Gastric Cancer

April 16, 2009
Charles D. Blanke, MD, FACP

,
Deborah Citrin, MD

,
Roderich E. Schwarz, MD, PhD

Gastric cancer is more common than esophageal cancer in Western countries but is less fatal. More than 21,000 new cases of gastric cancer will be diagnosed in the United States in the year 2008, with 10,880 deaths expected. Worldwide, gastric cancer represents approximately 930,000 new cases and accounts for more than 700,000 deaths. The incidence and mortality of gastric cancer have been declining in most developedcountries, including the United States; the age-adjusted risk (world estimate) fell 5% from 1985-1990.

Gastric cancer is more common than esophageal cancer in Western countries but is less fatal. More than 21,000 new cases of gastric cancer will be diagnosed in the United States in the year 2008, with 10,880 deaths expected. Worldwide, gastric cancer represents approximately 930,000 new cases and accounts for more than 700,000 deaths. The incidence and mortality of gastric cancer have been declining in most developedcountries, including the United States; the age-adjusted risk (world estimate) fell 5% from 1985-1990.

Gastric cancer is defined as any malignant tumor arising from the region extending between the gastroesophageal (GE) junction and the pylorus. It may not be possible to determine the site of origin if the cancer involves the GE junction itself, a situation that has become more common in recent years.

Epidemiology

Gender Gastric cancer occurs more frequently in men, with a male-to-female ratio of 2.3:1.0; mortality is approximately doubled in men.

Age The incidence of gastric cancer increases with age. In the United States, most cases occur between the ages of 65 and 74 years, with a median age of 70 for males and 74 for females.

Race Gastric cancer occurs 2.2 times more frequently in American blacks than whites; in black males, it tends to occur at a younger age (68 years).

Geography Evidence of an association between environment and diet and gastric cancer comes from the profound differences in incidence seen in various parts of the world. Almost 40% of cases occur in China, where it is the most common cancer, but age-adjusted incidence rates are highest in Korea.

Survival Most patients still present with advanced disease, and their survival remains poor. From 1989 to 1995, only 20% of patients with gastric cancer presented with localized disease. The relative 5-year survival rate for gastric cancer of all stages is 24%.

Incidence Significant increases in age-adjusted incidence rates for tumors arising in the gastric cardia have been seen in males. Rates for other gastric adenocarcinomas either have not significantly changed (black males) or have declined (white males). Overall, rates of gastric adenocarcinoma rose for white females between 1974 and 1994.

Etiology, risk factors, and prevention

Diet and environment Studies of immigrants have demonstrated that high-risk populations (eg, Koreans) have a dramatic decrease in the risk of gastric carcinoma when they migrate to the West and change their dietary habits. Low consumption of vegetables and fruits and high intake of salts, nitrates, and smoked or pickled foods have been associated with an increased risk of gastric carcinoma. Conversely, the increasing availability of refrigerated foods has contributed to the decline in incidence rates. Recent laboratory data from Japan suggest that oolong tea may contain a substance that can kill stomach cancer cells.

Occupational exposure in coal mining and processing of nickel, rubber, and timber has been reported to increase the risk of gastric carcinoma. Cigarette smoking may also increase the risk.

Intestinal metaplasia, a premalignant lesion, is common in locations where gastric cancer is common and is seen in 80% of resected gastric specimens in Japan.

Individuals with blood group A may have a greater risk of gastric carcinoma than individuals with other blood groups. The risk appears to be for the infiltrative type of gastric carcinoma (rather than the exophytic type).

Gastric resection Although reports have suggested that patients undergoing gastric resection for benign disease (usually peptic ulcer disease) are at increased risk of subsequently developing gastric cancer, this association has not been definitely proven. Gastric resection may result in increased gastric pH and subsequent intestinal metaplasia in affected patients.

Pernicious anemia Although it has been widely reported that pernicious anemia is associated with the subsequent development of gastric carcinoma, this relationship also has been questioned.

