Ethnic and racial differences in patients with Ewing sarcoma

Authors

  • Jennifer Worch MD,

    1. Department of Pediatrics, University of California at San Francisco School of Medicine, San Francisco, California
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  • Katherine K. Matthay MD,

    1. Department of Pediatrics, University of California at San Francisco School of Medicine, San Francisco, California
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  • John Neuhaus PhD,

    1. Department of Epidemiology/Biostatistics,University of California at San Francisco School of Medicine, San Francisco, California
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  • Robert Goldsby MD,

    1. Department of Pediatrics, University of California at San Francisco School of Medicine, San Francisco, California
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  • Steven G. DuBois MD

    Corresponding author
    1. Department of Pediatrics, University of California at San Francisco School of Medicine, San Francisco, California
    • Department of Pediatrics, University of California at San Francisco School of Medicine, 505 Parnassus Avenue, M646, San Francisco, CA 94143-0106
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    • Fax: (415) 502-4327


  • Presented in part at the 2009 American Society of Pediatric Hematology/Oncology (ASPHO) Annual Meeting, April 22 to 25, 2009, San Diego, California.

Abstract

BACKGROUND:

Ewing sarcoma (ES) was a malignant tumor of bone or soft tissue. One of the few risk factors for developing ES is race, with a higher incidence noted in populations of European rather than African or Asian ancestry. The goal of the current study was to evaluate racial and ethnic differences in presentation and overall survival (OS) among patients diagnosed with ES before age 40 years.

METHODS:

Data from the Surveillance, Epidemiology, and End Results database identified 1715 patients aged <40 years who were diagnosed with ES between 1973 and 2005. Racial and ethnic group differences were compared using chi-square tests. OS was estimated by Kaplan-Meier analysis and compared using log-rank tests and Cox models.

RESULTS:

Black patients had significantly more soft-tissue tumors compared with white non-Hispanic patients (P <.0001). Asian and white Hispanic patients were found to have an intermediate frequency of soft-tissue tumors that also differed from white non-Hispanic patients (P <.0001). White Hispanic patients presented with a higher proportion of larger tumors compared with white non-Hispanic patients (P = .042). Black patients tended to be older than white non-Hispanic patients (P = .012). Sex, frequency of pelvic tumors, and metastatic status did not appear to differ by ethnicity or race. OS was found to differ according to race and ethnicity. Even after controlling for known confounders, OS was significantly worse for black, Asian, and white Hispanic patients compared with white non-Hispanic patients (P = .0031, P = .0182, and P = .0051, respectively).

CONCLUSIONS:

Ethnic and racial differences in characteristics and outcomes of patients with ES do exist. Understanding the etiology of these differences will require further study. Cancer 2010. © 2010 American Cancer Society.

Ewing sarcoma (ES) is a highly malignant small round cell tumor of bone or soft tissue and is the second most frequent primary malignant bone tumor in children and adolescents.1 ES demonstrates an irregular geographic pattern of incidence and overall survival (OS).2, 3 Whites are much more frequently affected, whereas there are low rates in East Asian and African populations.4-7 To the best of our knowledge, ES has been poorly characterized in Hispanic populations.

For several adult malignancies, differences in clinical presentation and outcome by race and ethnicity have been previously demonstrated.8-11 In pediatric cancer, the impact of race and ethnicity on outcome is less clear.12, 13 Despite recognition that the incidence of ES differs by race, to the best of our knowledge disparities in clinical presentation and outcome have not been well studied for children and young adults with this disease. Given the stark differences in the incidence of this disease in black and Asian populations, we hypothesized that disease characteristics and outcomes might differ in these populations compared with white non-Hispanic patients. We performed a secondary data analysis using the Surveillance, Epidemiology, and End Results (SEER) program database to evaluate racial and ethnic differences in clinical presentation and OS among patients diagnosed with ES before the age of 40 years in the United States.

MATERIALS AND METHODS

Patient Population

The US National Cancer Institute's SEER database contains 1715 patients aged <40 years diagnosed between 1973 and 2005. Our analysis included 17 SEER registries representing data from multiple institutions from diverse geographic parts of the United States.14 The SEER program currently collects and publishes cancer incidence and survival data from 17 population-based cancer registries that cover approximately one‒quarter (26%) of the US population. In the SEER program registries, data regarding patient demographics, primary tumor site, tumor morphology and stage at diagnosis, first course of treatment, and follow-up for vital status are routinely assembled.

