Gastric Cancer

Overview

Gastric cancer is more common than esophageal cancer in Western countries but is less fatal. An estimated 26,370 new cases of gastric cancer will be diagnosed in the United States in 2016, with approximately 10,730 deaths from the disease. Worldwide in 2012, gastric cancer developed in approximately 930,000 individuals annually, accounting for 10% of neoplastic deaths. The incidence and mortality of gastric cancer have been declining in most developed countries, including the United States; the age-adjusted risk (world estimate) fell 5% from 1985 to 1990.

Gastric cancers include malignant tumors arising from the region extending between the gastroesophageal junction and the pylorus; those arising in the stomach within 5 centimeters of the gastroesophageal junction and actually crossing it are considered esophageal cancers. It may not be possible to determine the site of origin if the cancer involves the gastroesophageal 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; mortality is approximately double 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 more frequently in American blacks and Asians than in 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. While relatively rare in North America and many European nations, gastric cancer is still common in Japan, the former Soviet Union, and parts of Central America and South America.

Survival

Most patients still present with advanced disease, and their survival remains poor. From 1999 to 2006, only 23% of patients with gastric cancer presented with localized disease. The relative 5-year survival rate for patients with gastric cancer of all stages is 26%.

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 have fallen for men and women between 1975 and 2007.

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; those with refrigeration available may have some mitigation of the risk associated with high salt intake. 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, though alcohol exposure does not have a clear relation to risk of gastric cancer.

Helicobacter pylori

Helicobacter pylori, which colonizes approximately half of the world’s population, 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 as 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 an approximately threefold to fourfold increase in the 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.

Intestinal Metaplasia

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

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).

Gastrectomy

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 abnormalities of the adenomatous polyposis coli (APC) gene are seen in over 50%. The significance of these findings is not clear at present.

Overexpression, amplification, and/or mutations of oncogenes c-Ki-ras, HER2/neu (also known as 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.

Interleukin gene polypmorphisms are associated with gastric cancer risk, with some increasing the chances of developing disease and at least one appearing to be protective.

Gastric cancer may be part of several inherited cancer syndromes, including familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, BRAC1, BRCA2, and Li-Fraumeni syndrome. Hereditary diffuse gastric cancer occurs due to mutations in the E-cadherin (CDH1) gene. Studies of prophylactic gastrectomy in carriers demonstrate high rates of occult cancers, approximating 80%.

Carriers of mismatch repair gene mutations have an increased risk of developing gastric cancer.

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 cyclooxygenase 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.

Eradication of H pylori should decrease the incidence of gastric cancer by preventing it, and pilot trials assessing this strategy have been undertaken in Central and South America.

Signs and Symptoms

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

Hematemesis

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 surgical technique and 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

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, and EUS is particularly accurate in differentiating early T-stage from late T-stage disease. Furthermore, perigastric regional nodes (including the celiac access) 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.

Laparoscopy

Laparoscopy is particularly suited to detect small-volume visceral and peritoneal metastases missed on a 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

Positron emission tomographic (PET) scanning may be used to show distant metastatic disease and may also be helpful in assessing response to neoadjuvant therapy. In the latter setting, PET response correlates with better survival. As many as 40% of gastric cancers may not be detected by PET, and this modality may not be optimal for staging tumors of mucinous histology. It does not have an established role in routine preoperative imaging of potentially resectable patients as a single modality, but it is incorporated into staging when combined with CT imaging.

Pathology

Adenocarcinoma

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

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 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

Metastatic spread of disease from primaries in other organs (eg, breast cancer and melanoma) is also seen occasionally.

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. In younger women, the ovaries are at risk (Krukenberg tumors).

Staging and Prognosis

At present, epithelial gastric cancers are most commonly staged by the tumor-node-metastasis staging system (TNM) system (Table 1). Lymphomas, carcinoids, and sarcomas are not covered by these TNM criteria. The most recent update of the TNM does include a system encompassing GISTs, but this system is not yet widely used.

TABLE 1: TNM staging system for gastric cancer

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 endothelial growth factor (VEGF) and the presence of carcinoembryonic antigen (CEA) in peritoneal washings predict poor survival in surgically resected patients. 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.

It has long been known that survival rates for patients with gastric cancers are higher in Asian nations than in the United States, but it was not clear whether this represents results of superior surgical techniques or racial differences in underlying biology. Recent analysis of outcomes in Asian Americans vs white patients suggests that true differences exist in tumor biology, though the specifics have not yet been identified.