Genetic abnormalities The genetic abnormalities associated with gastric cancer are still poorly understood. Abnormalities of the tumor-suppressor gene TP53 (alias p53) are found in over 60% of gastric cancer patients and the adenomatous polyposis coli (APC) gene, in over 50%. The significance of these findings is not clear at present.

Overexpression, amplification, and/or mutations of oncogenes c-Ki-ras, HER-2/neu (aka c-erb-b2), and c-myc most likely play a role in the development of some gastric neoplasms. A high S-phase fraction has been associated with an increased risk of relapse as well.

E-cadherin has been linked to diffuse-type gastric cancer (see sidebar).

Family history Family members of a patient with gastric cancer have a twofold to threefold higher risk of stomach cancer than the general population.

Prevention Recent studies strongly implicate cyclo-oxygenase 2 (COX-2) in the development of many human cancers, including gastric cancer. Potential mechanisms of oncogenesis include stimulation of tumor angiogenesis, inhibition of apoptosis, immune suppression, and enhancement of invasive potential.

Furthermore, COX-2 inhibitors have been shown to decrease the size of gastric adenomas in mice. This information strongly suggests that COX-2 inhibitors may play a role in the prevention, and even treatment, of GI tumors. However, trials with COX-2 inhibitors in other advanced GI malignancies, such as colon cancer, have not been positive, so patients should not be treated with these agents outside the setting of a clinical trial.

Helicobacter pylori infection is associated with gastric lymphomas and adenocarcinomas. The overall risk of developing malignancy in the presence of infection is low; however, more than 40% to 50% of gastric cancers are linked with H pylori. The bacterium has been designated a class I carcinogen. Antibiotics alone can cure localized, node-negative MALT (mucosa-associated lymphoid tissue) lymphomas in about 50% of patients. With regard to gastric adenocarcinoma, H pylori infection is associated with a 2.8-fold increase in the relative risk of the disease compared with uninfected controls. Data from Japan and China suggest that H pylori infection can lead to chronic atrophic gastritis. This condition appears to be a major risk factor for gastric cancer. Eradication of H pylori should thus decrease the incidence of gastric cancer by preventing it.

Signs and symptoms

Most gastric cancers are diagnosed at an advanced stage. Presenting signs and symptoms are often nonspecific and typically include pain, weight loss, vomiting, and anorexia.

Hematemesis is present in 10% to 15% of patients.

Physical findings Peritoneal implants to the pelvis may be palpable on rectal examination (Blumer's shelf). Extension of disease to the liver may be appreciated as hepatomegaly on physical examination. Nodal metastases can be found in the supraclavicular fossa (Virchow's node), axilla, or umbilical region.

Ascites can accompany advanced intraperitoneal spread of disease.

Screening and diagnosis

Routine screening for gastric cancer is generally not performed in Western countries because the disease is so uncommon. However, screening appears more effective in high-incidence areas. Mass screening, as has been practiced in Japan since the 1960s, has probably contributed to the 2.5-fold improvement in long-term survival compared with Western countries, though differences in biology may also play a role.


 

Endoscopy and barium x-rays The diagnosis of gastric cancer in a patient presenting with any constellation of the symptoms previously described revolves around the use of upper endoscopy or double-contrast barium x-rays. The advantage of endoscopy is that it allows for direct visualization of abnormalities and directed biopsies. Barium x-rays do not facilitate biopsies but are less invasive and may provide information regarding motility.

CT scan Once a diagnosis has been established and careful physical examination and routine blood tests have been performed, a CT scan of the chest, abdomen, and pelvis should be obtained to help assess tumor extent, nodal involvement, and metastatic disease. CT may demonstrate an intraluminal mass arising from the gastric wall or focal or diffuse gastric wall thickening. It is not useful in determining the depth of tumor penetration unless the carcinoma has extended through the entire gastric wall. Direct extension of the gastric tumor to the liver, spleen, or pancreas can be visualized on CT, as can metastatic involvement of celiac, retrocrural, retroperitoneal, and porta hepatis nodes. Ascites, intraperitoneal seeding, and distant metastases (liver, lungs, bone) can also be detected.

