Gastric Cancer: A Primer on the Epidemiology and Biology of the Disease and an Overview of the Medical Management of Advanced Disease

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  • 1 From the Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, and the Department of Medicine, Weill Medical College of Cornell University, New York, New York.

Gastric cancer is a cause of significant morbidity and cancer-related mortality worldwide. Despite recent advances in targeted therapy and understanding of the biology and development of the malignancy, progress in the treatment of gastric cancer has been limited. Most newly diagnosed patients will present with incurable disease, and have a median survival of less than 1 year. Although the disease has widespread ethnic and epidemiologic differences, medical management of gastric cancer does not distinguish among the various disease subtypes. The recent report of the ToGA phase III study has validated Her2 as a molecular target in this disease, supporting the concept that a greater understanding of the biology of gastric cancer subsets may improve treatment selection and overall outcome of individual patients. This article summarizes the epidemiology and ethnic variation of this disease to crystalize subtypes of gastric cancer in the context of current and future medical management of advanced disease.

Gastric cancer is a global disease that represents an enormous global health burden. Although its incidence in the United States has declined over the past several decades,1 it remains a significant health problem throughout Southeast Asia, Eastern Europe, and Central America. Gastric cancer is the second most common cause of cancer-related deaths worldwide, with 700,349 deaths annually,2 and is the third most common malignancy worldwide, with 974,000 new cases in 2000. Gastric cancers are often grouped together, although the disease has considerable clinical and pathologic differences, distinguished by disease location, histology, and molecular characteristics. As the heterogeneity of this disease and its clinical consequences become better understood, the hope is that expanded screening and treatment options will improve patient outcomes and that distinct biologic subtypes can be characterized to allow for application of targeted therapies.

Many chemotherapeutic agents are active in the treatment of gastric adenocarcinoma. Modern combination chemotherapy regimens are easier to administer, better tolerated, and have shown modest but real gains in response rates and patient outcomes compared with earlier regimens. Long-term survivors are possible; many studies report that approximately 10% to 15% of patients newly diagnosed with metastatic disease will survive for 2 years and as many as 3% will survive 5 years. Finally, with the integration of molecularly targeted therapy, survival rates are expected to improve even further. This article summarizes the emerging biology and epidemiology of this disease and provides an overview of the current medical management of advanced disease.

Understanding the Diversity of Gastric Cancer: Environmental and Genetic Risk and Diverse Epidemiology
Three Different Types of Gastric Cancer

Virtually all stomach cancers are adenocarcinomas that can be pathologically distinguished as intestinal or diffuse according to the Lauren's classification.3 Intestinal gastric cancers are more prevalent in high-incidence areas and are responsible for much of the observed global ethnic variation.4 In contrast, the incidence of diffuse gastric cancer is approximately the same regardless of geography or race. Diffuse gastric cancer is far more infrequent than intestinal gastric cancer, occurring at an incidence of 4.7 of 100,000 people compared with 8.6 of 100,000 people for intestinal gastric cancer.5 A third subtype of gastric cancer has emerged in epidemiologic studies over the past several decades: gastric cardia/gastroesophageal junction (GEJ) tumors.6,7 Table 1 provides a summary of commonly identified risk factors for the development of gastric cancer categorized by disease subtype.

Non-Cardia Gastric Cancer: The pathogenesis of intestinal non-cardia gastric cancer follows a multistep progression that is likely initiated by chronic inflammation (e.g., as a result of Helicobacter pylori infection,8,9 chronic gastritis, or autoimmune gastritis). The disease progresses through chronic gastritis, intestinal metaplasia, and dysplasia.10,11 Environmental factors that increase the risk for developing the non-cardia gastric cancer include tobacco, high salt intake (reviewed by Wang et al.12), and alcohol consumption. Prospective studies have shown a significant dose-dependent relationship between smoking and gastric cancer risk, with the hazard ratio (HR) for distal gastric cancer ranging from 1.5 to 2.1.13,14 The use of nonsteroidal anti-inflammatory drugs reduces risk, with an estimated HR of 0.67 (95% CI, 0.56–0.80),15 as does eating a diet high in fruits and vegetables, with an estimated HR of 0.66 to 0.77.13,16