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 now have better-defined roles as adjuncts to surgery and in patients with unresectable tumors. Perioperative chemotherapy and chemoradiation therapy remain 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, although use of the findings to guide further treatment remains uncertain.

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 gastroesophageal 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 of nonulcerated T1 N0 lesions and pylorus-preserving gastrectomy. Laparoscopic resections are also being performed more frequently, with data from two randomized trials (KLASS and JCOG0912) showing no significant differences regarding morbidity and mortality between open and laparoscopic procedures to date for early-stage gastric cancer.

Extent of lymphadenectomy. The extent of lymph node resection, including the number of nodes 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. To support current TNM staging criteria, 16 or more lymph nodes should be obtained at minimum 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. Recent population data reviews have linked higher total lymph node numbers (up to 40) to superior survival.

Initial data in 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. An update of the randomized Dutch D1D2 trial has demonstrated a significant advantage to D2 dissection at 15 years in terms of deaths from gastric cancer (37% after D2, 48% after D1 dissection, P = .01). In addition, a significant long-term survival advantage was conferred by D2 dissection in female patients who underwent curative resection (35% vs 21%, P = .03) and in patients with stage II (33% vs 15%, P = .03) or N2 diseases (19% vs 0%, P = .07). Interestingly, the beneficial D2 dissection impact on local recurrence and survival does not seem to be enhanced by postoperative chemoradiotherapy, whereas chemoradiotherapy appears to improve both categories after mere D1 dissections. Gastrectomy with extended lymphadenectomy should primarily be performed in specialized centers by experienced surgeons, and splenectomy and pancreatectomy should be avoided; for adequate staging, at least 16 lymph nodes should be removed and analyzed.

Reconstruction methods. After distal gastrectomy, Billroth I gastroduodenostomy or, more commonly, Billroth II gastrojejunostomy methods are acceptable 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 usually performed.

Resection of extragastric organs. 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 (so-called conversion therapy), or it may be used in advanced but resectable disease felt to be at high risk for recurrence following surgery alone.

The MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial investigated perioperative treatment with epirubicin, cisplatin, and continuous 5-fluorouracil (5-FU) infusion (ECF) vs surgery alone, demonstrating improvements in progression-free and overall survival rates with the addition of chemotherapy. A similar benefit for perioperative chemotherapy was found in the French FNLCC/FFCD study, reported by Ychou et al, in which patients were randomized to perioperative 5-FU plus cisplatin or surgery alone. This trial demonstrated a significant reduction in risk of disease recurrence and improvement in overall survival. These results have been nonconsistently confirmed in other large randomized trials; EORTC (European Organisation for Research and Treatment of Cancer) 40954, which closed early due to poor accrual, did not demonstrate a survival advantage for those getting purely neoadjuvant chemotherapy. Nonetheless, in resectable patients, perioperative chemotherapy added to surgery is now a standard of care in many parts of the world.

CROSS (the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study), reported by Oppedijk et al, randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (with the dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m² of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over a period of 5 weeks. Most patients enrolled in the CROSS trial (75%) had adenocarcinoma. With a median follow-up of 45 months, preoperative chemoradiation was found to improve median overall survival from 24 months in the surgery-alone group to 49.4 months (hazard ratio [HR] = 0.657; 95% CI = 0.495–0.871; P = .003). Additionally, preoperative chemoradiation improved the rate of R0 resections (92% vs 69%, P < .001). R0 is defined as complete resection with no tumor within 1 mm of resection margins. A complete pathologic response was achieved in 29% of patients who underwent resection after chemoradiation therapy.

Adjuvant Therapy

TABLE 2: Treatment and survival by stage in patients with gastric carcinoma

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 adjuvant therapy in the hope of improving treatment results. A North American Intergroup trial (INT116) randomizing resected patients (stages IB-IV[M0]) to receive chemoradiation with 5-FU plus leucovorin therapy or observation showed significant improvement in median disease-free survival (median 19 vs 30 months) and overall survival (26 vs 35 months) with adjuvant therapy. The Cancer and Leukemia Group B (CALGB) study 80101 compared intensified chemotherapy with ECF plus radiation compared with 5-FU and radiation and found no differences between these two regimens. Given these results, the use of postoperative chemoradiation therapy, usually with continuous infusion of 5-FU or capecitabine is the standard of care in the United States. Population studies have suggested that adjuvant therapy is underutilized in the United States.