Endoscopic ultrasonography (EUS) is a staging technique that complements information gained by CT. Specifically, depth of tumor invasion, including invasion of nearby organs, can be assessed more accurately by EUS than by CT. Furthermore, perigastric regional nodes are more accurately evaluated by EUS, whereas regional nodes farther from the primary tumor are more accurately evaluated by CT. Specific ultrasonographic features may aid in the diagnosis and staging of patients with gastric lymphomas.

Capsule video endoscopy A capsule containing a tiny camera is swallowed by the patient. Two pictures per second are taken. Once clinical studies demonstrated that the procedure was safe and effective, the US Food and Drug Administration (FDA) cleared this device for clinical use in 2001. The capsule can be especially helpful in imaging the small intestine.

Laparoscopy Laparoscopy is particularly suited to detect small-volume visceral and peritoneal metastases missed on CT scan. It should be performed prior to curative-intent locoregional therapy or preoperative chemoradiation therapy.

Bone scan A bone scan should be obtained if the patient has bony pain or an elevated alkaline phosphatase level.

PET scan PET scanning may be used to show distant and metastatic disease and may also be helpful in assessing response to neoadjuvant therapy. In the latter setting, PET response correlates with better survival.

Pathology

Adenocarcinoma is the predominant form of gastric cancer, accounting for approximately 95% of cases. Histologically, adenocarcinomas are classified as intestinal or diffuse; mixed types occur but are rare. Intestinal-type cancers are characterized by cohesive cells that form glandlike structures and are often preceded by intestinal metaplasia. Diffuse-type cancers are composed of infiltrating gastric mucous cells that infrequently form masses or ulcers.

Primary lymphoma of the stomach is increasing in frequency and, occasionally, may be difficult to distinguish from adenocarcinoma.

Stromal tumors GI stromal tumors (GISTs) are mesenchymal tumors of the GI tract, most commonly arising from the stomach. These tumors share an ancestor with, or arise from, the interstitial cells of Cajal (the pacemaker cells of the gut). GISTs commonly express KIT (CD117), but this is not required for diagnosis. Most GISTs have mutations in either the C-KIT or PDGFR (platelet-derived growth factor receptor) genes.

Other histologic types Infrequently, other histologic types are found in the stomach, such as squamous cell carcinomas, small-cell carcinomas, and carcinoid tumors. Metastatic spread of disease from primaries in other organs (eg, breast cancer and malignant melanoma) is also seen occasionally.

Metastatic spread Gastric carcinomas spread by direct extension (lesser and greater omentum, liver and diaphragm, spleen, pancreas, transverse colon); regional and distant nodal metastases; hematogenous metastases (liver, lungs, bone, brain); and peritoneal metastases. Multicentricity characterizes up to 20% of gastric cancers.

Staging and prognosis

At present, epithelial gastric cancers are most commonly staged by the TNM system. Stromal tumors, lymphomas, carcinoids, and sarcomas are not covered by these TNM criteria. The most recent update of this staging system (Table 1) allows for a more precise nodal classification based on the number of lymph nodes involved.

A more detailed Japanese staging system has been shown to have prognostic importance in gastric cancer. However, these results have not yet been duplicated in the United States, and this system is not widely used around the world. Resected GISTs can be assigned a numeric risk of recurrence based on tumor size, mitotic rate, and location of the primary.

Prognostic factors Aneuploidy may predict a poor prognosis in patients with adenocarcinoma of the distal stomach. High plasma levels of vascular endo-thelial growth factor (VEGF) and the presence of carcinoembryonic antigen (CEA) in peritoneal washings predict poor survival in surgically resected patients.

As with colorectal cancer, intratumoral levels of dihydropyrimidine dehydrogenase (DPD) may be prognostic of gastric cancer; low levels appear to predict better response to fluorouracil (5-FU)–based chemotherapy and longer survival.The prognostic implications of tumor-suppressor genes and oncogenes are an area of active investigation. Patients with cancers of the diffuse type fare worse than those with intestinal-type lesions.