Diffuse Gastric Cancer: Diffuse gastric cancer has no known precursor lesion, although mutation or epigenetic silencing of the E-cadherin gene seems to be a key carcinogenic event.17 E-cadherin loss is seen through immunohistochemistry in approximately 50% of patients with sporadic diffuse gastric cancer, and confirmed by genome sequencing,18 suggesting that this pathway may present a common precursor event in the development of diffuse gastric cancer, distinct from the chronic inflammation and gastric atrophy that characterize intestinal non-cardia gastric cancer.

Table 1

Summary of Environmental, Clinical, and Genetic Risk Factors Associated with Gastric Cancer

Table 1

Hereditary diffuse gastric cancer (HDGC) is a genetic predisposition syndrome that was defined in 1999 by the International Gastric Cancer Linkage Consortium (IGCLC).19,20 HDGC is caused by loss of function mutations in the E-cadherin (CDH1) gene. The current recommendation for patients harboring a CDH1 mutation is prophylactic gastrectomy, which is believed to dramatically reduce the risk for developing gastric cancer.21 Notably, HDGC represents approximately 30% of all familial gastric cancers. The genetic origin of the remainder is yet to be identified.22

Proximal Gastric Cancer (Gastric Cardia and GEJ): Proximal gastric cancer is commonly grouped together with GEJ and distal esophageal adenocarcinoma. Perhaps the strongest epidemiologic evidence supporting proximal gastric cancer as distinct from non-cardia gastric cancer is the differential effect of H pylori infection on the development of these diseases. Specifically, although H pylori infection is associated with increased risk for developing noncardia gastric adenocarcinoma, infection with H pylori seems to protect against the development of more proximal tumors in some case-control cohort studies.23,24 Severe atrophic gastritis and reduced acid production, a common consequence of chronic H pylori infection, significantly reduces the risk for gastrointestinal reflux disease (GERD),25,26 thereby presumably reducing the risk for proximal gastric/GEJ adenocarcinoma related to GERD. However, other studies have found conflicting results on whether H pylori eradication therapy increases the risk for proximal gastric cancer.7 Thus, although whether H pylori infection protects against the development of proximal gastric cancer is unknown, H pylori is clearly not associated with an increased risk for developing proximal gastric cancer, thereby distinguishing it from distal gastric cancer.

Ethnic Diversity of Gastric Cancer

In 2008, an estimated 21,500 new cases of gastric cancer were diagnosed (14th most common cancer diagnosis) and 10,880 deaths occurred (13th most common cause of cancer death) in the United States.27 Incidence in the United States has a marked ethnic variation, with minority populations having an age-standardized risk for gastric cancer almost twice that of the white population. According to statistics provided by the National Cancer Institute (SEER data; http://seer.cancer.gov/) for the years between 2002 and 2006, Caucasians were only 57% as likely as African Americans to be diagnosed with stomach cancer and 46% to 62% as likely as other minority ethnic groups to develop gastric cancer (Table 2). Table 2 also shows that minority populations in the United States have the highest disease-specific mortality, whereas Asian/Pacific Islander patients seem to have the best survival.

These observations are consistent with large registry28 and single institution studies.29 In a large SEER-based epidemiology study, Byfield et al.30 compared the presentation and outcome of Asian-Pacific Islanders with United States non-Hispanic white patients with gastric cancer. The investigators compared Asian-Pacific Islanders born in the United States with those born abroad, and found that only the foreign born Asian-Pacific Islanders had a more favorable survival than non-Hispanic whites (HR, 0.86, 95% CI 0.82–0.90).30 This study highlights the role of environment on patient presentation and outcome.

