Survival of metastatic gastric cancer: Significance of age, sex and race/ethnicity
Original Article
Survival of metastatic gastric cancer: Significance of age, sex and race/ethnicity
Dongyun Yang1*, Andrew Hendifar2*, Cosima Lenz1, Kayo Togawa1, Felicitas Lenz2, Georg Lurje2, Alexandra Pohl2, Thomas Winder2, Yan Ning2, Susan Groshen1, Heinz-Josef Lenz1,2
1Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA; 2Division of Medical Oncology, Sharon Carpenter Laboratory, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
* Both authors contributed equally to this work.
This work was funded by the NIH grant P30 CA 14089, supported by the San Pedro Guild and the Dhont Foundation.
Corresponding to: Heinz-Josef Lenz, MD, FACP. Sharon A. Carpenter Laboratory, Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90033. Tel: +1-323-865-3967, Fax: +1-323-865-0061. Email:
Background: Despite the success of modern chemotherapy in the treatment of large bowel cancers, patients with metastatic gastric cancer continue to have a dismal outcome. Identifying predictive and prognostic markers is an important step to improving current treatment approaches and extending survival.
Methods: Extracting data from the US NCI’s Surveillance, Epidemiology, and End Results (SEER) registries, we compared overall survival for patients with metastatic gastric cancer by gender, age, and ethnicity using Cox proportional hazards models. 13,840 patients (≥ 18 years) were identified from 1988-2004. Males and females were categorized by age grouping and ethnicity.
Results: 19% of Hispanic patients were diagnosed < 45 years of age as compared to 5.5% of Caucasians. Caucasian patients and men were more likely to be diagnosed with tumors in the gastric cardia (P<0.001). In our survival analysis, we found that women had a lower risk of dying as compared to men (P<0.001). Overall survival diminished with age (P<0.001). The median overall survival was 6 months in patients of ≤ 44 years old as compared to 3 months in patients 75 years and older. Gender differences in overall survival significantly varied by race and tumor grade/differentiation (P for interaction = 0.003 and 0.005, respectively).
Conclusion: This is the largest study of metastatic gastric cancer patients from the SEER registry to show that age, gender, and tumor location are significant independent prognostic factors for overall survival in patients with metastatic gastric cancer.
Key words
gastric cancer, gender, age, ethnicity, survival
J Gastrointest Oncol 2011; 2: 77-84. DOI: 10.3978/j.issn.2078-6891.2010.025
Although its incidence and mortality has declined over the last half-century, gastric cancer remains the fourth most common cancer and the second most frequent cause of cancer death in the world (1,2). The American Cancer Society estimates that in 2008, there were 21,500 new cases of gastric cancer and 10,880 deaths in the United States (3). As gastric cancer incidence declines, the frequency of prox imal gastric and gastroesophageal junctional adenocarcinomas continues to rise and has become a significant clinical challenge (4,5). There is substantial geographic variation in the incidence and mortality of gastric cancer, with the highest rates in East Asia and the lowest in North America (2). H. pylori infection, dietary factors, and smoking patterns may contribute to these disparities (6-9).
The survival rates for gastric cancer are among the worst of any solid tumor. Despite the success of modern chemotherapy in the treatment of large bowel cancers, the 5-year survival of patients with advanced gastric cancer is 3.1% (1,4). The role of surgery is also limited as only 23% of stage IV gastric cancer patients receiving a palliative gastrectomy are alive one year after surgery (4). Progress was recently made as treating Her-2-Neu (H2N) overexpressing gastric cancers with Traztuzumab was found to significantly improve survival (10). Identifying additional predictive and prognostic markers is an important step to improving current treatment approaches and extending survival.
Two distinct histologic types of gastric cancer, the “intestinal type” and “diffuse type”, have been described (11). The diffuse type of gastric cancer is undifferentiated and characterized by the loss of E-cadherin expression; an adhesion protein that helps maintains cellular organization (12). The well differentiated intestinal type is sporadic and highly associated with environmental exposures, especially H. pylori infection (13). There are also biologic differences between these subtypes of gastric cancer that may guide treatment approaches. H2N is over expressed more often in the intestinal vs the diffuse type, 30% vs 6% in one study (14). The Beta-catenin/Wnt signaling pathway is also recognized to play a large role in the molecular carcinogenesis of the intestinal type cancer (15).
Despite the genetic heterogeneity of gastric cancer, several biological determinants of risk and prognosis have been identified. Genetic polymorphisms of cytokines released with “oxidative stress” such as IL-Iβ, IL-10, and TNF-A have been associated with increased gastric cancer risk (16-18). Over expression of the oncogenes, tie-1, CMET and AKT have been found to confer a poor prognosis in both subtypes (19-21). Tumor expression of the isoenzyme COX-2 is an independent prognostic factor for gastric cancer survival (22). This benefit may be mediated by a reduction in lymphangiogenesis, another correlate of prognosis (22,23). Recently Her-2/Neu over expression, an important predictive and prognostic factor in breast cancer has been independently associated with a poor prognosis in gastric cancer (24,25).
