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Journal of Clinical Oncology, Vol 26, No 8 (March 10), 2008: pp. 1282-1288 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0699 Effect of Race on the Outcome of Pediatric Patients With Hodgkin's Lymphoma
From the Departments of Oncology, Biostatistics, and Radiological Sciences St Jude Children's Research Hospital; the University of Tennessee Health Science Center, Memphis, TN; and Department of Pediatrics, Wake Forest University, Winston-Salem, NC Corresponding author: Monika L. Metzger, MD, Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794; e-mail: monika.metzger{at}stjude.org
Purpose Some cooperative groups have found a survival disadvantage in black children with various childhood cancers. We examine the effects of race on clinical outcomes among children with Hodgkin's lymphoma (HL) treated with contemporary therapy at a tertiary care children's hospital. Patients and Methods Retrospective analysis of 327 children and adolescents diagnosed with HL between 1990 and 2005. Patients were treated with risk-directed multimodal therapy regardless of race, ethnicity, or ability to pay. Event-free and overall survival rates were compared for black and white children. Clinical characteristics, socioeconomic factors, and biologic features were analyzed for prognosis of treatment failure. Results The 262 white and 65 black patients did not differ significantly in presenting features, clinical characteristics, or enrollment in a clinical trial. More black patients (71% v 45%) resided in poor counties (P < .001). While black and white children were equally likely to have progressive disease or early relapse, black children were 3.7 times (95% CI, 1.7 to 8.0) more likely to relapse 12 months or more after diagnosis. The 5-year event-free survival was 71% ± 6.1% (SE) for black and 84% ± 2.4% for white children (P = .01). However, the 5-year survival rate did not differ between white and black children (94.4% v 94.7%). While black race and low hemoglobin concentration were independent predictors of treatment failure, only low hemoglobin concentration independently predicted poor survival. Conclusion Black children with Hodgkin's lymphoma have lower event-free survival than white children, but both populations have the same 5-year overall survival.
The impact of race on disease outcome has been examined in several pediatric malignancies.1-5 For example, two large cooperative group studies in the United States have documented racial and ethnic differences in survival for childhood acute lymphoblastic leukemia (ALL).6,7 Further, data from the Surveillance Epidemiology and End Results in the United States between 1975 and 1995 indicate that white children with Hodgkin's lymphoma (HL) have a higher 5-year survival than do black children (92% v 84%).8 These racial differences in cancer survival may be attributable to disease biology, advanced disease stage at presentation, host pharmacogenetics, or differences in access to care. Black and white children with ALL treated at St Jude Children's Research Hospital, where access to care, psychosocial support, patient education, adherence monitoring, and effective antileukemic therapy were provided equally to both racial groups, had similar outcomes.9 Likewise, among patients with HL treated at St Jude between 1981 and 1992, white and black children had similar 5-year survival (93% v 96%).4 These findings suggest that equal access to effective treatment can overcome potentially adverse social, economic, demographic, or disease variables. Here, we compared treatment outcome between white and black children with HL treated with combined chemotherapy and radiation therapy in the modern era at St Jude.
Study Population From January 1990 through December 2005, 329 children with newly diagnosed HL were treated at St Jude Children's Research Hospital. Chemotherapy and radiation therapy regimens varied according to treatment period, and clinical trials implemented between 1990 and 2001 have been described elsewhere.10-12 Patients with high-risk HL diagnosed since 2001 and those with intermediate-risk HL diagnosed since mid-2004 received 12 weeks of compacted, multiagent, dose-intensive "Stanford V" chemotherapy (vinblastine, nitrogen mustard, prednisone, vincristine, etoposide, doxorubicin, and bleomycin), followed by response-based, low-dose, involved-field radiation.13 All patients were staged according to the Ann Arbor staging classification14 with computed tomography scans; lymphangiograms and gallium scans have gradually been replaced by positron emission tomography scans in the last decade. After receiving institutional review board approval, we reviewed medical records for demographic information, details of therapy, and disease and survival outcomes.