Gastric cancer not only is a racially diverse disease with a significantly increased incidence in United States minority populations but also shows a marked racial health disparity, with black patients having an apparently more aggressive phenotype and worse prognosis, and Asians having the best prognosis. Dietary and socioeconomic factors among these groups are unlikely to explain the variation in incidence and mortality, thereby implicating differences in disease biology that will likely need to be elucidated as this disease is managed globally.

Table 2

SEER Incidence and United States Mortality Age-Adjusted Rates by Race/Ethnicity and Gender

Table 2
Clinical Implications of Biologic Variation

Clinical implications of gastric cancer disease biology are increasingly being identified. For example, although adjuvant chemoradiation was established as a standard treatment option in 2001,31 a recent update of the INT-0116 study suggested that the subset of patients with diffuse gastric cancer seemed to experience less benefit from adjuvant chemoradiation than those with other types of gastric cancer.32 Alternatively, diffuse gastric cancer seemed to have improved survival in a subset analysis in the First-Line Advanced Gastric Cancer Study (FLAGS), which compared cisplatin/S1 versus cisplatin/fluorouracil (FU).33 Another example of heterogeneity is shown with adjuvant chemotherapy. In one large prospective study from Japan, adjuvant S1 was established as a standard care option.34 However, adjuvant chemotherapy has not been established in the West, and a recent study from Italy again failed to show a benefit of even more intensive adjuvant chemotherapy.35 This discord suggests possible biologic differences between Asian and Western patients that require further investigation.

These studies suggest clinical implications of disease biology and reinforce the need for an improved understanding of the diverse and heterogenous nature of gastric cancer. The hope is that understanding the differences in subtypes of gastric cancer and the molecular underpinnings of the notable racial differences will enable investigators to more easily identify molecular drivers that may be therapeutically exploited to improve medical management of the disease.

Medical Management of Advanced, Incurable Disease

Chemotherapy for treating metastatic gastric cancer has a benefit over best supportive care, as shown in 4 randomized trials.3639 A meta-analysis of 3 studies reported an HR of 0.39 (P < .00001) for overall survival favoring chemotherapy.40 Additionally, patients undergoing chemotherapy more frequently had an improved or prolonged higher quality of life than those undergoing best supportive care (P < .05).36 Notably, none of these trials used cisplatin or other current chemotherapy agents known to have activity in gastric cancer (e.g., docetaxel, irinotecan, oxaliplatin, and capecitabine), suggesting that palliation with chemotherapy may offer a greater benefit than previously reported.

With chemotherapy, median survival for metastatic disease from gastric cancer is approximately 8 to 10 months. Although rare, extended survival has been described (10%–18%).4143 Several prognostic indexes have been developed to differentiate good-, intermediate-, and poor-risk patients.4447 Generally, as validated by The Royal Marsden Hospital in 2009,44 important prognostic factors include performance status and extent of metastatic disease. First-line therapy generally includes a platinum (cisplatin) and fluoropyrimidine (CF), and a minority of patients undergo second-line therapy.48 Many trials and meta-analyses have shown that combination chemotherapy is superior to single-agent therapy.40 Tables 3 and 4 describe several significant phase III trials with current 3- and 2-drug chemotherapy regimens.

Three-Drug Combination Therapy

Two primary approaches are available for 3-drug chemotherapy regimens for treating advanced gastric adenocarcinoma: cisplatin and fluoropyrimidine with either epirubicin (ECF) or docetaxel (DCF). The addition of epirubicin to CF has never been formally compared with CF alone in a phase III randomized trial, but ECF has become an accepted standard regimen, with overall survival and quality-of-life benefits.40,49,50

One study that randomized 574 patients to treatment with either ECF or mitomycin/CF (MCF) showed that response to therapy (42.4% vs. 44.1%, respectively) and survival (median survival, 9.4 months vs. 8.7, respectively) were equivalent.49 Although ECF appeared to have greater toxicity, global quality-of-life scores were maintained in the ECF arm.49