Treatment

PRIMARY TREATMENT OF LOCALIZED DISEASE

Management of gastric cancer relies primarily on surgical resection of the involved stomach, with reconstruction to preserve intestinal continuity, as resection provides the only chance for cure. Radiotherapy and chemotherapy have potential roles as adjuncts to surgery and in patients with unresectable tumors. Preoperative chemo and chemoradiation therapy are active areas of current investigation.

Surgery

The objectives of operative treatment for potentially curable gastric cancers are confirmation of resectability, performance of a complete resection, facilitation of appropriate pathologic staging, and reestablishment of GI continuity and function.


 

Confirmation of resectability Laparoscopy has emerged as an excellent tool to assess the extent of disease and resectability before the surgeon performs an open laparotomy. Laparoscopy adds to the accuracy of preoperative imaging primarily in cases of peritoneal spread or small liver metastases. As a result, morbidity, hospital stay, and costs have been reduced significantly in patients with unresectable lesions. In addition, peritoneal washings can be obtained. 

The initial experience with laparoscopic ultrasonography has shown that its value lies in identifying lesions with a high risk of recurrence (T2b or >, N+), for which a preoperative chemotherapy protocol may be available.

Extent of resection The extent of gastric resection depends on the site and extent of the primary cancer. Subtotal gastrectomy is preferred over total gastrectomy, because it leads to comparable survival but lower morbidity. A 5-cm margin of normal stomach appears to be sufficient in proximal and distal resections. For lesions of the GE junction or the proximal third of the stomach, proximal subtotal gastrectomy can be performed. If total gastrectomy is necessary, transection of the distal esophagus and proximal duodenum is required, and omentectomy is performed. In Japan, there is a growing experience with more limited resections of early-stage gastric cancer. This trend includes endoscopic mucosal resection (EMR) of nonulcerated T1 N0 lesions and pylorus-preserving gastrectomy. Laparoscopic resections are also being performed more frequently.

Extent of lymphadenectomy The extent of lymph node resection, including the number removed at the time of gastrectomy, continues to be controversial. Preferably, lymphadenectomy includes the lymphatic chains along the celiac, left gastric, splenic, and hepatic arteries, which allows for more precise lymph node staging. The exact level designation of lymph nodes varies with the site and intragastric location of the primary tumor. Based on the TNM staging criteria, 15 or more lymph nodes should be obtained and examined for an accurate N classification. Removal of lymph nodes immediately adjacent to the stomach (paracardial, paragastric at the lesser or greater curvature, parapyloric) has been termed D1 dissection. A more extensive D2 dissection would also remove retroperitoneal “second echelon” lymph nodes along the celiac trunk, left gastric artery, hepatic artery, splenic artery, and splenic hilus.

Improved long-term survival rates for Japanese patients had been attributed to the extended lymphadenectomies routinely performed in this country. Because the improvement in survival after gastrectomy during recent decades was usually associated with the performance of extended lymph node dissections (D2 dissections or greater), this practice appeared to be sensible if performed with acceptable complication rates. Retrospective data had shown that D2 lymphadenectomy is safe and does not increase morbidity.

O

n the other hand, two European randomized trials showed no significant differences in overall long-term survival between D1 and D2 dissection groups. Both studies found higher postoperative morbidity and mortality in the D2 (extended) group, largely due to a higher rate of splenectomy and/or partial pancreatectomy performed with those dissections. When a subset of patients with N2 disease were studied in long-term follow-up in the Dutch randomized trial, a survival advantage was shown with D2 dissection. Extended lymphadenectomy should primarily be performed in specialized centers by experienced surgeons, and splenectomy and pancreatectomy should be avoided; for adequate staging, at least 15 lymph nodes should be removed and analyzed.

Reconstruction methods After distal gastrectomy, Billroth I gastroduodenostomy or, more commonly, Billroth II gastrojejunostomy is an appropriate method for reconstruction. Reflux esophagitis is a common problem when the gastric reservoir is too small. After total or subtotal gastrectomy, a Roux-en-Y esophagojejunostomy is commonly performed.

