-8, 1999.

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, adjuvant external-beam radiation therapy with combined chemotherapy has been evaluated in the United States.

In a phase III Intergroup trial (SWOG-9008), 556 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction were randomly assigned to receive surgery alone or surgery plus postoperative chemotherapy (5-fluorouracil [5-FU] and leucovorin) and concurrent radiation therapy (45 Gy). With 5 years' median follow-up, a significant survival benefit was reported for patients who received adjuvant combined modality therapy.[2][Level of evidence: 1iiA] Median survival was 36 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm (P = .005). Three-year overall survival (OS) rates were 50%, and relapse-free survival rates were 48% with adjuvant chemoradiation therapy versus 3-year OS rates of 41% and relapse-free survival rates of 31% for surgery alone (P = .005). The rate of distant metastases was 18% for the surgery-alone arm and 33% for the chemoradiation-therapy arm. Because distant disease remains a significant concern, the aim of the Cancer and Leukemia Group B study (CALGB-80101) was to augment the postoperative chemoradiation regimen used in INT-0116. Neoadjuvant chemoradiation therapy such as in the RTOG-9904 trial, which is now completed, and the SWOG-S0425 (NCT00335959) trial, which is now closed, was clinically evaluated.[3]

Investigators in Europe evaluated the role of preoperative and postoperative chemotherapy without radiation therapy.[4] In the randomized phase III trial (MRC-ST02), 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 before and after surgery or to receive surgery alone. Compared with the surgery group, the perioperative chemotherapy group had a significantly higher likelihood of progression-free survival (hazard ratio [HR] for progression, 0.66; 95% confidence interval [CI], 0.53-0.81; P < .001) and of OS (HR for death, 0.75; 95% CI, 0.60-0.93; P = .009). Five-year OS was 36.3%; 95% CI, 29 to 43 for the perioperative chemotherapy group and 23%; 95% CI, 16.6 to 29.4 for the surgery group.[4][Level of evidence: 1iiA]

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.
2. Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345 (10): 725-30, 2001.
3. 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.
4. 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.

Stage 0 Gastric Cancer

Standard treatment options:

• 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 has confirmed these results.[1]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage 0 gastric cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

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.

Stage I Gastric Cancer

Standard treatment options:

1. One of the following surgical 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. Postoperative chemoradiation therapy for patients with node-positive (T1 N1) and muscle-invasive (T2 N0) disease.[2]

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, since it has been demonstrated to provide equivalent survival when compared with total gastrectomy and is associated with decreased morbidity.[3][Level of evidence: 1iiA] 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 should include greater and lesser curvature perigastric regional lymph nodes. Note that in patients with stage I gastric cancer, perigastric lymph nodes may contain cancer.

In patients with node-positive (T1 N1) and muscle-invasive (T2 N0) disease, postoperative chemoradiation therapy may be considered. A prospective multi-institution phase III trial (SWOG-9008) evaluated postoperative combined chemoradiation therapy versus surgery alone in 556 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction and reported a significant survival benefit with adjuvant combined modality therapy.[2][Level of evidence: 1iiA] With a median follow-up of 5 years, median survival was 36 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm (P = .005). Three-year overall survival (OS) rates were 50%, and relapse-free survival rates were 48% with adjuvant chemoradiation therapy versus 3-year OS rates of 41% and relapse-free survival rates of 31% for surgery alone (P = .005). However, only 36 patients in the trial had stage IB tumors (18 patients in each arm).[4] Since 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.

Treatment options under clinical evaluation:

• Neoadjuvant chemoradiation therapy such as in the SWOG-S0425, which is now closed, and the RTOG-9904 trial, which is now completed.[5]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I gastric cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References:

1. Brennan MF, Karpeh MS Jr: Surgery for gastric cancer: the American view. Semin Oncol 23 (3): 352-9, 1996.
2. Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345 (10): 725-30, 2001.
3. 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.
4. Kelsen DP: Postoperative adjuvant chemoradiation therapy for patients with resected gastric cancer: intergroup 116. J Clin Oncol 18 (21 Suppl): 32S-4S, 2000.
5. 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.

