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Gastric cancer


Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
TREATMENT OPTION OVERVIEW
STAGE 0 GASTRIC CANCER
STAGE I GASTRIC CANCER
STAGE II GASTRIC CANCER
STAGE III GASTRIC CANCER
STAGE IV GASTRIC CANCER
RECURRENT GASTRIC CANCER

GENERAL INFORMATION

(Separate summaries containing information on prevention of gastric cancer and screening for gastric cancer are also available in PDQ.)

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 in patients especially under 40 years of age has increased dramatically.

In localized distal gastric cancer, more than 50% of the 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.

Radical surgery represents the standard form of therapy having curative intent. Lesser surgical procedures may also play an important role in palliative therapy for patients with gastric cancer. Neoadjuvant or postoperative chemotherapy and/or radiation therapy are under clinical evaluation.[1-3]

Acknowledged risk factors for gastric cancer include: Helicobacter pylori gastric infection, older age, male gender, diet including dry salted foods, atrophic gastritis, pernicious anemia, cigarette smoking, Menetrier's disease, and familial polyposis.[4-6]

References:

  1. Hermans J, Bonenkamp JJ, Boon MC, et al.: Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. Journal of Clinical Oncology 11(8): 1441-1447, 1993.

  2. Hallissey MT, Dunn JA, Ward LC, et al.: The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet 343(8909): 1309-1312, 1994.

  3. Zhang ZX, Gu XZ, Yin WB, et al.: Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. International Journal of Radiation Oncology, Biology, Physics 42(5): 929-934, 1998.

  4. Kurtz RC, Sherlock P: The diagnosis of gastric cancer. Seminars in Oncology 12(1): 11-18, 1985.

  5. Scheiman JM, Cutler AF: Helicobacter pylori and gastric cancer. American Journal of Medicine 106(2): 222-226, 1999.

  6. Fenoglio-Preiser CM, Noffsinger AE, Belli J, et al.: Pathologic and phenotypic features of gastric cancer. Seminars in Oncology 23(3): 292-306, 1996.


CELLULAR CLASSIFICATION

The cellular classification relates only to adenocarcinomas and not to other cell types such as lymphoma and sarcomas.[1] Adenocarcinomas can be divided into the following subtypes:

fungating or polypoid
ulcerating
superficial spreading
diffusely spreading (linitis plastica)
Microscopically, four histologic types of adenocarcinoma may prove to have prognostic significance:[2]
intestinal
pylorocardial (or antral)
signet ring cell [3]
anaplastic (undifferentiated)
Other histologies include:
papillary adenocarcinoma
mucinous adenocarcinoma
adenosquamous carcinoma
squamous cell carcinoma
mixed adeno- and choriocarcinoma

References:

  1. Fine G, Chan K: Alimentary tract. In: Kissane JM, Ed.: Anderson's Pathology. Saint Louis: CV Mosby, Vol 2, 8th ed., 1985, pp 1055-1095.

  2. Stomach. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 71-76.

  3. Maehara Y, Sakaguchi Y, Moriguchi S, et al.: Signet ring cell carcinoma of the stomach. Cancer 69(7): 1645-1650, 1992.


STAGE INFORMATION

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[1,2]


-- TNM definitions --
Primary tumor (T)
  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 or submucosa
  T2:  Tumor invades the muscularis propria or the subserosa*
  T3:  Tumor penetrates the serosa (visceral peritoneum) without invading
       adjacent structures**,***
  T4:  Tumor invades adjacent structures***

*Note:  A tumor may penetrate the muscularis propria with extension into the
 gastrocolic or gastrohepatic ligaments or into the greater or lesser omentum
 without perforation of the visceral peritoneum covering these structures.  In
 this case, the tumor is classified T2.  If there is perforation of the
 visceral peritoneum covering the gastric ligaments or omentum, the tumor
 should be classified T3.

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

***Note:  Intramural extension to the duodenum or esophagus is classified by
the depth of greatest invasion in any of these sites, including stomach.