Resection of extragastric organs may be required to control T4 disease. Such a resection can be associated with long-term survival. Splenectomy should be avoided unless it is indicated by direct tumor extension, because it significantly increases the rate of complications.

NEOADJUVANT THERAPY

Prompted by the promising results and acceptable toxicity of preoperative (neoadjuvant) chemoradiation therapy in other parts of the GI tract (eg, esophagus, rectum), there is growing interest in neoadjuvant therapy for gastric cancer. Neoadjuvant treatment may be performed in an attempt to convert an initially unresectable cancer to resectable status, or it may be used in advanced but resectable disease.

Most promising to date are the results from the European Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial using pre- and postoperative ECF (epirubicin, cisplatin, and 5-FU). Cunningham and associates randomized patients to receive preoperative and postoperative chemotherapy versus surgery alone. The 5-year survival rate for those offered systemic ECF therapy in addition to surgery was 36%, versus 23% for those who only underwent surgery. Chemotherapy also enhanced resectability. It remains to be seen whether these positive results, achieved with relatively uncommon (in the United States) chemotherapy and without irradiation, will lead to the adoption of this regimen in the United States.

ADJUVANT THERAPY

The 5-year survival rate after “curative resection” for gastric cancer is only between 30% and 40% (Table 2). Treatment failure stems from a combination of local or regional recurrence and distant metastases. Investigators have studied adjuvanttherapy in the hope of improving treatment results. A North American Intergroup trial randomizing resected patients (stages IB–IV[M0]) to receive chemoradiation therapy or observation showed significant improvement in median disease-free (median 19 vs 30 months) and overall (26 vs 35 months) survival with adjuvant therapy, and the use of postoperative chemoradiation therapy, usually with continuous infusion of 5-FU, is the standard of care in the United States. 

Radiotherapy

Radiotherapy can decrease the rate of locoregional failure but has not been shown to improve survival as a single postoperative modality. Postoperative radiotherapy may be appropriate in patients who are not candidates for chemotherapy.


 

Chemotherapy

Chemotherapy alone as a surgical adjunct does not have a defined role in the United States. Randomized trials of chemotherapy plus surgery versus resection alone have showed no definite survival advantage, with the possible exception of patients with widespread nodal involvement who may do better with chemotherapy. Interestingly, onemeta-analysis included both Western and Asian studies; it showed a significant survival benefit with the use of chemotherapy in the Asian trials, but there was no benefit in the Western studies, possibly due to differences in biology or drug metabolism. No specific regimen could be recommended.

Chemoradiation therapy

Patients with T3–T4 any N M0 tumors are at highest risk of locoregional recurrence after potentially curative surgery (surgery in which all macroscopic tumor has been resected with no evidence of metastatic disease) for gastric cancer. Even patients with node-negative disease (T3 N0) have a gastric cancer-related mortality of about 50% within 5 years. Mortality is significantly worse in patients with node-positive disease or in those with incomplete (R1, R2) resection.

In the North American Intergroup trial mentioned in the section on “Adjuvant therapy,” patients were randomized to receive chemoradiation therapy or observation following resection of stages IB–IV (M0) adenocarcinoma of the stomach. Chemoradiation therapy following resection of these high-risk patients significantly improved both disease-free and overall survival. Because of the apparent benefit of reducing locoregional recurrences, but not distant recurrences, it is possible that more routine use of D2 lymphadenectomy may modify this recommendation in the future. D2 lymphadenectomy was performed in only 10% of the patients in this trial. Subgroup analysis revealed that outcome did not differ based upon the type of lymphadenectomy (P = .80). Still, since only a small percentage of patients underwent the recommended D2 dissection, further research is necessary before firm conclusions can be made in this area.

Despite this trial, significant controversy regarding the need for adjuvant treatment persists and is perhaps growing. Many studies support the contention that aggressive, formal D2 resection may obviate the need for adjuvant treatment in many cases. Other studies and subgroup analyses support the recommendations for adjuvant treatment as concluded in the North American trial. These conflicting results, as well as distinct differences in results between Eastern and Western nations, suggest that this issue may take many years to resolve. In the interim, it is appropriate to recommend adjuvant chemoradiotherapy in the vast majority of cases in North America.