Stage II Gastric Cancer

Standard treatment options:

1. One of the following surgical 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. Postoperative chemoradiation therapy.[2]
3. Perioperative chemotherapy.[3]
4. Postoperative chemotherapy.

Surgical resection with regional lymphadenectomy is the treatment of choice for patients with stage II 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. 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 [4] and in some series is associated with increased morbidity.[5,6]

Postoperative chemoradiation therapy may be considered for patients with stage II gastric cancer. A prospective multi-institution phase III trial (SWOG-9008) evaluated postoperative combined chemoradiation therapy versus surgery alone in 556 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction and reported a significant survival benefit with adjuvant combined modality therapy.[2][Level of evidence: 1iiA] With a median follow-up of 5 years, median survival was 36 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm (P = .005). Three-year overall survival (OS) rates were 50%, and relapse-free survival rates were 48% with adjuvant chemoradiation therapy versus 3-year OS rates of 41% and relapse-free survival rates of 31% for surgery alone (P = .005).The rate of distant metastases was 32% for the surgery-alone arm and 40% for the chemoradiation therapy arm. Because distant disease remains a significant concern, the aim of the Cancer and Leukemia Group B study (CALGB-80101), which is now closed, was to augment the postoperative chemoradiation regimen used in SWOG-9008.[7] Neoadjuvant chemoradiation therapy remains under clinical evaluation, such as in the SWOG-S0425 (NCT00335959) trial, which is now closed and the RTOG-9904 trial, which is now completed.[8]

Investigators in Europe evaluated the role of preoperative and postoperative chemotherapy without radiation therapy.[3] In the randomized phase III trial (MRC-ST02), 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 (ECF) before and after surgery or to receive surgery alone. Compared with the surgery group, the perioperative chemotherapy group had a significantly higher likelihood of progression-free survival (hazard ratio [HR] for progression, 0.66; 95% confidence interval [CI], 0.53-0.81; P < .001) and of OS (HR for death, 0.75; 95% CI, 0.60-0.93; P = .009). Five-year OS was 36.3%, 95% CI, 29 to 43 for the perioperative chemotherapy group and 23%, 95% CI, 16.6 to 29.4 for the surgery group.[3][Level of evidence: 1iiA]

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.[9] 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 HR for death in the S-1 group, as compared with the surgery-only group, was 0.68 (95% CI, 0.52-0.87; P = .003).[9][Level of evidence: 1iiA]

Subsequently, investigators in Asia evaluated the role of capecitabine/oxaliplatin as adjuvant therapy after gastric cancer resection. In the CLASSIC (NCT00411229) trial, 37 centers in South Korea, China, and Taiwan randomly assigned 1,035 patients with stage IIA, IIB, IIIA, or IIIB gastric cancer who had undergone a curative D2 gastrectomy to receive adjuvant chemotherapy (eight 3-week cycles of capecitabine plus oxaliplatin) or follow-up post-surgery alone.[10] 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 was 83% in the chemotherapy group and 78% in the surgery-alone group (HR, 0.72; 95% CI, 0.52-1.00; P = .0493).[10][Level of evidence: 1iiA] Further follow-up is anticipated.

Treatment options under clinical evaluation:

1. Postoperative chemoradiation therapy with ECF as evidenced in the CALGB-80101 trial, which is now closed.[7]
2. Neoadjuvant chemoradiation therapy as evidenced in the SWOG-S0425 trial, which is now closed, and the RTOG-9904 trial, which is now completed.[8]

All newly diagnosed patients with stage II gastric cancer should be considered candidates for clinical trials.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage II gastric cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References:

1. Brennan MF, Karpeh MS Jr: Surgery for gastric cancer: the American view. Semin Oncol 23 (3): 352-9, 1996.
2. Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345 (10): 725-30, 2001.
3. 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.
4. 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.
5. 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.
6. 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.
7. Fuchs C, Tepper JE, Niedwiecki D, et al.: Postoperative adjuvant chemoradiation for gastric or gastroesophageal adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (RT): interim toxicity results from Intergroup trial CALGB 80101. [Abstract] American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, 26-28 January 2006, San Francisco, California. A-61, 2006.
8. 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.
9. 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.
10. 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.