Radiotherapy

Locoregional recurrence as a component of failure is common in patients undergoing curative resection for gastric cancer. 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 postoperative adjunct does not have a defined role in the United States. Individual randomized trials of chemotherapy plus surgery vs resection alone have mostly not demonstrated a definite survival advantage, with the possible exception of patients with widespread nodal involvement and older patients, who may do better with chemotherapy. Meta-analyses of postoperative chemotherapy plus surgery vs resection alone have shown minor reductions in death rates, but no specific regimen can be recommended. Alternative chemotherapy delivery methods such as intraperitoneal chemotherapy have been evaluated in phase III trials with promising results, and are an area of future study.

Neoadjuvant chemoradiation has also been explored as a way to improve tolerability of chemoradiation and to improve resectability and pathologic response rates compared with chemotherapy. A phase III randomized trial suggested that neoadjuvant treatment with chemotherapy and radiation provides superior pathologic outcomes compared with neoadjuvant chemotherapy. A trend toward improved survival with chemotherapy and radiation was seen. An ongoing phase III international trial (TOPGEAR) will evaluate the use of ECF preoperatively compared with 2 cycles of ECF followed by chemoradiotherapy with 5-FU and radiotherapy to 45 Gy. Both groups will receive 3 cycles of ECF postoperatively.

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 (INT-0116) previously 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 rates. 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 the 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. A 10-year update of this trial was published in 2012; Smalley et al reported that patients who were offered chemoradiation continued to enjoy improved survival (HR = 1.32) and disease-free survival (HR = 1.51).

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 to patients in North America who undergo initial gastrectomy. Studies by CALGB and other groups do not support that intensification of therapy above that delivered on INT0116 will improve disease-free or overall survival.

Newer radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT) and advanced image guidance, have been explored as a way to reduce the toxicity and improve accuracy of radiation treatments. These techniques may be especially helpful in reducing small bowel and kidney damage during chemoradiation, although data from large series are not yet available to confirm these results from small series.

A recent retrospective study from Korea evaluated chemoradiation compared with observation in patients who underwent a D2 dissection. Overall survival in this series was higher for patients who received adjuvant therapy, suggesting that a D2 dissection does not preclude the need for adjuvant therapy. This benefit, however, could be predominantly derived from the systemic treatment component. The role of radiation therapy in addition to capecitabine (Xeloda) and cisplatin was evaluated in a large Korean phase III trial of patients undergoing D2 gastrectomy (ARTIST [Adjuvant Chemoradiation Therapy in Stomach Cancer Trial]); there was no disease-free survival benefit from the radiation overall, but some benefit in the node-positive patient subset (HR = 0.69; P = .047). Another Asian trial (CLASSIC [Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer]) has shown a disease-free survival benefit to postoperative chemotherapy alone with capecitabine and oxaliplatin (Eloxatin) after D2 gastrectomy (3-year disease-free survival 74% vs 59%; HR = 0.56; P < .001).

Studies by the CALGB and other groups do not support that intensification of therapy with ECF above that delivered with 5-FU alone in INT0116 will improve disease-free or overall survival.

Imatinib mesylate (Gleevec) given for 3 years or longer now represents standard of care in the postoperative setting, for selected GIST patients. The American College of Surgeons Oncology Group (ACOSOG) Z9001 randomized trial found that 1 year of imatinib mesylate extends recurrence-free survival but not overall survival, compared with placebo following resection of intermediate- or high-risk GIST. On the placebo arm, KIT mutation in exon 11 was prognostic for worse recurrence-free survival; patients with rectal primaries receiving imatinib also had poorer outcomes. Interestingly, only one event occurred among patients harboring the PDGFR D842V mutation, believed to be imatinib-resistant. Thus, tumor pathology and mutational status were both prognostic and predictive of recurrence-free survival after surgical resection of GIST (Lancet 373: 1097–1104, 2009). The recently presented SSGXVIII/AIO trial showed a better recurrence-free survival and overall survival in patients with high-risk, resected GIST receiving 36 months of adjuvant imatinib, compared with 12 months of treatment.