On January 1, 1973, SEER began collecting data on cancer cases. Currently, the following population-based cancer registries are part of the SEER program: Alaska Native Tumor Registry, Arizona Indians, Los Angeles, San Francisco-Oakland, San Jose-Monterey, Greater California, Connecticut, Detroit, Atlanta, Rural Georgia, Hawaii, Iowa, Kentucky, Louisiana, New Jersey, New Mexico, Seattle-Puget Sound, and Utah. Data for 2005 include the standard set based on July 1 populations and a set that has been adjusted for the population shifts due to hurricanes Katrina and Rita. Inclusion criteria for geographic areas to be selected for the SEER program are based on their ability to operate and maintain a high-quality, population-based cancer reporting system and their epidemiologically significant population subgroups. The population covered by SEER is comparable to the general US population with a trend toward being somewhat more urban and to have a higher proportion of foreign-born persons than the general US population.15

All patients with histologically confirmed ES; peripheral primitive neuroectodermal tumors; and Askin tumors of the bone, soft tissue, and organs were eligible for the study. Patients were identified using the corresponding International Classification of Diseases (ICD) 0-2 and ICD 0-3 codes for these diagnoses. Patients aged ≥40 years at the time of diagnosis (n = 239) were excluded from the analysis.

SEER classifies race into 28 mutually exclusive groups using information from the medical record. Race was classified as white, black, or Asian if there was concordant evidence in the SEER registries coding “Race/ethnicity” and “Race recode (W, B, AI, API)”. Hispanic ethnicity was determined using stated ethnicity in the medical record, national origin on the death certificate, life history and/or spoken language, place of birth, and surname. Classification of Hispanic patients was based on concordant evidence in the SEER variables “NHIA derived Hispanic origin” and “Spanish surname or origin”. In case of discordance between these variables (n = 2), missing values (n = 15), or no more evidence of Hispanic ethnicity than Spanish surname (n = 19), data were declared as unknown and excluded from the analysis.

For this analysis, patients were grouped into 4 different groups as white non-Hispanic, white Hispanic, Asian non-Hispanic (Asian), and black non-Hispanic (black) based on their race and ethnicity classification. Native American patients (n = 14), Asian Hispanic patients (n = 1), and black Hispanic patients (n = 1) were excluded due to small patient numbers.

We examined the variables of age (<20 years at diagnosis vs ≥20 years at diagnosis), sex, tumor size (≤5 cm vs >5 cm), tumor site (soft tissue vs bone), pelvic site, stage of disease (metastatic vs localized), and year of diagnosis (in sequential 5-year blocks) to evaluate racial and ethnic differences in clinical presentation. On the basis of the SEER historical staging system, disease stage was categorized as localized/regional or distant. In sensitivity analyses, age was also evaluated as a continuous variable and year of diagnosis was evaluated according to specific calendar year intervals that corresponded to the sequential national phase 3 clinical trials open to US patients with ES. Analyses with these variables coded in this manner yielded results that were similar to the presented analyses.

Data regarding treatment received were also collected, with radiotherapy dichotomized as not given or given if performed at any time point during treatment (including radioactive implants and radioisotopes). Similarly, surgery was dichotomized as not used (except for diagnostic biopsy) or used as a component of local control. Data regarding the use of limb-sparing surgery were not reliably available. Adequate data to control for socioeconomic status, environmental factors, and access to health care were not available. Variables from the SEER database such as county or SEER registry were deemed inadequate to control for these factors.

Statistical Analysis

Selected patient and tumor characteristics that appeared to differ between groups were evaluated statistically using chi-square tests with the white non-Hispanic group, the group with the largest sample size, as the reference. OS was estimated using Kaplan-Meier survival curves, and group differences were compared using the log-rank test, again using the white non-Hispanic group as the reference. OS was expressed as Kaplan-Meier estimate with 95% confidence interval (95% CI). OS time was calculated as the number of completed months between the date of diagnosis and whichever occurred first: the date of death, the date last known to be alive, or December 31, 2005. The median follow-up time for the analyzed cohort was 92 months.

Cox proportional hazards models were used to assess the effect of race and ethnicity on OS while controlling for known confounders. The proportional hazards assumption was tested using time-varying covariates and confirmed with log-log survivor function plots. For combined race and ethnicity models, the proportional hazards assumption could not be confirmed when metastatic status was included as a variable. Subsequent models were stratified by metastatic status, and these models met the proportional hazards assumption. For sensitivity models that evaluated ethnicity separately from race, the proportional hazards assumption was only confirmed after stratifying for metastatic status and year of diagnosis.

The SEER database was accessed using SEER*Stat (version 6.4.4). All statistical analyses were performed using SAS (version 9; SAS Institute, Inc, Cary, NC) and STATA (version 10; StataCorp, College Station, Tex) statistical software.

RESULTS

Patient Characteristics

A total of 1715 patients with ES diagnosed before age 40 years were reported to SEER between 1973 and 2005. After excluding 41 patients with unknown race/ethnicity, 14 Native American patients, 1 Asian Hispanic patient, and 1 black Hispanic patient, the current study population included 1658 patients. Of these, 78.6% were white non-Hispanic, 14.0% were white Hispanic, 4.9% were Asian, and 2.5% were black. The clinical characteristics of the study population according to race and ethnicity are shown in Table 1.