Regional lymph nodes (N)
The regional lymph nodes are the perigastric nodes, found along the lesser and
greater curvatures, and the nodes located along the left gastric, common
hepatic, splenic, and celiac arteries.  For pN, a regional lymphadenectomy
specimen will ordinarily contain at least 15 lymph nodes.  Involvement of other
intra-abdominal lymph nodes, such as the hepatoduodenal, retropancreatic,
mesenteric, and para-aortic, is classified as distant metastasis.
  NX:  Regional lymph node(s) cannot be assessed
  N0:  No regional lymph node metastasis
  N1:  Metastasis in 1 to 6 regional lymph nodes
  N2:  Metastasis in 7 to 15 regional lymph nodes
  N3:  Metastasis in more than 15 regional lymph nodes

Distant metastasis (M)
  MX:  Distant metastasis cannot be assessed
  M0:  No distant metastasis
  M1:  Distant metastasis

-- AJCC stage groupings --

-- Stage 0 -- 
  Tis, N0, M0

-- Stage IA -- 
  T1, N0, M0

-- Stage IB --
   T1, N1, M0
   T2, N0, M0

-- Stage II --
  T1, N2, M0
  T2, N1, M0
  T3, N0, M0

-- Stage IIIA --
  T2, N2, M0
  T3, N1, M0
  T4, N0, M0

-- Stage IIIB --
  T3, N2, M0

-- Stage IV -- 
  T4, N1, M0
  T1, N3, M0
  T2, N3, M0
  T3, N3, M0
  T4, N2, M0
  T4, N3, M0
  Any T, Any N, M1

References:

  1. Stomach. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 71-76.

  2. Roder JD, Bottcher K, et al. for the German Gastric Cancer Study Group: Classification of regional lymph node metastasis from gastric carcinoma. Cancer 82(4): 621-631, 1998.


TREATMENT OPTION OVERVIEW

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.


STAGE 0 GASTRIC CANCER

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

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. American Journal of Medicine 85(5): 658-661, 1988.


STAGE I GASTRIC CANCER

Surgical resection including regional lymphadenectomy is the treatment of choice for 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. 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.

Treatment options:

Standard:

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 centimeters of the cardia or distal antrum)

Regional lymphadenectomy is recommended with all of the above procedures. Splenectomy is not routinely performed.[1]

References:

  1. Brennan MF, Karpeh MS: Surgery for gastric cancer: the American view. Seminars in Oncology 23(3): 352-359, 1996.


STAGE II GASTRIC CANCER

Surgical resection with regional lymphadenectomy is the treatment of choice for 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 [2] and in some series is associated with increased morbidity.[3,4]

Treatment options:

Standard:

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 centimeters of the cardia)

Regional lymphadenectomy is recommended with all of the above procedures. Splenectomy is not routinely performed.[1]

Under clinical evaluation:

Neoadjuvant or postoperative chemotherapy and/or radiation therapy are under
clinical evaluation.[5-7] Adjuvant postoperative 5-fluorouracil-based
chemotherapy following curative resection for localized gastric
cancer demonstrated no survival benefit in a meta-analysis of randomized
trials published since 1980.[5] Few studies have evaluated postoperative or
neoadjuvant radiation without chemotherapy. A prospective randomized trial
from the British Stomach Cancer Group failed to demonstrate a survival
benefit for postoperative adjuvant radiation, although loco-regional failures
were decreased from 27% to 10%.[6] In a trial from China, 370 patients with
stage II, III, or IV adenocarcinoma of the gastric cardia were randomized to
receive 40 Gy of external-beam radiation followed by radical surgery or
radical surgery alone. There was a significant survival advantage at 5 and
10 years for the patients who received radiation and surgery over the
patients who received surgery alone. However, preoperative radiation therapy
had no effect on the rate of distant metastases.[7] Adjuvant external-beam
radiation therapy with combined chemotherapy is currently being evaluated in
the United States. In a phase III intergroup trial (INT-0116), patients
with complete resections, negative margins, and no evidence of residual
disease were randomized to receive surgery alone or surgery plus
postoperative chemotherapy and concurrent radiation therapy. This study has
closed accrual and preliminary results will be reported soon.

References:

  1. Brennan MF, Karpeh MS: Surgery for gastric cancer: the American view. Seminars in Oncology 23(3): 352-359, 1996.

  2. Kitamura K, Yamaguchi T, Sawai K, et al.: Chronologic changes in the clinicopathologic findings and survival of gastric cancer patients. Journal of Clinical Oncology 15(12): 3471-3480, 1997.

  3. 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): 745-748, 1995.

  4. 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): 995-999, 1996.

  5. Hermans J, Bonenkamp JJ, Boon MC, et al.: Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. Journal of Clinical Oncology 11(8): 1441-1447, 1993.

  6. Hallissey MT, Dunn JA, Ward LC, et al.: The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet 343(8909): 1309-1312, 1994.

  7. Zhang ZX, Gu XZ, Yin WB, et al.: Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. International Journal of Radiation Oncology, Biology, Physics 42(5): 929-934, 1998.