Stage III Gastric Cancer

Standard treatment options:

1. Radical surgery. Curative resection procedures are confined to patients who do not have extensive nodal involvement at the time of surgical exploration.
2. Postoperative chemoradiation therapy.[1]
3. Perioperative chemotherapy.[2]
4. Postoperative chemotherapy.

All patients with tumors that can be resected should undergo surgery. 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).

Postoperative chemoradiation therapy may be considered for patients with stage III gastric cancer. A prospective multi-institution phase III trial (SWOG-9008) evaluating postoperative combined chemoradiation therapy versus surgery alone in 556 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction reported a significant survival benefit with adjuvant combined modality therapy.[1][Level of evidence: 1iiA] With a median follow-up of 5 years, median survival was 36 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm (P = .005). Three-year overall survival (OS) rates were 50%, and relapse-free survival rates were 48% with adjuvant chemoradiation therapy versus 3-year OS rates of 41% and relapse-free survival rates of 31% for surgery alone (P = .005). Because distant disease remains a significant concern, the aim of the Cancer and Leukemia Group B study (CALGB-80101), which is now closed, was to augment the postoperative chemoradiation regimen used in the SWOG-9008 trial, for example, and the preoperative chemotherapy and chemoradiation therapy regimen used, for example, in the RTOG-9904 trial, which is now completed.

Investigators in Europe evaluated the role of preoperative and postoperative chemotherapy without radiation therapy.[2] In the randomized phase III trial (MRC-ST02), 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-fluorouracil (ECF) before and after surgery or to receive surgery alone. Compared with the surgery group, the perioperative chemotherapy group had a significantly higher likelihood of progression-free survival (hazard ratio [HR] for progression, 0.66; 95% confidence interval [CI], 0.53-0.81; P < .001) and of OS (HR for death, 0.75; 95% CI, 0.60-0.93; P = .009). Five-year OS was 36.3%; 95% CI, 29 to 43 for the perioperative chemotherapy group and 23%; 95% CI, 16.6 to 29.4 for the surgery group.[2][Level of evidence: 1iiA]

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.[3] Patients were randomized 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 HR for death in the S-1 group, as compared with the surgery-only group, was 0.68 (95% CI, 0.52-0.87; P = .003).[3][Level of evidence: 1iiA]

Subsequently, investigators in Asia evaluated the role of capecitabine/oxaliplatin as adjuvant therapy after gastric cancer resection. In the CLASSIC (NCT00411229) trial , 37 centers in South Korea, China, and Taiwan randomly assigned 1,035 patients with stage IIA, IIB, IIIA, or IIIB gastric cancer who had undergone a curative D2 gastrectomy to receive adjuvant chemotherapy (eight 3-week cycles of capecitabine plus oxaliplatin) or follow-up post-surgery alone.[4] 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 was 83% in the chemotherapy group and 78% in the surgery-alone group (HR, 0.72; 95% CI, 0.52-1.00; P = .0493).[4][Level of evidence: 1iiA] Further follow-up is anticipated.

Treatment options under clinical evaluation:

1. Postoperative chemoradiation with ECF such as in the CALGB-80101 trial, which is now closed.[5]
2. Neoadjuvant chemoradiation therapy has been under clinical evaluation, such as in the SWOG-S0425 (NCT00335959) trial, which is now closed, and the RTOG-9904 trial, which is now completed.[6]

All newly diagnosed patients with stage III gastric cancer should be considered candidates for clinical trials.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage III gastric cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References:

1. Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345 (10): 725-30, 2001.
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.
3. 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.
4. 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.
5. Fuchs C, Tepper JE, Niedwiecki D, et al.: Postoperative adjuvant chemoradiation for gastric or gastroesophageal adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (RT): interim toxicity results from Intergroup trial CALGB 80101. [Abstract] American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, 26-28 January 2006, San Francisco, California. A-61, 2006.
6. 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.