GISTs have a high risk of recurrence, even following complete resection. The American College of Surgical Oncologists performed a phase III trial of surgery alone versus surgery followed by 1 year of adjuvant imatinib (Gleevec) in patients with resected intermediate or high-risk gastrointestinal stromal tumors (GISTs). Accrual to the trial was halted early when it was apparent those given postoperative imatinib had a markedly lower 1-year relapse-free survival rate than did those treated with surgery alone (97% vs 83%; P = .0000014). Interestingly, there was no difference in overall survival, leaving open the question of whether patients should be treated immediately following surgery versus waiting for relapse and using imatinib in the salvage setting. Most North American GIST experts favor immediate imatinib.

Unresectable tumors

Patients with unresectable gastric cancers and no evidence of metastatic disease can be expected to survive approximately 6 months without any treatment.

Palliative resection Palliative resection, bypass, and/or stenting may be appropriate for some patients with obstructive lesions. Palliative resection may also be suitable for patients with bleeding gastric cancers that are not resectable for cure. Generally, resection appears to offer better palliative results than bypass.

Radiotherapy Radiation therapy alone can provide palliation in patients with bleeding or obstruction who are not operative candidates. Radiotherapy may convert unresectable cancers to resectable tumors.

Chemoradiation therapy Patients with locally advanced disease may be appropriately treated with chemoradiation therapy. This approach can provide relatively long-lasting palliation and may render some unresectable cancers resectable. Older studies have shown that postoperative chemoradiation therapy can reduce relapse rates and prolong survival in patients with incompletely resected stomach cancer.

MEDICAL TREATMENT OF ADVANCED GASTRIC CANCER

When possible, all newly diagnosed patients with disseminated gastric cancer should be considered candidates for clinical trials, and those with good performance status should be offered systemic therapy. Even though cure is not expected with chemotherapy, such treatment may provide palliation in selected patients and sometimes durable remissions. At least four randomized chemotherapy trials have suggested improvement in survival and probably quality of life versus best supportive care alone.

Single-agent therapy

Several agents have established activity in gastric cancer: 5-FU, platinums (cisplatin, oxaliplatin [Eloxatin], and carboplatin,mitomycin, etoposide, some anthracyclines (doxorubicin and epirubicin), taxanes (paclitaxel and docetaxel [Taxotere]), irinotecan, antimetabolites (pemetrexed [Alimta], methotrexate, trimetrexate (Neutrexin), and oral fluoropyrimidines (uracil and tegafur [UFT], S-1, capecitabine [Xeloda]). 5-FU and cisplatin have been used most commonly. The responses seen with single-agent chemotherapy have been traditionally partial and mostly short-lived, with little, if any, impact on overall survival.

Novel agents recently tested in patients with advanced gastric cancer include the epidermal growth factor receptor inhibitor cetuximab (Erbitux) and the VEGF inhibitor bevacizumab (Avastin). Bevacizumab appears promising when given with chemotherapy.

Combination chemotherapy

Response rates are consistently higher when combination chemotherapy regimens are used in gastric cancer. Combination therapy has been generally preferred over single agents (Table 3).

In the 1980s, the combination of 5-FU, doxorubicin, and mitomycin (FAM) was considered the standard regimen in the treatment of advanced gastric cancer. However, the North Central Cancer Treatment Group (NCCTG) randomly compared this regimen with 5-FU plus doxorubicin and single-agent 5-FU and found no difference in survival among the patients treated with the three regimens.

Several different regimens, including FAMTX (5-FU, doxorubicin, and methotrexate) and ELF (etoposide, leucovorin, and 5-FU), have been tested. Most regimens show markedly better response rates and longer survival in early trials than in phase III studies. No combination has been confirmed as superior.