Definition of Race
Socioeconomic Status Variables
Statistical Methods
Patient Characteristics at Diagnosis The median age of the 327 evaluable patients (180 males and 147 females) was 15.5 years (range, 3 to 22 years) at diagnosis of lymphoma; 80% (n = 262) were white and 20% (n = 65) were black (Table 1). The two racial groups did not differ significantly by clinical or biologic features (Table 1). However, black patients tended to have more other histologies and slightly more stage III or IV disease than did white patients. Similar percentages of black and white children participated in clinical trials (91% and 88%, respectively).
Although 74% of black and 62% of white patients had insurance of some kind (P = .19), black patients were less likely to have private insurance than whites (32.3% v 50.4%; P = .009) and more likely to have public insurance (41.5% v 11.8%; Table 1). Furthermore, 70.8% of black children and 44.6% of white children resided in counties where more than 23.1% of children live in poverty (the median proportion of children living in poverty for our sample; P < .001).
Treatment Outcome
Survival Eighty three percent of surviving black patients and 85% of surviving white patients were contacted or seen within the past 2 years (P = .35). Patients who remained alive were followed for a median of 8.7 years (range, 1.2 to 16.2 years). At the time of last follow-up, 14 white patients and five black patients had died. The causes of death were progressive lymphoma in 10 whites and four blacks; accidents in two whites and one black; and secondary acute myeloid leukemia and cardiac failure in one white each (Table 2). The 5-year OS (SE) did not differ significantly between black and white patients (94.4% [3.2%] v 94.7% [1.5%]; P = .41; Fig 2). No black children experienced a second malignancy, compared with five white children (follicular carcinoma of the thyroid, mucoepidermoid carcinoma of the parotid gland, Ewing sarcoma, acute myeloid leukemia, and spinal atypical rhabdoid tumor).
Prognostic Factors Prognostic factors significantly associated with risk of relapse and death in univariate analysis were presence of B symptoms, advanced stage of disease, bulky mediastinal mass, low hemoglobin concentration, and high erythrocyte sedimentation rate at diagnosis (Tables 3 and 4). Additional prognostic factors only associated with risk of relapse were black race and increased WBC count at presentation (Table 3). In multivariable analysis, black race (HR, 1.8; 95% CI, 1.1 to 3.1; P = .03) and low hemoglobin concentration at presentation (HR, 2.7; 95% CI, 1.6 to 4.6; P = .0002) were independent predictors of treatment failure, while low hemoglobin concentration (HR, 2.9; 95% CI, 1.1 to 7.5; P = .03) was the only significant predictor of poor survival.
The results of this analysis indicate that black children with newly diagnosed HL treated with contemporary combined-modality therapy at our institution have the same 5-year OS compared with white children (94.4% and 94.7%, respectively). However, black patients have lower 5-year DFS and EFS (70.8%, same for both) compared with white patients (DFS, 86.1%; EFS, 83.5%, respectively).
Survival by race has been evaluated in several pediatric cancer populations.1-3,5,7,9,20 For instance, black children with ALL are more likely to have unfavorable biologic prognostic features21,22; however, intensification of chemotherapy and improved supportive care have abrogated this prognostic disadvantage.9 We could not find in the literature any prior analysis of the association of race and outcome in pediatric HL. Race was not considered in our previous collaborative studies of pediatric HL, where male sex, advanced stage of disease, bulky mediastinal mass ( In a study of adults with HL, Zaki et al found that among 2,583 adults treated with radiation as single-modality therapy, black patients were more likely to die from their primary disease than were white patients (32% v 22%).23 In that study, as in ours, black patients had a higher risk for recurrence than did white patients (31% v 40%; P < .01); however, the risk of death between the two groups did not differ in the first 5 years after diagnosis and only became significant 5 to 10 years after diagnosis. One hypothesis for the difference in EFS in our patients could be that black and white children have different sensitivities to radiotherapy. However, in an analysis of patterns of treatment failure among pediatric patients who received multimodal therapy with chemotherapy plus involved-field radiation, race was not a risk factor for local treatment failure.24 Childhood survivors of HL are at increased risk for secondary neoplasms, with a cumulative incidence of more than 10% at 20 years.25 In the current study, no black patient experienced a secondary neoplasm with 426 person-years of follow-up since diagnosis. This contrasts to seven secondary neoplasms in white patients; five white patients developed