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NCI/PDQ^® Health professionals: Gastric Cancer Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 3 de diciembre del 2012

TABLE OF CONTENTS

• General Information About Gastric Cancer
  • Incidence and Mortality
  • Epidemiology
  • Risk Factors
  • Prognosis
  • Related Summaries

• Cellular Classification of Gastric Cancer

• Stage Information for Gastric Cancer
  • Definitions of TNM

• Treatment Option Overview

• Stage 0 Gastric Cancer
  • Current Clinical Trials

• Stage I Gastric Cancer
  • Current Clinical Trials

• Stage II Gastric Cancer
  • Current Clinical Trials

• Stage III Gastric Cancer
  • Current Clinical Trials

• Stage IV and Recurrent Gastric Cancer
  • Current Clinical Trials

• Changes to This Summary (12/03/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

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General Information About Gastric Cancer

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Incidence and Mortality

Estimated new cases and deaths from gastric cancer in the United States in 2012: 1

• New cases: 21,320.
• Deaths: 10,540.

Epidemiology

Management of adenocarcinoma histology, which accounts for 90% to 95% of all gastric malignancies, is discussed in this summary. The site of cancer origin within the stomach has changed in frequency in the United States over recent decades. 2 Cancer of the distal half of the stomach has been decreasing in the United States since the 1930s. However, in the last 2 decades, the incidence of cancer of the cardia and gastroesophageal junction has been rapidly rising. The incidence of this cancer has increased dramatically, especially in patients younger than 40 years.

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: 3 4 5

• 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

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. 6 7 Tumor grade may also provide some prognostic information. 8

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 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
2. 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]
3. Kurtz RC, Sherlock P: The diagnosis of gastric cancer. Semin Oncol 12 (1): 11-8, 1985. [PUBMED Abstract]
4. Scheiman JM, Cutler AF: Helicobacter pylori and gastric cancer. Am J Med 106 (2): 222-6, 1999. [PUBMED Abstract]
5. 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]
6. Siewert JR, Bíttcher 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]
7. 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]
8. 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

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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

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Definitions of TNM

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

Table 1. Primary Tumor (T)^a

^aReprinted with permission from AJCC: Stomach. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 117-26.^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 classified by the depth of the greatest invasion in any of these sites, including the stomach.

TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Tis	Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria.
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 subserosal connective tissue without invasion of visceral peritoneum or adjacent structures.c,d
T4	Tumor invades serosa (visceral peritoneum) or adjacent structures.c,d
T4a	Tumor invades serosa (visceral peritoneum).
T4b	Tumor invades adjacent structures.

Table 2. Regional Lymph Nodes (N)^a

^aReprinted with permission from AJCC: Stomach. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 117-26.^bA designation of pN0 should be used if all examined lymph nodes are negative, regardless of the total number removed and examined.

NX	Regional lymph node(s) cannot be assessed.
N0	No regional lymph node metastasis.b
N1	Metastases in 12 regional lymph nodes.
N2	Metastases in 36 regional lymph nodes.
N3	Metastases in 7 regional lymph nodes.
N3a	Metastases in 715 regional lymph nodes.
N3b	Metastases in 16 regional lymph nodes.

Table 3. Distant Metastasis^a

^aReprinted with permission from AJCC: Stomach. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 117-26.

M0	No distant metastasis.
M1	Distant metastasis.

Table 4. Anatomic Stage/Prognostic Groups^a

^aReprinted with permission from AJCC: Stomach. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 117-26.

Stage	T	N	M
0	Tis	N0	M0
IA	T1	N0	M0
IB	T2	N0	M0
	T1	N1	M0
IIA	T3	N0	M0
	T2	N1	M0
	T1	N2	M0
IIB	T4a	N0	M0
	T3	N1	M0
	T2	N2	M0
	T1	N3	M0
IIIA	T4a	N1	M0
	T3	N2	M0
	T2	N3	M0
IIIB	T4b	N0	M0
	T4b	N1	M0
	T4a	N2	M0
	T3	N3	M0
IIIC	T4b	N2	M0
	T4b	N3	M0
	T4a	N3	M0
IV	Any T	Any N	M1