STAGE III GASTRIC CANCER

All patients with tumors that can be resected should undergo surgery. Up to 15% of selected stage III patients can be cured by surgery alone, particularly if lymph node involvement is minimal (<7 lymph nodes). Overall survival is poor with available single and multimodal approaches to treatment. All newly diagnosed patients with stage III gastric cancer should be considered candidates for clinical trials.[1,2]

Treatment options:

Standard:

Radical surgery: Curative resectional procedures are confined to patients
who at the time of surgical exploration do not have extensive nodal
involvement.

Under clinical evaluation:
Neoadjuvant or postoperative chemotherapy and/or radiation therapy are under
clinical evaluation.[3-5] Adjuvant postoperative 5-fluorouracil-based
chemotherapy following curative resection for localized gastric
cancer demonstrated no survival benefit in a meta-analysis of randomized
trials published since 1980.[3] Few studies have evaluated postoperative or
neoadjuvant radiation without chemotherapy. A prospective randomized trial
from the British Stomach Cancer Group failed to demonstrate a survival
benefit for postoperative adjuvant radiation, although loco-regional failures
were decreased from 27% to 10%.[4] In a trial from China, 370 patients with
stage II, III, or IV adenocarcinoma of the gastric cardia were randomized to
receive 40 Gy of external-beam radiation followed by radical surgery or
radical surgery alone. There was a significant survival advantage at 5 and
10 years for the patients who received radiation and surgery over the
patients who received surgery alone. However, preoperative radiation therapy
had no effect on the rate of distant metastases.[5] Adjuvant external-beam
radiation therapy with combined chemotherapy is currently being evaluated in
the United States. In a phase III intergroup trial (INT-0116), patients
with complete resections, negative margins, and no evidence of residual
disease were randomized to receive surgery alone or surgery plus
postoperative chemotherapy and concurrent radiation therapy. This study has
closed accrual and preliminary results will be reported soon.

References:

  1. Douglass HO, Nava HR: Gastric adenocarcinoma: management of the primary disease. Seminars in Oncology 12(1): 32-45, 1985.

  2. Douglass HO: Gastric cancer: overview of current therapies. Seminars in Oncology 12(3, Suppl 4): 57-62, 1985.

  3. Hermans J, Bonenkamp JJ, Boon MC, et al.: Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. Journal of Clinical Oncology 11(8): 1441-1447, 1993.

  4. Hallissey MT, Dunn JA, Ward LC, et al.: The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet 343(8909): 1309-1312, 1994.

  5. Zhang ZX, Gu XZ, Yin WB, et al.: Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. International Journal of Radiation Oncology, Biology, Physics 42(5): 929-934, 1998.


STAGE IV GASTRIC CANCER

All newly diagnosed patients should be considered candidates for clinical trials if possible. Endoscopic destruction of obstruction of the gastric cardia is very helpful to patients whose tumors have occluded the gastric inlet. Although neither cure nor prolongation of life is achieved with chemotherapy, in some patients substantial palliation and occasional durable remissions are possible.

Because survival is poor with all available single and multimodal approaches to treatment, no single approach can be considered state of the art. Palliative resection should be reserved for patients with continued bleeding or obstruction. Palliative radiation therapy may also alleviate bleeding, pain, and obstruction.

Treatment options:

Palliative chemotherapy with:
fluorouracil [1,2]
FAMTX: fluorouracil + doxorubicin + high-dose methotrexate [3-5]
FAM: fluorouracil + doxorubicin + mitomycin-C [6,7]
FAP: fluorouracil + doxorubicin + cisplatin [8,9]
ECF: epirubicin + cisplatin + fluorouracil [10]
ELF: etoposide + fluorouracil + leucovorin [4]
PELF: cisplatin + epidoxorubicin + leucovorin + fluorouracil with
glutathione and filgrastim [11]

References:

  1. Comis RL, Carter SK: Integration of chemotherapy into combined modality treatment of solid tumors. III. Gastric cancer. Cancer Treatment Reviews 1(3): 221-238, 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. Journal of the American Medical Association 253(14): 2061-2067, 1985.

  3. Kelsen D, Atiq OT, Saltz L, et al.: FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer. Journal of Clinical Oncology 10(4): 541-548, 1992.

  4. Ajani JA, Ota DM, Jackson DE, et al.: Current strategies in the management of locoregional and metastatic gastric carcinoma. Cancer 67(1): 260-265, 1991.

  5. Wils JA, Klein HO, Wagener DJ, et al.: Sequential high-dose methotrexate and fluorouracil combined with doxorubicin - a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. Journal of Clinical Oncology 9(5): 827-831, 1991.