Stage IV and Recurrent Gastric Cancer

Standard treatment options:

1. Palliative chemotherapy with:
   • Fluorouracil (5-FU).[1,2,3]
   • Epirubicin, cisplatin, and 5-FU (ECF).[4,5]
   • Epirubicin, oxaliplatin, and capecitabine (EOX).[6]
   • Cisplatin and 5-FU (CF).[7,3]
   • Docetaxel, cisplatin, and 5-FU.[8]
   • Etoposide, leucovorin, and 5-FU (ELF).[9]
   • 5-FU, doxorubicin, and methotrexate (FAMTX).[7]
2. Trastuzumab, cisplatin, and either 5-FU or capecitabine in patients with HER2-positive tumors (3+ on immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH]-positive).
3. Endoluminal laser therapy, endoluminal stent placement, or gastrojejunostomy, may be helpful to patients with gastric obstruction.[10]
4. Palliative radiation therapy may alleviate bleeding, pain, and obstruction.
5. Palliative resection should be reserved for patients with continued bleeding or obstruction.

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.[11,12,13][Level of evidence: 1iiA] During the last 20 years, multiple randomized studies evaluating different treatment regimens (monotherapy vs. combination chemotherapy) have been performed in patients with metastatic gastric cancer with no clear consensus emerging as to the best management approach. A meta-analysis of these studies demonstrated an hazard ratio (HR) of 0.83 for overall survival (OS) (95% confidence interval [CI], 0.74-0.93) in favor of combination chemotherapy.[14]

Of all the combination regimens, 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 FAMTX.[15] The group who received ECF had a significantly longer median survival (8.9 vs. 5.7 months, P = .0009) than the FAMTX group.[15][Level of evidence: 1iiA] 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).[5][Level of evidence: 1iiA]

Oxaliplatin and capecitabine are often substituted for cisplatin and 5-FU within the ECF regimen as a result of data from the REAL-2 trial (ISRCTN51678883).[6] This randomized trial of 1,002 patients with advanced esophageal, gastroesophageal (GE) junction, or gastric cancer utilized a 2 × 2 design to demonstrate noninferior median OS in patients treated with capecitabine rather than 5-FU (HR_death = 0.86; 95% CI, 0.82-0.99) and in patients treated with oxaliplatin in place of cisplatin (HR_death = 0.92; 95% CI, 0.80-1.10).

An international collaboration of investigators randomly assigned 445 patients with metastatic gastric cancer to receive docetaxel, cisplatin, and 5-FU (DCF) or CF.[16] Time-to-treatment progression (TTP) was the primary endpoint. 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 versus 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%).[16][Level of evidence: 1iiA] There were high toxicity rates in both arms.[17] 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.

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.[17] The results of a study that randomly assigned 245 patients with metastatic gastric cancer to receive CF, FAMTX, or ELF demonstrated no significant difference in response rate, progression-free survival, or OS between the arms.[7] 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.[7][Level of evidence: 1iiDiv]

Trastuzumab

In an open-label, international phase III trial, patients with HER2-positive metastatic, inoperable locally advanced, or recurrent gastric or GE junction cancer were randomly assigned to chemotherapy with or without the anti-HER2 monoclonal antibody trastuzumab.[18] HER2 positivity was defined as either 3+ staining by IHC or a HER2 to CEP17 ratio of two or more using FISH. Tumors from 3,665 patients were HER2 tested; 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. 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).[18][Level of evidence: 1iiA] There was no significant difference in rates of any adverse event, and cardiotoxic effects were equally rare in both arms.

Second-line Chemotherapy

When patients develop progression of disease after first-line chemotherapy, there is no standard treatment option. Investigators in Korea randomly assigned patients with advanced gastric cancer who had received one or two prior chemotherapy regimens involving both a fluoropyrimidine and a platinum agent to either salvage chemotherapy or best supportive care in a 2:1 fashion.[19] 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. 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).[19][Level of evidence: 1iiA]

Ramucirumab

Ramucirumab is a fully humanized monoclonal antibody directed against the vascular endothelial growth factor receptor-2. In the international, phase III, placebo-controlled, REGARD trial (NCT00917384), 355 patients with stage IV gastric or gastroesophageal junction cancer who had progressed on a first-line fluorouracil- or platinum-containing regimen were randomly assigned in a 2:1 fashion to ramucirumab or placebo.[20] Patients who were assigned to ramucirumab had a significantly improved median OS of 5.2 months compared with patients assigned to the placebo who had a median OS of 3.8 months (HR, 0.776; P = .047). Rates of hypertension were higher in the ramucirumab group than in the placebo group. Ramucirumab is an acceptable treatment in cisplatin or 5-fluorouracil refractory, stage IV, gastric cancer.[20][Level of evidence: 1iiA]