The prognostic significance of age, gender, and ethnicity in metastatic gastric cancer is unclear. The prevailing belief that young patients with gastric cancer have a more aggressive disease has been recently called into question (26,27). Several prospective and population studies since 1996 have consistently shown that age is not a prognostic factor for survival, despite the higher prevalence of “diffuse type” cancer which typically has a worse outcome (28,29). However, according to a recent population-based study of gastric cancer, a significant impact of age on survival was found in patients with stage IV disease (30).
As compared to women, men are twice as likely to develop and die from gastric cancer, in the US (1). Although this may represent varying environmental exposures between genders, studies demonstrate that menstrual factors such as age of menopause and years of fertility are associated with gastric cancer incidence (31). Interestingly, woman may be more likely to have a “diffuse type histology” (32).
There are also significant ethnic and racial differences in gastric cancer incidence and survival. Asian patients consistently have increased survival rates compared to their western counterparts (33). Ethnic Asians living in the US share this benefit which suggests that these differences are not likely treatment related (34). Other racial differences in the US are notable as the incidence and mortality is 50% higher in African Americans than Caucasians (35).
Our study sought to evaluate the clinical correlates of survival in metastatic gastric cancer. Specifically we examined the inf luence of age, gender, ethnicity on survival. We also explored the interactions between patient characteristics and tumor histology, grade, size, and location (cardia vs non-cardia).
Patients and methods
Data source
Adult patients with metastatic gastric cancer were identified from the SEER registry 1988-2004 database, which collects information on all new cases of cancer from 17 populationbased registries covering approximately 26% of the US population.
Study population
The disease was defined by the following International Classification of Diseases for Oncology (ICD-O-2) codes: C16.0-C16.9. We identified patients (n=15,360) who had metastatic disease defined by SEER Extent of Disease code: 85. We restricted eligibility to adults (aged 18 years or older) who were diagnosed with metastatic gastric cancer (MGC) in 1988 and later (n=15,348); because the record of extent of disease was not available for accurate staging prior to 1988. We excluded cases (less than 10% of adult patients with metastatic gastric cancer) who were diagnosed at death certificate or autopsy, no follow-up records (survival time code of 0 months), as well as lacking documentation on race/ethnicity. A total of 13,840 MGC patients of 18 years and older were included in the final sample for the current analysis.
Variable definitions
Information on age at diagnosis, sex, race, and ethnicity, marital status, treatment type, primary site, tumor grade and differentiation, histology, tumor size, and lymph node involvement, and overall survival were coded and available in SEER database. The primary endpoint in this study was overall survival that was defined as the months lapsing from diagnosis to death. For the patients who were still alive at last follow-up, overall survival was censored at the date of last follow-up or December 31, 2004, whichever came first.
Age. We chose the cut points for age groups based on the previous studies (18-44, 45-54, 55-64, 65-74, and 75 and older).
Ethnicity. Patients were divided into five ethnic groups, “Caucasian” (Race/Ethnicity code, 1), “African American” (Race/Ethnicity code, 2), “Asian” (Race/Ethnicity code, 4-97), “Hispanic” (Spanish/Hispanic Origin code, 1-8), and Native American (Race/Ethnicity code, 3).
Primary site. According to the latest guidelines for gastric cancer classificationa, the stomach is anatomically delineated into the upper, middle, and lower thirds by dividing the lesser and greater curvatures at two equidistant points and joining these points. The sites were defined by the following codes from ICD-O-2: Cardia, (C16.0), Body (C16.1-2, C16.5-6), Lower (C16.3-4), and Overlapping lesion of stomach (C16.8). For the ones that are not specified, they were categorized together as Stomach, NOS (C16.9).
Marital status. Subjects were categorized into “Not married” (including never married, separated, divorced, widowed, and unknowns) and “Married” (including common law).
Treatment type. SEER variables, RX Summ-radiation and RX summ-surg prim site were used to define treatment types: “Surgery” for patients who had surgery (local tumor destruction and excision, and gastrectomy) and/no radiation, “Radiation therapy only” for patients who only had radiation therapy, “Untreated” for patients who did not have surgery nor radiation therapy, and “Unknown”. Information on chemotherapy was not available in SEER.
Grade. Grade was defined by the following ICD-O-2 codes; well/moderately differentiated (Code 1-2), poorly differentiated/undifferentiated (Code 3-4), and others (Code 5-9).