An incremental improvement in overall survival was also reported in a large randomized phase II/III trial comparing DCF with CF alone.43 Notably, although the dose intensity of cisplatin and FU was identical in both arms (cisplatin, 25 mg/m2/week, and FU, 1000 mg/m2/week), the absolute dose of cisplatin and FU administered during each treatment was less in the DCF arm, presumably to permit the addition of docetaxel.43 The addition of docetaxel to CF showed significant improvements in all measures of efficacy: time-to-treatment failure (primary end point) improved from 3.7 to 5.6 months (HR, 1.47; P < .001), median overall survival improved from 8.6 to 9.2 months (HR, 1.29; P = .02), and response rate increased (25% vs. 37%; P = .01). However, although the toxicity observed with DCF was anticipated, it was still of concern. Specifically, 82% of patients developed grade 3/4 neutropenia, with 29% experiencing febrile neutropenia.43 The DCF regimen showed a significant improvement in rate of decline in performance status51 and decrease in rate of decline in global health status.52 Based on these data, the FDA and the European Union approved DCF in the first-line treatment setting for advanced (incurable) gastric cancer.

Table 3

Recent Phase III Systemic Chemotherapy Trials for Metastatic or Unresectable Gastric Cancer Evaluating 3-Drug Chemotherapy Regimens

Table 3
Table 4

Recent Phase III Trials of Current Chemotherapy Regimens Using 2-Drug Combinations

Table 4

However, despite the reported clinical benefit, the toxicity with DCF remains significant, and the regimen as currently designed is best limited to highly functioning patients with minimal comorbidity.53 Furthermore, significant effort has been made to modify this regimen to reduce toxicity while maintaining efficacy.5456 One particular study reported by the Swiss Group for Clinical Research examined a phase II random assignment study of an alternative DCF regimen (FU administered as a 3-week low-dose infusion), compared with ECF and docetaxel and cisplatin (DC).56 In this study, DC plus infusional FU regimen appeared to be superior to DC in response (36.6% vs 18.4%). However, both DCF and DC had similar overall survival (10.4 vs. 11.0 months). ECF seemed to have an intermediate response rate (25%), with median survival of 8.3 months,56 but was the only regimen with an improvement in global quality of life scores at 4 months. A formal phase III study of DCF versus ECF has not been performed, and probably will not. Both regimens have merits and drawbacks; for instance, DCF perhaps has a quicker time to response56 but greater toxicity (using cross-trial comparison).49,56,57

The authors have reported on an alternative, or modified DCF (mDCF) regimen in the phase II setting.54,58 This regimen involves 48-hour infusional FU administered with every-other-week dosing of cisplatin and docetaxel and seems to have reduced toxicity compared with parent DCF.58 A formal random assignment phase II evaluation of mDCF versus parent DCF with growth factor support is ongoing (http://www.clinicaltrial.gov/ct2/show/NCT00515411) with final results anticipated in 2011.58

The REAL-2 study was a large 2 x 2 random assignment study evaluating the equivalency of oxaliplatin to cisplatin, and capecitabine to infusional FU.59 The motivation for this study was to limit toxicity, and thus the study was powered for noninferiority at an HR of 1.23 (i.e., a regimen is considered equivalent to the standard ECF arm if it was within 23% of ECF activity).60 The study enrolled 1002 patients from June 2000 to May 2005, with results showing that oxaliplatin is equivalent to cisplatin and capecitabine is equivalent to infusional low-dose FU. Median survivals were 10.9 and 9.6 months for capecitabine and FU, respectively, and 10.4 and 10.0 months for oxaliplatin and cisplatin, respectively.60

Based on these data, 2 primary 3-drug combination regimens remain for first-line therapy of incurable gastric cancer: DCF (or similar) or ECF (or equivalent regimen).