Table 1. Prevalence of Patient and Tumor Characteristics by Race and Ethnicity
 WhiteAsianBlack
Non-HispanicHispanicNon-HispanicNon-Hispanic
n=1303n=232n=81n=42
  • a

    P < .05 compared with the reference group of white non-Hispanic patients.

Age <20 y68.4%69.4%63.0%50.0%a
 (891/1303)(161/232)(51/81)(21/42)
Male60.0%59.1%63.0%61.9%
 (782/1303)(137/232)(51/81)(26/42)
Primary site    
 Bone79.7%62.6%61.3%54.8%
 (1038/1302)(144/230)(49/80)(23/42)
 Soft tissue20.3%37.4%a38.8%a45.2%a
 (264/1302)(86/230)(31/80)(19/42)
Pelvis23.5%22.6%20.0%11.9%
 (306/1302)(52/230)(16/80)(5/42)
Nonpelvis76.5%77.4%80.0%88.1%
 (996/1302)(178/230)(64/80)(37/42)
Tumor size, cm    
 ≤527.8%19.1%31.4%28.0%
 (144/518)(25/131)(16/51)(7/25)
 >572.2%80.9%a68.60%72.0%
 (374/518)(106/131)(35/51)(18/25)
Distant metastases at the time of diagnosis29.8%35.0%30.7%27.8%
(348/1168)(72/206)(23/75)(10/36)

Significant differences were noted according to age, primary tumor site (soft tissue vs bone), and tumor size, whereas there was no difference noted with regard to sex, pelvic site, or metastatic status at diagnosis (Table 1). A lower proportion of black patients were diagnosed at age <20 years compared with white non-Hispanic patients (P = .012). A greater proportion of black patients presented with soft-tissue tumors rather than bone tumors compared with white non-Hispanic patients (P <.0001). Asian and white Hispanic patients had an intermediate frequency of soft-tissue tumors that also differed from white non-Hispanic patients (P <.0001). White Hispanic patients were more likely to have tumors measuring >5 cm in maximum dimension compared with white non-Hispanic patients (P <.042). A greater proportion of white Hispanic cases were diagnosed in more recent years compared with the other groups (data not shown; P <.0001), possibly due to changes in the SEER program to include more regions with higher Hispanic populations.

Differences in OS by Race and Ethnicity

There was a statistically significant difference in OS noted by race and ethnicity (P = .031) (Fig. 1). This difference appeared to be driven mainly by the inferior OS for black patients (5-year OS rate of 40.7%; 95% CI, 25.6-55.3%) compared with white non-Hispanic patients (5-year OS rate of 52.2%; 95% CI, 49.1-55.1%) (P = .015). The OS rates for white Hispanic patients (51.8%; 95% CI, 44.0-59.0%) and Asian patients (47.8%; 95% CI, 35.5-59.1%) did not differ significantly from the OS rate for white non-Hispanic patients (P = .29 and P = .09, respectively).

Figure 1.

Kaplan-Meier estimates of overall survival by race and ethnicity are shown among patients with Ewing sarcoma.

Using a Cox proportional hazards model stratified by metastatic status and controlling for age, year of diagnosis, and pelvic site, black, Asian, and white Hispanic patients each demonstrated an inferior OS compared with white non-Hispanic patients. The hazard ratios (HRs) of death for black, Asian, and white Hispanic patients compared with white non-Hispanic patients were 1.84 (P = .003), 1.48 (P = .018), and 1.41 (P = .005), respectively (Table 2). A second model was constructed that also controlled for tumor size, but this model included only approximately 42% of the patients due to missing data. In this sensitivity model, black and white Hispanic patients continued to have significantly higher HRs for death compared with white non-Hispanic patients (HR, 2.34 [P = .001] and HR, 1.46 [P = .023], respectively). The HR for death for Asian patients remained 1.48 (P = .08), but this result was no longer statistically significant.

Table 2. Racial and Ethnic Differences in Overall Survival in Patients With Ewing Sarcoma Based on a Cox Proportional Hazards Model Controlling for Age, Pelvic Tumor Site, Metastatic Disease, and Year of Diagnosis
Race/EthnicityHazard Ratio95% Confidence IntervalP
  • a

    Values in parentheses reflect a sensitivity model that also controlled for tumor size.

White, Non-HispanicReferenceReference 
White, Hispanic1.411.11-1.79.005
(1.46)a(1.05-2.03)(.023)
Asian, Non-Hispanic1.481.07-2.05.018
(1.48)(0.95-2.29)(.08)
Black, Non-Hispanic1.841.23-2.76.003
(2.34)(1.41-3.89)(.001)

Cox proportional hazards models were also constructed to analyze race and ethnicity separately. The results from these models are in concordance with our findings from the final combined race/ethnicity model, demonstrating higher HR of death for black and Asian patients compared with white patients and for Hispanic patients compared with non-Hispanic patients.