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 ramucirumab (8 mg/kg) added on days 1 and 15 or a placebo added on days 1 and 15.[21] Patients assigned to ramucirumab had a significant improvement in median OS of 9.6 months compared with patients assigned to a placebo who had a median OS of 7.4 months (HR, 0.807; P = .017). Grade 3 or higher neutropenia, fatigue, hypertension, and abdominal pain were more common in the ramucirumab group. The combination of paclitaxel and ramucirumab is an acceptable second-line-chemotherapy regimen in patients with stage IV gastric or gastroesophageal junction cancer.[21][Level of Evidence: 1iA]

Treatment options under clinical evaluation:

• Palliative chemotherapy with:
  • Irinotecan and cisplatin.
  • Folic acid, 5-FU, and irinotecan (FOLFIRI).
  • Leucovorin, 5-FU, and oxaliplatin (FOLFOX).

Phase II studies evaluating irinotecan-based or oxaliplatin-based regimens demonstrate similar response rates and TTP to those found with ECF or CF, but the former may be less toxic.[22,23,24,25,26,27] There are conflicting data regarding relative efficacy of any one regimen for another. Ongoing studies are evaluating these newer regimens.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage IV gastric cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References:

1. Comis RL, Carter SK: Integration of chemotherapy into combined modality therapy of solid tumors. IV. Malignant melanoma. Cancer Treat Rev 1 (4): 285-304, 1974.
2. Cullinan SA, Moertel CG, Fleming TR, et al.: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 253 (14): 2061-7, 1985.
3. Ohtsu A, Shimada Y, Shirao K, et al.: Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 21 (1): 54-9, 2003.
4. Waters JS, Norman A, Cunningham D, et al.: Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer 80 (1-2): 269-72, 1999.
5. Ross P, Nicolson M, Cunningham D, et al.: Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20 (8): 1996-2004, 2002.
6. Cunningham D, Starling N, Rao S, et al.: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358 (1): 36-46, 2008.
7. Vanhoefer U, Rougier P, Wilke H, et al.: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18 (14): 2648-57, 2000.
8. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al.: Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24 (31): 4991-7, 2006.
9. Ajani JA, Ota DM, Jackson DE: Current strategies in the management of locoregional and metastatic gastric carcinoma. Cancer 67 (1 Suppl): 260-5, 1991.
10. Ell C, Hochberger J, May A, et al.: Coated and uncoated self-expanding metal stents for malignant stenosis in the upper GI tract: preliminary clinical experiences with Wallstents. Am J Gastroenterol 89 (9): 1496-500, 1994.
11. 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.
12. 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.
13. 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.
14. 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.
15. Webb A, Cunningham D, Scarffe JH, et al.: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15 (1): 261-7, 1997.
16. 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.
17. Ilson DH: Docetaxel, cisplatin, and fluorouracil in gastric cancer: does the punishment fit the crime? J Clin Oncol 25 (22): 3188-90, 2007.
18. Bang YJ, Van Cutsem E, Feyereislova A, et al.: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376 (9742): 687-97, 2010.
19. Kang JH, Lee SI, Lim do H, et al.: Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol 30 (13): 1513-8, 2012.
20. Fuchs CS, Tomasek J, Yong CJ, et al.: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383 (9911): 31-9, 2014.
21. Wilke H, Muro K, Van Cutsem E, et al.: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15 (11): 1224-35, 2014.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. Cavanna L, Artioli F, Codignola C, et al.: Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC). Am J Clin Oncol 29 (4): 371-5, 2006.

Changes to This Summary (02 / 02 / 2017)

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 2017 (cited American Cancer Society as reference 1).

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® - NCI's Comprehensive Cancer Database 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 who care for cancer 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 reviewer for Gastric Cancer Treatment is:

• Jennifer Wo, MD (Massachusetts General Hospital)

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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Last Revised: 2017-02-02