Two-Drug Combination Therapy and Salvage Therapy

Patient selection is critical when considering 3-drug chemotherapy. Patients with gastric cancer commonly present with symptoms reflective of the primary tumor site and metastases. For example, gastric cancer commonly spreads to the peritoneum leading to early compromise of bowel function, causing the common presenting symptoms of fatigue, weight loss, abdominal pain, and nutritional impairment.56 In the V-325 study, 57% of enrolled patients had more than a 5% loss in weight in the 3 months before study initiation and more than 80% had symptoms referable to their disease.52

Therefore, many patients with gastric cancer may present with a compromised performance status and would not be good candidates to undergo 3-drug combination therapy. In these patients, 2-drug combination alternatives may be more tolerable and provide a better clinical outcome. Although none of the random assignment phase III studies comparing doublet chemotherapy regimens have shown superiority (see Table 4), several regimens have reported improvement in the side effect profile. For example, oxaliplatin plus FU and leucovorin (FLO) was associated with significantly less nausea, vomiting, fatigue, thromboembolic events, and serious adverse events than cisplatin plus FU and leucovorin (FLP), although at the expense of peripheral neuropathy.61 Similarly, in a separate random assignment study involving irinotecan, fewer patients discontinued irinotecan/FU than CF because of toxicity; irinotecan-based therapy was associated with significantly less myelosuppression and stomatitis.62

Randomized phase III studies involving doublets again show that oxaliplatin and capecitabine are both noninferior to FU, with a more manageable toxicity profile.61,63 Irinotecan-based regimens are also active and equivalent to cisplatin-based therapy, and again have less toxicity.62 Most data supporting S-1 are from Japan and Asia, and trials in Western populations have been disappointing.64 As understanding of the biology of gastric cancer improves, particularly with regard to chemotherapy sensitivity and resistance, certain cytotoxic therapies may become preferred for certain gastric cancer disease subtypes. However, these data are currently sparse and have not been confirmed clinically.

Table 5

Selected Second-Line Phase II Studies for Incurable Gastric Cancer

Table 5

The many available treatment options allow for second-line or salvage treatment in patients who develop resistance to first-line therapy and have maintained an adequate performance status. Median time to progression after first-line chemotherapy for metastatic gastric cancer is typically 3 to 5 months.65

No second-line regimen has been established, and historically only a minority of patients are considered for second-line treatment. No mature phase III data have compared second-line chemotherapies; however, in one study, Thuss-Patience et al.66 described 40 patients randomly assigned to best supportive care or irinotecan single-agent treatment. Although small, a significant advantage was seen for second-line chemotherapy over best supportive care (4.4 vs. 2.6 months; P = .0027).66 Table 5 summarizes selected recent studies evaluating second-line salvage regimens in incurable gastric cancer. Notably, patients who were well enough to receive second-line therapy performed remarkably well. Specifically, median time to progression ranged from 2 to 4 months, and overall survival ranged from 5 to almost 11 months, without significant toxicity. Together, these studies show that second-line therapy indeed should be considered for functional patients who experience progression on first-line therapy.

Targeted Therapy for Gastric Cancer
Her2-Positive Gastric Cancer

Her2 is a member of the epidermal growth factor receptor family of tyrosine kinase receptors responsible for cell growth, survival, adhesion, migration, and differentiation. Her2-driven cancer cells can be targeted several ways. Trastuzumab is a monoclonal antibody with high affinity for the Her2 receptor and inhibits Her2 signaling when bound to the receptor.67 Lapatinib is an oral tyrosine kinase inhibitor of both Her2 and EGFR (Erb1), and is approved in combination with chemotherapy for Her2-positive breast cancer.68 For Her2-positive gastric cancer, compelling and practice-changing data now show a benefit of trastuzumab plus chemotherapy.