Histological type. Histological types were defined by the following ICD-O-3 codes: 8140- for adenocarcinoma, 8490 for Signet ring cell carcinoma, and the rest of the types were categorized as ‘Others’.
The size of the primary tumor and the presence of lymph node involvement were not of interest in the current analysis. Our cohort consisted entirely of patients with metastatic disease.
Statistical analysis
Subjects were grouped by age to 18-44, 45-54, 55-64, 65-74, and 75 and older. We stratified them by sex, race, marital status, treatment type, grade, histological type, and primary site. Descriptive statistics were calculated for categorical variables using frequencies and proportions. Sex, race, tumor grade, marital status, primary site, histological type, and treatment type were independent variables. Differences among age groups in each subgroup were evaluated using the chi-square test.
We constructed Cox proportional hazards models to examine the association between age and survival in men and female separately. We compared survival across age groups adjusting for potential confounders including geographic region and year of diagnosis. By conducting this ana lysis separately by gender, we were able to determine pattern differences between genders. The Cox proportional hazards model included year of diagnosis and participating SEER registry site as stratification variables. Marital status, treatment, primary site, histology, tumor grade and differentiation, size of primary tumor, and lymph node involvement were used as covariates. Hazard Ratios (HRs) and 95% confidence intervals were generated, with hazard ratios less than 1.0 indicating survival benefit (or reduced mortality). Pairwise interactions (age and sex, age and race, and sex and race) were checked using stratified models and were tested by comparing corresponding likelihood ratio statistics between the baseline and nested Cox proportional hazards models that included the multiplicative product terms (36). Departure of the proportional hazard assumption of Cox models will be examined graphically such as log-log survival curves or smoothed plots of weighted Schoenfeld residuals (37) and by including a time-dependent component individually for each predictor.
All analyses were conducted using P<0.05 as the significance level and statistical analyses were performed with the use of SAS software (version 9.1; SAS Institute, Cary, NC).
Patient baseline characteristics
The final cohort for analysis consisted of 13,840 patients, 8710 men (63%), and 5130 women (37%). Their age distribution is as follows: 1,207 (9%) aged 18−44; 1,698 (12%) aged 45−54; 2,701 (20%) aged 55−64; 3,901 (28%) aged 65−74; and 4,333 (31%) aged 75 years and older. The median age was 68 years (range: 18−104). 60% of the MGC cohort were White, 13% African American, 13% Asian, 14 % Hispanic, and 1% Native American. Tumor characteristics and treatment received are shown in Table 1.
Age and ethnicity in MGC
5.5 % of Whites with MGC were between 18-44 years of ages as compared to 10% of African Americans, 11% of Asians, and 19% of Hispanic patients. 36% of White gastric cancer patients were diagnosed over 75 years of age; 29% of Asian, 27% of AA, and 20% of Hispanic.
Tumor location: cardia vs non-cardia
The incidence of cardia and non-cardia tumors varied significantly depending on gender and ethnic background. 30% of men and 14% of women had gastric ca arising from the cardia. The incidence of cardia cancers also varied significantly across ethnicities. 32% of Whites had cardia primaries, 13% of AA’s, 11% of Asians, and 14% of Hispanics.
Survival analysis
The median overall survival (OS) in patients with MGC was only 4 months. The prognostic significance of several clinical and tumor characteristics were limited as the median OS varied little when stratified by sex, race, tumor site, grade/ differentiation, and histology (Table 1).
However, age, use of local treatment, tumor differentiation, and tumor site were found to have a clinically significant effect. The youngest group of patients had an improved OS when compared to their older counterparts (Table 1), as the median OS for patients 44 years or younger was 6 months compared to 3 months in patients 75 years or older. Survival was significantly worse in every successive age decile. Patients who had received any treatment had significantly improved survival. Gastrectomy or local surgery had a median OS of 8 months compared to a median OS of 3 months in patients who were not treated with surgery or radiation [HR = 0.600 (0.561, 0.643)] (Table 1). Similarly, patients receiving radiation treatment had a survival benefit [HR = 0.802 (0.746, 0.862)].
Tumor characteristics had a significant impact on survival. As expected, patients with poorly differentiated tumors had a worse survival than those with moderately or well differentiated tumors [HR 1.19, P
In multivariate analysis, sex, age, treatment, and tumor characteristics were significantly associated with overall survival. Females had lower risk of dying compared to males (HR=0.916, 95%CI: 0.881−0.952) and mortality increased with age at diagnosis (P<0.001, Table 1). There was no significant difference in OS across race/ethnicity groups (P=0.16, Table 1).