  6. Macdonald JS, Schein PS, Woolley PV, et al.: 5-Fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Annals of Internal Medicine 93(4): 533-536, 1980.

  7. Douglass HO, Lavin PT, Goudsmit A, et al.: An Eastern Cooperative Oncology Group evaluation of combinations of methyl-CCNU, mitomycin C, Adriamycin, and 5-fluorouracil in advanced measurable gastric cancer (EST-2277). Journal of Clinical Oncology 2(12): 1372-1381, 1984.

  8. Moertel CG, Rubin J, O'Connell MJ, et al.: A phase II study of combined 5-fluorouracil, doxorubicin, and cisplatin in the treatment of advanced upper gastrointestinal adenocarcinomas. Journal of Clinical Oncology 4(7):1053-1057, 1986.

  9. Gastrointestinal Tumor Study Group: Triazinate and platinum efficacy in combination with 5-fluorouracil and doxorubicin: results of a three-arm randomized trial in metastatic gastric cancer. Journal of the National Cancer Institute 80(13): 1011-1015, 1988.

  10. Waters JS, Norman A, Cunningham D, et al.: Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. British Journal of Cancer 80(1/2): 269-272, 1999.

  11. Cascinu S, Labianca R, Alessandroni P, et al.: Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer. Journal of Clinical Oncology 15(11): 3313-3319, 1997.


RECURRENT GASTRIC CANCER

Because survival is poor with all available single and multimodal approaches to treatment, patients should be considered candidates for phase I and II clinical trials testing new anticancer drugs or biologicals. A role for antifolates, cisplatin and its analogues, and for pharmacologic modulation may be developing.[1] Patients with obstructive tumors in the gastric cardia may be relieved of dysphagia by endoscopic Nd:Yag or electrocautery destruction of the obstructing lesion. Radiation therapy may also help control bleeding, pain, and obstruction.

Treatment options:

Palliative chemotherapy with:
fluorouracil [2]
FAMTX: fluorouracil + doxorubicin + high-dose methotrexate [3-5]
FAM: fluorouracil + doxorubicin + mitomycin-C [6]
FAP: fluorouracil + doxorubicin + cisplatin [1,7]
ELF: etoposide + fluorouracil + leucovorin [4]
FLAP: fluorouracil + leucovorin + doxorubicin + cisplatin [8]
PELF: cisplatin + epidoxorubicin + leucovorin + fluorouracil with
glutathione and filgrastim [9]

References:

  1. Gastrointestinal Tumor Study Group: Triazinate and platinum efficacy in combination with 5-fluorouracil and doxorubicin: results of a three-arm randomized trial in metastatic gastric cancer. Journal of the National Cancer Institute 80(13): 1011-1015, 1988.

  2. Comis RL, Carter SK: Integration of chemotherapy into combined modality treatment of solid tumors. III. Gastric cancer. Cancer Treatment Reviews 1(3): 221-238, 1974.

  3. Kelsen D, Atiq OT, Saltz L, et al.: FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer. Journal of Clinical Oncology 10(4): 541-548, 1992.

  4. Ajani JA, Ota DM, Jackson DE, et al.: Current strategies in the management of locoregional and metastatic gastric carcinoma. Cancer 67(1): 260-265, 1991.

  5. Wils JA, Klein HO, Wagener DJ, et al.: Sequential high-dose methotrexate and fluorouracil combined with doxorubicin - a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. Journal of Clinical Oncology 9(5): 827-831, 1991.

  6. Macdonald JS, Schein PS, Woolley PV, et al.: 5-Fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Annals of Internal Medicine 93(4): 533-536, 1980.

  7. Moertel CG, Rubin J, O'Connell MJ, et al.: A phase II study of combined 5-fluorouracil, doxorubicin, and cisplatin in the treatment of advanced upper gastrointestinal adenocarcinomas. Journal of Clinical Oncology 4(7):1053-1057, 1986.

  8. Vaughn DJ, Meropol NJ, Holroyde C, et al.: A phase II study of 5-fluorouracil, leucovorin, adriamycin, and cisplatin (FLAP) for metastatic gastric and gastroesophageal junction adenocarcinoma: a Penn Cancer Clinical Trial Group and Roswell Park Cancer Institute Community Oncology Research Program Trial. American Journal of Clinical Oncology 20(3): 242-246, 1997.

  9. Cascinu S, Labianca R, Alessandroni P, et al.: Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer. Journal of Clinical Oncology 15(11): 3313-3319, 1997.

Date Last Modified: 10/1999



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