a secondary neoplasm as their first event with 1,990 person-years of follow-up, and two white patients developed second cancers (breast carcinoma and melanoma) after treatment for relapsed HL. In the Childhood Cancer Survivor Study, a large cohort of patients (n = 8,767) with a variety of primary cancers were evaluated, and racial groups did not differ in the 15-year cumulative incidence of secondary neoplasms.26 However, the contribution of race to the risk of developing a subsequent malignancy has not been well studied in large cohorts of pediatric HL survivors.25,27-29 Socioeconomic factors are tightly linked with considerations of race in health outcomes, and lower socioeconomic status has been correlated with poorer treatment compliance among adolescents.30 The vast majority of our patients came from a catchment area with a larger proportion of black patients (21%) than the national average (12.3%, according to the 2000 US Census), as well as a larger proportion of children living in counties with more children living in poverty (median, 23.1%) than the national average (17.8%, 2004 US Census Bureau). Therefore, it is not surprising that there is a clear economic disparity between whites and blacks in our cohort, as illustrated by the fact that more than 70% of our black children lived in poor areas compared with only 45% white children, as well as the fact that only 32% of black children were privately insured compared with 50% white children. Our center underwrites all treatment costs not covered by third-party payers, subsidizes transportation for patients to come for treatment and follow-up, and provides free food and lodging for those who live out of town while they are in Memphis,TN, to receive care. However, families of children with cancer still have a substantial socioeconomic burden related to time away from home and work, such that poverty may impact on treatment outcome. Perhaps the most pertinent limitation of the study is the concept of race itself. Race is a social construct that has no precise biologic meaning. Even though racial identification for this study was taken from patients’ and families’ self-report, the 2000 US Census demonstrated that more than 7 million Americans identify themselves as members of more than one racial or ethnic group.31 In this context, race can only be seen as a surrogate marker for other social, economic, environmental, and cultural factors that can impact health. Racial and ethnic disparities in the United States have widely been described and may lead to important information about the etiology of cancer and genetic differences in metabolism of chemotherapeutic agents. However, any study of race-based genetic contributions to the outcomes of cancer therapy should be accompanied by an effort to address all known environmental or social factors, such as access to care, that influence outcomes.32,33 This emphasis on universal access to high-quality care is even more important in low-income countries, where the effect of socioeconomic factors on outcomes is so pronounced that any biologic effect of race would be obscured. While black and white patients with HL have the same 5-year OS with multimodal therapy, black patients have a slightly higher disease-related mortality (80%) compared with white patients (71%) and require longer follow-up, as patients requiring salvage therapy after relapse can be expected to suffer more treatment-related morbidity and mortality.
The author(s) indicated no potential conflicts of interest.
Conception and design: Monika L. Metzger, Sharon M. Castellino, Melissa M. Hudson, Sue C. Kaste, Matthew J. Krasin, Scott C. Howard Financial support: Melissa M. Hudson Administrative support: Monika L. Metzger Provision of study materials or patients: Monika L. Metzger, Melissa M. Hudson, Sue C. Kaste, Larry E. Kun, Scott C. Howard Collection and assembly of data: Monika L. Metzger, Melissa M. Hudson, Sue C. Kaste, Scott C. Howard Data analysis and interpretation: Monika L. Metzger, Melissa M. Hudson, Shesh N. Rai, Sue C. Kaste, Matthew J. Krasin, Ching-Hon Pui, Scott C. Howard Manuscript writing: Monika L. Metzger, Sharon M. Castellino, Melissa M. Hudson, Sue C. Kaste, Matthew J. Krasin, Ching-Hon Pui, Scott C. Howard Final approval of manuscript: Monika L. Metzger, Sharon M. Castellino, Melissa M. Hudson, Shesh N. Rai, Sue C. Kaste, Matthew J. Krasin, Larry E. Kun, Ching-Hon Pui, Scott C. Howard
We thank Tom Lang for invaluable editorial assistance.
Supported by Grants No. CA-21765, CA-51001, CA-36401, CA-78224, CA-60419, and GM-61393 from the National Institutes of Health, and by the American Lebanese Syrian Associated Charities. C-H.P., MD, is an American Cancer Society Professor. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Freeman-Halton test as appropriate.
33% mediastinal to thoracic ratio), increased WBC count (> 13,500/mm3), and low hemoglobin concentration (< 11.0 g/dL) were associated with poor OS.