 

However, ECF approaches standard of care in Canada and in some parts of Europe. This regimen has proved superior to FAMTX in terms of objective response rate and survival and superior to the mitomycin, cisplatin, 5-FU (MCF) regimen in terms of toxicity. A combination of docetaxel, cisplatin, and 5-FU was shown to offer superior survival rates versus cisplatin and 5-FU; however, grade 3/4 toxic events occurred in 81% of patients treated with triple therapy. The search for the optimal combination regimen continues, with the promising newer agents being introduced in combination regimens.

Newer agents with somewhat similar mechanisms of action to those of classic drugs have been tried in patients with advanced gastric cancer. S-1, alone or in combination, is particularly promising (see sidebar).

Gastric cancer patients should be encouraged to participate in well-designed clinical trials. Outside experimental regimens, the recommended therapy for patients with good performance status is a 5-FU- or cisplatin–based regimen.

Chemotherapy in the elderly

The benefits of chemotherapy for the general population with metastatic gastric cancer are well established. Until recently, however, there were few trials examining systemic treatment in the elderly.

Trumper and associates examined the results of 1,080 patients entered onto three randomized trials of chemotherapy and compared the outcomes between patients aged 70 and older and those younger than age 70. There were no significant differences in grade 3/4 hematologic or nonhematologic toxicities. Additionally, no significant differences were identified in response rates between the age groups. Multivariate analysis controlling for performance status, locally advanced disease status, and treatment showed no significant differences in overall or failure-free survival by age. The authors concluded that patients with gastric cancer aged 70 and older obtain the same benefit as younger patients from palliative chemotherapy with respect to symptomatic and standard responses and survival without increased toxicities.

SUGGESTED READING

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 25:3205–3209, 2007.

Bennett JJ, Gonen M, D’Angelica M, et al: Is detection of asymptomatic recurrence after curative resection associated with improved survival in patients with gastric cancer? J Am Coll Surg 201:503–510, 2005.

Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11–20, 2006.

Cunningham D, Jost LM, Purkalne G, et al: ESMO Guidelines Task Force. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of gastric cancer. Ann Oncol 16(suppl 1):i22–i23, 2005.

Cunningham D, Starling N, Rao S, et al: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36–46, 2008.

DeMatteo R, Owzar K, Maki R, et al: Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumors (GIST): North American Intergroup Phase III trial ACOSOG Z9001. Proc Am Soc Clin Oncol 25[18s]:10079, 2007.

Demetri GD, Benjamin RS, Blanke CD, et al: NCCN Task Force report: Management of patients with gastrointestinal stromal tumor (GIST)–Update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 59(suppl 2):S1–S29, 2007.

Di Bartolomeo M, Buzzoni R, Mariani L, et al: Feasibility of sequential therapy with FOLFIRI followed by docetaxel/cisplatin in patients with radically resected gastric adenocarcinoma: A randomized phase III trial. Oncology 71:341–346, 2006.

Hartgrink HH, van de Velde CJ, Putter H, et al: Extended lymph node dissection for gastric cancer: Who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol 22:2069–2077, 2004.

Miettinen M, Lasota J: Gastrointestinal stromal tumors: Pathology and prognosis at different sites. Semin Diagn Pathol 23:70–83, 2006.

Miner TJ, Jaques DP, Karpeh MS, et al: Defining palliative surgery in patients receiving noncurative resections for gastric cancer. J Am Coll Surg 198:1013–1021, 2004.

Nakajima T, Kinoshita T, Nashimoto A, et al: Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer. Br J Surg 94:1468–1476, 2007.

Sakuramoto S, Sasako M, Yamaguchi T, et al: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357:1810–1820, 2007.

Sasako M, Sano T, Yamamoto S, et al: Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia or subcardia: A randomised controlled trial. Lancet Oncol 7:644–651, 2006.

Smith DD, Schwarz RR, Schwarz RE: Impact of total lymph node count on staging and survival after gastrectomy for gastric cancer: Data from a large US-population database. J Clin Oncol 23:7114–7124, 2005.

Sumpter K, Harper-Wynne C, Cunningham D, et al: Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabinewith fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer 92:1976–1983, 2005.

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