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. [PUBMED Abstract]
2. Roder JD, Bíttcher 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. [PUBMED Abstract]
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. [PUBMED Abstract]

Treatment Option Overview

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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 as compared to 27 months for the surgery-alone arm (P = .005). Three-year overall survival (OS) rates and relapse-free survival rates were 50% and 48%, respectively, with adjuvant chemoradiation therapy versus 41% and 31%, respectively, 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) 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], 0.530.81; P < .001) and of OS (HR for death, 0.75; 95% CI, 0.600.93; 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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

Stage 0 Gastric Cancer

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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 for U.S. clinical trials from NCI's list of 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 Web site.

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]

Stage I Gastric Cancer

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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 as compared to 27 months for the surgery-alone arm (P = .005). Three-year overall survival (OS) rates and relapse-free survival rates were 50% and 48%, respectively, with adjuvant chemoradiation therapy versus 41% and 31%, respectively, 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 for U.S. clinical trials from NCI's list of 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 Web site.

References:

1. Brennan MF, Karpeh MS Jr: Surgery for gastric cancer: the American view. Semin Oncol 23 (3): 352-9, 1996. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
4. 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]
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. [PUBMED Abstract]

Stage II Gastric Cancer

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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 as compared to 27 months for the surgery-alone arm (P = .005). Three-year overall survival (OS) and relapse-free survival rates were 50% and 48%, respectively, with adjuvant chemoradiation therapy versus 41% and 31%, respectively, 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], 0.530.81; P < .001) and of OS (HR for death, 0.75; 95% CI, 0.600.93; 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, 0.520.87; 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 trial (NCT00411229), 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, 0.440.72; P < .0001). The 3-year OS was 83% in the chemotherapy group and 78% in the surgery-alone group (HR, 0.72; 95% CI, 0.521.00; 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 for U.S. clinical trials from NCI's list of 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 Web site.

References:

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

Stage III Gastric Cancer

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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 as compared to 27 months for the surgery-alone arm (P = .005). Three-year overall survival (OS) and relapse-free survival rates were 50% and 48%, respectively, with adjuvant chemoradiation therapy versus 41% and 31%, respectively, 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], 0.530.81; P < .001) and of OS (HR for death, 0.75; 95% CI, 0.600.93; 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, 0.520.87; 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 trial (NCT00411229), 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, 0.440.72; P < .0001). The 3-year OS was 83% in the chemotherapy group and 78% in the surgery-alone group (HR, 0.72; 95% CI, 0.521.00; 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 for U.S. clinical trials from NCI's list of 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 Web site.

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. [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. 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]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

Stage IV and Recurrent Gastric Cancer

Back Up

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], 0.740.93) 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 junction, or gastric cancer utilized a 2 í 2 design to demonstrate noninferior median OS in patients treated with capecitabine rather than 5-FU (HRdeath = 0.86; 95% CI, 0.820.99) and in patients treated with oxaliplatin in place of cisplatin (HRdeath = 0.92; 95% CI, 0.801.10).

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, 4.95.9; vs. 3.7 months; 95% CI, 3.44.5; HR, 1.47; 95% CI, 1.191.82; 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, 8.410.6; vs. 8.6 months; 95% CI, 7.29.5; HR, 1.29; 95% CI, 1.01.6; 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]

In an open-label, international phase III trial, patients with HER2-positive metastatic, inoperable locally advanced, or recurrent gastric or gastroesophageal 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, 1216) in patients assigned to trastuzumab and 11.1 months (95% CI, 1013) in patients assigned to chemotherapy alone (HR, 0.74; 95% CI, 0.600.91; P = .0046). 18[Level of evidence: 1iiA] There was no significant difference in rates of any adverse event, and cardiotoxicity was equally rare in both arms.

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]

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. 20 21 22 23 24 25 There are conflicting data regarding relative efficacy of any one regimen for another. Ongoing studies are evaluating these newer regimens.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of 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 Web site.

References:

1. Comis RL, Carter SK: Integration of chemotherapy into combined modality treatment of solid tumors. III. Gastric cancer. Cancer Treat Rev 1 (3): 221-238, 1974. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
8. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al.: Phase III study of docetax