Sex, race, grade/differentiation and MGC
The effect of sex on OS was signif icantly varied by race and tumor differentiation in patients with MGC (Pfor interaction=0.003 and 0.005, respectively, Table 2). White and African American woman had significantly lower risk of dying compared to their male counterparts. In Asian, Hispanic, and Native American populations, men and women had equivalent survival (Table 2.) Women also had a significantly lower risk of dying compared to males in patients whose tumors were poorly differentiated or undifferentiated or had unknown tumor grade (Table 2).
This cohort of metastatic gastric cancer patients from the SEER database represents a wide cross-section of patients with variable socioeconomic and ethnic backgrounds. Our analysis also included a robust variety of pathology and is likely a more generalizable representation than can be found in clinical trials or case series.
As expected, we found tumor characteristics such as grade, differentiation, and histology were associated with survival in advanced gastric cancer. Notably, there was a survival advantage attributable to gastric cardia lesions when compared to non-cardia lesions. This sur vival advantage persisted after controlling for the increased prevalence of cardia lesions in Caucasians and men.
Survival differences between cardia and non-cardia lesions may reflect differences in pathogenesis and tumor biology. H. pylori infection is recognized as a unique risk factor for non-cardia lesions while gastroesophageal reflux disease plays a role in the development of proximal lesions (38,39). Interestingly, there is growing evidence that H2N expression is variably expressed in proximal and distal gastric cancer lesions (40). The proto-oncogene Her-2/neu (H2N) is located on chromosome 17q21 and encodes a transmembrane tyrosine kinase growth factor receptor featuring substantial homology with the EGFR (41,42). Over-expression of the H2N protein has been identified in from 10 to 34% of breast cancers and is associated with a poor prognosis (43). Over-expression of H2N has been reported in gastric and gastro-esophageal tumors (24). Additionally, there are studies describing H2N as a poor prognostic factor in gastric cancer (40). Further studies are needed to investigate its role in the development of proximal and distal gastric lesions.
In addition to tumor characteristics, patient features, such as age and sex, also had significant prognostic impact. Ethnicity – often described in gastric cancer literature as having a prominent prognostic role – had no effect on survival. We could not confirm previous reports that Asian and Hispanic patients with gastric cancer have an improved outcome. We did find that a higher percentage of Hispanic patients present at a younger age. 36% of our Hispanic patients presented at ages less than 54 yo vs 16% of white patients. These findings are consistent with a single institution study, which found that Hispanics present at a younger age when compared to other ethnicities (44).
After adjusting for sex, race, marital status , treatment type, primary site, histology, the year of diagnosis and SEER site, we found significant increased cancerspecific mortality among men and older age groups. The survival for our youngest age group was 2 fold higher than the oldest age group. Our findings do not confirm previous reports that younger patients with metastatic gastric cancer have poorer survival. Outside of treatment with surgery, young age was the best prognostic marker. We could not address the role of systemic chemotherapy on overall survival in the current study due to lack of information in SEER. This likely ref lects the higher rate of treatment we found in the younger patients and unlikely represents differences in tumor biology or kinetics.
Consistent with previous reports, we found that women with MGC lived longer than men. We did not find any association between gender disparities and age. Women of every age group, pre-and postmenopausal, had an equivalent survival advantage. When examined more closely, we found that this difference was limited to African American and White patients. There were no gender differences in the Hispanic and Asian patients. These differences were not attributable to the presence of cardia or non-cardia lesions. Although there have been no reports of variable expression of H2N by gender, there are gender differences in expression of estrogen receptor (ER) and ER messenger RNA in gastric cancer (45). A possible explanation for the survival advantages in women may be found in a recent study addressing the interactions between the estrogen receptor and her- 2neu receptor pathways in breast cancer development and treatment response. Hurtado and colleagues found her-2-neu up regulation following the silencing of PAX-2 in cell lines treated with tamoxifen, which suggests that tamoxifen-estrogen receptor and estradiol-estrogen receptor complexes inhibits transcription of Her-2-Neu via Pax-2 (46).
Despite the clinical and genetic variability of advanced gastric cancer, we were able to identify clinical correlates for improved outcomes, which included gender and age. We did not find an association between ethnicity and survival. This is thought provoking as there are clear differences in the age of presentation and the prevalence of cardiac tumors. Hispanic patients were twice as likely to develop gastric cancer at < 45 years old than Caucasians. Conversely Caucasians were twice as likely to develop gastric cardia lesions vs non-proximal cancers. Further research into biological basis for these differences is warranted.
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Cite this article as: Yang D, Hendifar A, Lenz C, Togawa K, Lenz F, Lurje G, Pohl A, Winder T, Ning Y, Groshen S, Lenz H. Survival of metastatic gastric cancer: Significance of age, sex and race/ethnicity. J Gastrointest Oncol. 2011;2(2):77-84. DOI:10.3978/j.issn.2078-6891.2010.025

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