In the Scandinavian Sarcoma Group Trial XVIII, reported in JAMA in 2012, patients with resected GISTs deemed to be at high risk of recurrence were randomized to imatinib mesylate, at 400 mg per day, for 1 vs 3 years. Those receiving the drug for a longer period had better 5-year relapse-free (66% vs 48%) and overall (92% vs 82%) survival. More patients getting therapy for a longer period of time had high-grade adverse events, possibly due simply to the prolonged exposure to toxic effects of therapy. A high fraction of those on the 3-year arm dropped out (26%), other than for reasons of recurrence, raising the question of how to improve compliance when administering postoperative targeted therapies.

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 Gastrectomy and Regional Therapies for Advanced Disease

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. Regional therapy with preoperative intraperitoneal and systemic therapy and hyperthermic intraperitoneal chemotherapy (HIPEC) have recently been explored as methods to reduce rates of peritoneal failures in patients with peritoneal carcinomatosis. Although promising results have been generated in trials utilizing regional therapy, it has not yet become a part of standard therapy.

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. Several randomized chemotherapy trials have suggested improvement in survival and probably quality of life vs best supportive care alone across first and second lines of therapy.

Single-agent drug therapy

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

TABLE 3: Chemotherapy regimens for gastric cancer

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, though it remains unclear whether doublets or triplets represent ideal therapy (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 NCCTG (North Central Cancer Treatment Group) 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 are associated with markedly better response rates and longer survival in early trials than in phase III studies. No combination has been confirmed as superior. However, ECF (epirubicin, cisplatin, 5-FU) 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 vs cisplatin and 5-FU; however, grade 3/4 toxic events occurred in 81% of patients treated with triple therapy. Modifications of this regimen have been proposed. The search for the optimal combination regimen continues, with the promising newer agents usually 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. Oxaliplatin- and cisplatin-containing regimens have been compared, with the former perhaps being more efficacious. Additionally, regimens substituting oral capecitabine for intravenous 5-FU are popular because of ease of administration and fewer catheter-related complications. S-1 is another version of an oral fluoropyrimidine. Phase III studies of S-1 in the West have been promising in regard to reduction of toxicity, but efficacy has not been superior. S-1 plus cisplatin improved survival for patients with advanced incurable gastric cancer patients vs S-1 alone in the Japanese SPIRITS trial.

Second-line therapy

Increasingly, patients with advanced/metastatic gastric cancer who progress through first-line chemotherapy maintain a good performance status and remain candidates for chemotherapy. There have been several clinical trials showing the benefit of docetaxel, irinotecan, and paclitaxel in the second-line setting.  Irinotecan was evaluated as a second-line therapy vs best supportive care (BSC) and revealed an overall survival benefit and an improvement in tumor-releated symptoms. Median overall survival was 4 months for patients treated with irinotecan (95% CI = 1.7–4.9) and 2.4 months for BSC (HR = 0.48; 95% CI = 0.25–0.92). The COUGAR-2 study, reported by Ford et al, evaluated docetaxel vs BSC; although response rates were low, there was an improvement in overall survival for patients receiving docetaxel (5.2 months vs 3.6 months; HR = 0.67; P = .01). Health-related quality-of-life measurements indicated no detrimental effect of chemotherapy, and potential improvements in pain and nausea. Another study, from Japan, was reported by Hironaka et al; it compared paclitaxel vs irinotecan in the second-line setting, and revealed similar overall survival results for the two study arms: 9.5 months and 8.4 months, respectively. Second-line treatment now represents a standard of care in gastric cancer, for patients who maintain a good performance status. 

Targeted Therapy in Gastric Cancer

Biomarkers and novel agents

Whole genome molecular profiling of gastric cancers has identified a number of somatic gene mutations and pathways that may be driving carcinogenesis in cancers of the upper gastrointestinal tract. These potential therapeutic targets include signaling pathways such as epidermal growth factor receptor (EGFR), VEGF receptor, human epidermal growth factor receptor 2 (HER2), AKT, mTOR (mammalian target of rapamycin), FGFR (fibroblast growth factor receptor), MEK (mitogen-activated protein kinase kinase), and others. Determining the dominant pathway of individual tumor promotion would theoretically allow for selection of a rational treatment. Other ways in which to tailor therapy include determining mechanisms of resistance to treatment by assessing gene expression levels in the pathways for metabolism of these drugs. 