The ToGA phase III study compared trastuzumab plus cisplatin/capecitabine with cisplatin/capecitabine alone for metastatic Her2-positive gastric cancer.69 Her2-positive gastric cancer was defined as fluorescence in situ hybridization-positive and/or a score of IHC 3+, and the primary end point was overall survival. Among 3807 patients centrally tested for Her2 status, 22.1% were Her2-positive. In the final patient population of 584 patients, the addition of trastuzumab to cisplatin/capecitabine significantly improved median overall survival from 11.1 to 13.8 months (HR, 0.74; 95% CI, 0.60–0.91; P = .0046).69 Secondary end points of progression-free survival and response were also significantly improved with the addition of trastuzumab, without adding toxicity. Specifically, no differences in congestive heart failure were seen between the treatment arms.69

Table 6

Select First-Line Combination Phase II Studies of Chemotherapy With an Antiangiogenic Agent

Table 6

For Her2-positive gastric cancer, the addition of trastuzumab to chemotherapy is now a standard of care option. Lapatinib has shown single-agent activity in Her2-amplified gastric cell lines, is additive or synergistic with chemotherapy,70 and is currently being examined in the first-line setting for Her2-positive gastric cancer, in addition to chemotherapy (LOGIC, http://clinicaltrials.gov/ct2/show/NCT00680901).

Her2 expression also highlights differences in gastric cancer subtypes. Although Her2 positivity was the same between Europe (23.6%) and Asia (23.5%), Her2 positivity was higher in GEJ (33.2%) than gastric cancer (20.9%), and was higher for intestinal gastric cancer (32.5%) than for diffuse (6%).71

Antiangiogenic Therapy in Gastric Cancer

Angiogenesis inhibition has also proven encouraging in phase II evaluation (Table 6). The initial study of irinotecan, cisplatin, and bevacizumab was instrumental in developing this class of targeted therapy in this disease. Concerns about using antiangiogenic agents stem from the risk for upper gastrointestinal bleeding and perforation in patients with gastric cancer. The authors confirmed that the addition of bevacizumab to chemotherapy was not associated with an increase in gastrointestinal bleeding,72 and the risk for perforation was not significantly greater than with chemotherapy alone.73 A subsequent study of a mDCF with bevacizumab was also noteworthy, showing a median overall survival of 16.2 months in 44 previously untreated patients with metastatic or unresectable gastroesophageal cancer.54 Similar results were seen with the addition of sorafenib to docetaxel and cisplatin, further supporting the examination of antiangiogenic inhibition in advanced gastric cancer.74 A pivotal phase III trial, AVAGAST (NCT00548548), combining bevacizumab with platinum/fluoropyrimidine, has recently completed accrual with results expected in 2010.

Conclusions

Gastric cancer is an aggressive disease with a high mortality rate. Despite recent progress in cancer treatments, survival for patients with metastatic gastric cancer has not significantly improved. However, with improved understanding of the epidemiology of the disease and ability to categorize it into distinct clinical and pathologic entities, the hope is that therapy for advanced gastric cancer will also improve. Most modern combination regimens are easy to administer and well tolerated, and outcomes have improved over time. The integration of targeted therapy is promising, and will usher the treatment of gastric cancer into a new era. This, coupled with an improved understanding of the biology of the disease in effort to better select patients for particular therapy, will significantly improve treatment paradigms for this deadly disease, with the hope of also improving patient survival.

Dr. Shah has disclosed that he receives research support from sanofi-aventis and GlaxoSmithKlne. Dr. Kelsen has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in the article or their competitors.

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    Chau I, Norman AR, Cunningham D. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer—pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004;22:23952403.

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    Ajani JA, Moiseyenko VM, Tjulandin S. Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group. J Clin Oncol 2007;25:32103216.

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    Van Cutsem E, Moiseyenko VM, Tjulandin S. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006;24:49914997.

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Correspondence: Manish A. Shah, MD, 1275 York Avenue, H910, New York, NY 10065. E-mail: shah1@mskcc.org
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