DISCUSSION

To the best of our knowledge, the current study is the most comprehensive analysis of racial and ethnic differences in patient characteristics and outcome for patients with ES presented to date. On univariate analysis, OS was found to be significantly worse for black patients compared with white non-Hispanic patients. In addition, after controlling for recognized prognostic factors, OS was significantly worse for black, Asian, and white Hispanic patients compared with white non-Hispanic patients. These differences in outcome may broadly reflect socioeconomic differences, biologic differences, or a combination of these factors. Socioeconomic differences could encompass treatment disparities, delays in diagnosis, differences in protocol adherence, and differences in local control strategies. Biologic differences may include variations in tumor aggressiveness as well as host factors such as pharmacogenomic differences in drug metabolism.16 The contribution of each of these factors to the observed differences cannot be ascertained using the SEER database and will require further study.

To the best of our knowledge, the influence of race and ethnicity on survival of children with cancer has not been fully analyzed.13 Some studies have reported less of an impact of race and ethnicity on outcomes,12, 17 whereas others have reported clear differences in survival by race and ethnicity.18, 19 For example, poorer outcome for specific types of acute lymphoblastic leukemia (ALL) have been reported in black and Hispanic children compared with white children.18, 19 As in the current study, the etiology for these differences is not clear and may include a combination of factors such as biological differences and differential access to healthcare. For example, black children were significantly more likely than white children to have higher risk prognostic features in childhood ALL, including certain immunophenotypes and the t(1;19) chromosomal translocation.17 In addition, a higher incidence of leukemia8 and fewer cases of the favorable TEL-AML1 translocation were noted among Hispanic children.20 These differences in outcomes reinforce the need to understand these differences and to try to adjust treatment to reduce outcome disparities among racial and ethnic groups.13 This point is particularly important in ES, in which the standard treatment approach has been defined from clinical trials enrolling mainly white non-Hispanic patients. These approaches may not be optimal for patients from other racial or ethnic groups.

Although the SEER database allowed for the evaluation of a relatively large number of patients with a rare tumor, the use of this database also resulted in several major limitations. First, race, ethnicity, and tumor histology could not be confirmed. Second, to develop a large enough cohort of patients with different race and ethnicity groups for analysis, we included patients treated in the 1970s. Given that the therapy for ES has evolved since the 1970s, some of our findings may not apply in the setting of current practice. Third, a substantial amount of data are missing from the SEER database. We had intended to evaluate for differences in treatment by race and ethnicity. Unfortunately, data regarding local control were of limited quality, with approximately half of patients without any apparent local control. Data regarding the use of chemotherapy and on the use of high-dose chemotherapy with autologous stem cell rescue were also not available.

Tumor size is a recognized prognostic factor in ES.21-23 However, in the current study, tumor size was not available for approximately half of the analyzed population. Due to these large numbers of missing values, our final model did not control for tumor size. Approximately 90% of patients had complete data for other confounding variables and were included in these final models. In a sensitivity model that also controlled for tumor size, white Hispanic and black patients continued to demonstrate a significantly inferior outcome compared with white non-Hispanic patients. In this sensitivity model, Asian patients did not demonstrate a statistical difference from the reference group. This lack of difference may reflect small patient numbers, particularly since the point estimate of the HR did not change but the 95% CI widened.

A higher proportion of white Hispanic patients with ES were registered in SEER over the past decade compared with white non-Hispanic patients with ES. This effect might be explained in part by the growing US Hispanic population. Furthermore, the SEER program has been specifically adding more population-based cancer registries with a higher census of Hispanic residents. Because outcomes for patients with ES have improved over time,24 we controlled for the changing demographics of the SEER database by controlling for year of diagnosis.

The results of the current study demonstrate differences in OS according to race and ethnicity even after accounting for known prognostic factors in ES. Although the reasons for these differences remain unknown, several factors suggest that biologic differences may at least contribute to these differences. First, the striking difference in incidence by race suggests a genetic component to this disease. Second, patients other than white non-Hispanic patients were more likely to present with soft-tissue rather than bone tumors. Finally, a previous group demonstrated that Japanese patients had a higher frequency of somatic loss of chromosome 19 compared with white patients.25 Further investigations into the biologic and genetic differences in ES tumors according to race and ethnicity are required. Similarly, further studies into possible environmental differences and healthcare disparities are required to evaluate the role of these factors in explaining the observed outcome differences.

CONFLICT OF INTEREST DISCLOSURES

Supported by the Campini Foundation, Hope Street Kids, and National Institutes of Health (NIH)/National Center for Research Resources/OD UCSF-CTSI Grant No. KL2 RR024130. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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