Identifying a target

HER2. HER2 is a member of the EGFR family, and amplification of HER2 is noted in 7% to 34% of gastric cancer cases. Amplification of HER2 may predict resistance to conventional modalities of treatment. ToGA was a randomized phase III study to evaluate the anti-HER2 monoclonal antibody trastuzumab (Herceptin) in combination with chemotherapy in metastatic/recurrent HER2-expressing gastric cancer. The study screened 3,807 patients, of whom 22.1 % were found to be positive; 594 patients were randomized to fluoropyrimidine plus cisplatin with or without trastuzumab. A statistically significant improvement in overall survival, from 11.1 months to 13.8 months (HR = 0.74; 95% CI = 0.60-0.91, P = .0046) was reported for the patients receiving trastuzumab. A post-hoc analysis of HER2 expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis, reported by Bang et al, revealed that patients with high expression of HER2 (IHC2+ and FISH-positive or IHC3+) had a significantly improved overall survival compared with patients who had low expression (IHC 0 or 1+ and FISH-positive). This was the first study to incorporate a biologic agent into the treatment of upper gastrointestinal cancer, with practice-changing results. Ongoing studies are incorporating trastzumab into perioperative therapy in esophagogastric cancer. In addition, the availability of novel HER2-targeting agents such as pertuzumab, trastuzumab emtansine (T-DM1), and the dual anti-HER2 and anti-HER3 antibody MM-111 expands the possibilities for further investigation in this setting.

EGFR. The EGFR pathway is thought to play a role in the pathogenesis of upper gastrointestinal cancers. Several phase II studies have evaluated immunoglobulin G1 (IgG1) monoclonal antibodies and tyrosine kinase inhibitors in this setting, both as single agents and in combination with chemotherapy. EXPAND was a randomized phase III, international, multicenter study evaluating capecitabine plus cisplatin with or without cetuximab in 904 untreated, unselected patients with advanced, unresectable esophagogastric cancer. This study, reported by Lordick et al, did not meet its primary endpoint of significantly prolonging progression-free survival (4.4 months vs 5.6 months), nor did it have a significant impact on overall survival (9.4 months vs 10.7 months) or response (29% vs 30%). REAL-3 was a randomized phase III trial evaluating combination chemotherapy with epirubicin, oxaliplatin, and capecitabine, with or without panitumumab (Vectibix) in an unselected population with gastroesophageal junction cancer. The results, reported by Okines et al, revealed a worsening of overall survival (8.8 months vs 11.3 months; HR = 1.37, P = .013) for patients receiving panitumumab. An exploration of molecular correlates, in an attempt to identify which patients may have responded to treatment, has not clearly defined a biomarker. Second-line studies of cetuximab used as a single agent and in combination with irinotecan (eg, by Schoennemann et al and Gold et al) have not met their primary endpoints. Thus, further study of EGFR-directed therapy has not improved patient outcomes in this population.

Dual targeting. In the Southwest Oncology Group (SWOG) trial S0413, dual targeting of the EGFR pathway with the human epidermal growth factor receptor 1 (HER1) and HER2 tyrosine kinase inhibitor lapatinib demonstrated a modest single-agent response rate (7%) in esophagogastric cancers. Subsequent studies of this agent in combination with chemotherapy have yielded disappointing results. The TRIO-013/LOGiC trial, reported by Hecht et al, evaluated 487 patients with HER2-positive advanced gastroesophageal adenocarcinoma who were randomized to capecitabine plus oxaliplatin with or without lapatinib. The primary endpoint, overall survival, was 12.2 months vs 10.5 months (HR = 0.91; 95% CI = 0.73–1.12; P = .35) in the lapatinib arm vs the control arm. A prespecified subgroup analysis showed that Asian patients in this trial may have experienced an improvement in survival with lapatinib, as may patients under 60 years of age. TyTAN, a trial of second-line therapy, accrued 261 HER2-amplified Asian patients with advanced gastric cancer and randomly assigned them to receive paclitaxel with or without lapatinib. The combination led to a non-significant 2.1-month improvement in overall survival, Bang reported. Among patients in the prespecified subgroup with strong HER2 positivity, statistically significant benefits were shown for the combination, in terms of both overall and progression-free survival. Afatinib, an irreversible pan-HER inhibitor, is under investigation in trastuzumab-refractory advanced disease (ClinicalTrials.gov identifier: NCT01522768) but has no known role in locally advanced disease at this time.

VEGF inhibition. Multiple trials of monoclonal antibodies and tyrosine kinase inhibitors targeting the VEGF/angiogenic pathway have been reported, with several promising phase II studies leading to phase III studies. The randomized phase III AVAGAST trial evaluated capecitabine plus cisplatin with or without bevacizumab as first-line treatment for patients with advanced gastric cancer. The 773 patients accrued demonstrated a median overall survival of 10.1 months with placebo and 12.1 months with bevacizumab (HR = 0.87; P = .1002). Progression-free survival, the secondary endpoint, was significantly longer (29.5 vs 38 months; P = .0121) for patients receiving bevacizumab. In a post hoc subgroup analysis, regional differences were noted, in that Asian-Pacific patients had a better overall survival, independent of other prognostic variables. Patients from Europe and the Americas with one or more unfavorable prognostic factors also appeared to derive a survival benefit with bevacizumab (6.8 months vs 11.5 months in North and South America and 12.1 months vs 13.9 months in Europe), Ohtsu et et reported. In the second-line setting, an unselected population of patients treated with VEGFR inhibition has led to a positive results. Ramucirumab, a fully human, IgG1 monoclonal antibody that inhibits VEGFR2, was evaluated vs best supportive care in REGARD, a placebo-controlled, double-blind, randomized phase III international trial. Fuchs et al reported that among 355 patients with metastatic gastric or gastroesophageal junction adenocarcinoma, those who received ramucirumab had a median overall survival of 5.2 months, compared with 3.8 months for placebo; this translated into a 28% reduced risk of dying (P = .0473). Based on these results, ramucirumab received FDA approval in this patient population. The RAINBOW study was a randomized, multicenter, double-blind, placebo controlled phase III clinical trial of weekly paclitaxel with or without ramucirumab in patients with metastatic gastric cancer who progressed on first-line therapy with platinum and fluoropyrimidine. As Wilke et al reported, this study demonstrated significantly prolonged overall survival, from a median of 7.36 months to 9.63 months (P = .0169). Thus, multiple studies have shown that targeting the VEGF pathway in the second-line setting with ramucirumab has consistently led to positive results for patients with advanced gastric cancer. An understanding of appropriate patient selection may guide future studies in the setting of locally advanced disease.

c-Met. c-Met, a cell surface receptor for hepatocyte growth factor (HGF), regulates multiple cellular processes such as cell proliferation, invasion, and angiogenesis. High levels of c-Met are associated with a more aggressive gastric/gastroesophageal junction cancer phenotype. Rilotumumab, a fully humanized monoclonal antibody designed to inhibit the hepatocyte growth factor/scatter factor (HGF/SF)/Met pathway, was evaluated in a randomized phase II trial, in which biomarker analysis showed benefit was greatest for patients with high Met expression. Unfortunately, two randomized phase III trials-RILOMET 1 and the MetGastric study-evaluating monoclonal antibodies targeting the HGF ligand and its receptor, respectively, have been reported as negative (see Shah et al, ASCO 2015 abstract 4012, and Cunningham et al, ASCO 2015 abstract 4000). Given these findings, at this time there is no role for Met-pathway inhibition therapy with our current selection biomarker. 

DNA repair capacity in relation to ERCC1 mRNA levels. The nucleotide excision repair, or NER, pathway has been identified to repair bulky, helix-distorting DNA lesions caused by platinum compounds. Recognition and repair of the platinum-induced damage results in platinum resistance. Critical in this pathway is the ERCC1 gene (and protein), and low expression has been associated with platinum sensitivity. Several studies across tumor types have evaluated ERCC1 mRNA levels and potential response to outcome in patients treated with platinum compounds. ERCC1 has shown a statistically significant relationship to response and survival in patients with advanced gastric cancer. The SWOG 1201 trial (ClinicalTrials.gov identifer: NCT01498289) is randomizing patients to platinum-containing (FOLFOX) vs non–platinum-containing (docetaxel and irinotecan) regimens to validate ERCC1 prospectively. 

Conclusions

As novel therapeutics are increasingly introduced into the armamentarium of cancer care, oncologists may consider targeted therapy for diseases with limited treatment options and poor outcomes. Unfortunately, among patients with gastric or gastresophageal cancer, only trastuzumab (in  HER2-positive patients) and ramucirumab have advanced survival. All other agents of interest, have led to negative randomized phase III studies in unselected populations. Accrual to clinical trials needs to be encouraged to allow for identification of patient populations who may benefit from identifiable therapies, targeting driving pathway in those particular tumor types. The goal is to understand the molecular biology of these diseases to offer patients rationally designed therapeutic plans.

Suggested Reading

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