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Journal of Clinical Oncology, Vol 25, No 18 (June 20), 2007: pp. 2522-2527 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.2749 Social and Racial Differences in Selection of Breast Cancer Adjuvant Chemotherapy Regimens
From the University of Rochester, Rochester, NY; RAND Corporation, Pittsburgh, PA; University of Washington, Seattle, WA; and the Duke Comprehensive Cancer Center and the Department of Medicine, Duke University, Durham, NC Address reprint requests to Jennifer J. Griggs, MD, MPH, Department of Medicine, Hematology/Oncology, University of Michigan, 1500 E Medical Center Dr, 4310 CCGC, Ann Arbor, MI 48109-0936; e-mail: jengrigg{at}umich.edu
Purpose: Breast cancer outcomes are worse among black women and women of lower socioeconomic status. The purpose of this study was to investigate racial and social differences in selection of breast cancer adjuvant chemotherapy regimens.
Methods: Detailed information on patient, disease, and treatment factors was collected prospectively on 957 patients who were receiving breast cancer adjuvant chemotherapy in 101 oncology practices throughout the United States. Adjuvant chemotherapy regimens included in any of several published guidelines were considered standard. Receipt of nonstandard regimens was examined according to clinical and nonclinical factors. Differences between groups were assessed using
Results: Black race (P = .008), lower educational attainment (P = .003), age Conclusion: The more frequent use of non–guideline-concordant adjuvant chemotherapy regimens in black women and women with lower educational attainment may contribute to less favorable outcomes in these populations. Addressing such differences in care may improve cancer outcomes in vulnerable populations.
Practice guidelines for the diagnostic evaluation, surgery, systemic therapy, and radiation therapy of breast cancer have been developed and disseminated by the National Comprehensive Cancer Network and other groups.1-3 Several studies have demonstrated that breast cancer outcomes are superior in patients treated according to clinical practice guidelines.4-7 Receipt of guideline-concordant cancer care varies according to nonclinical factors such as geography, race, and insurance status.8-12 For example, one study demonstrated that rates of guideline-concordant care for a variety of cancers were lower for patients with only Medicaid or Medicare compared with those with private insurance.8 In another study of 898 patients with non–small-cell lung cancer, age, race, ethnicity, and marital status were all factors associated with receipt of nonstandard therapy.10 Race has also been shown to be associated with lower rates of radiation therapy after breast-conserving surgery for breast cancer13 and with receipt of staging procedures and surgery after staging in non–small-cell lung cancer.12 Several studies have demonstrated that low socioeconomic status (SES)14,15 and black race15-17 are associated with lower rates of adjuvant chemotherapy, but little information is available on patterns of care in the selection of adjuvant chemotherapy regimen. Adjuvant chemotherapy, administered after removal of the primary tumor to reduce the risk of distant recurrence, has been shown to reduce the risk of metastatic breast cancer recurrence by up to 38%.18 Multiple chemotherapy regimens have been studied in the adjuvant treatment of breast cancer, and several groups have generated guidelines for the selection of an adjuvant chemotherapy regimen based on the results of clinical trials.1,20-22 The purpose of this study was to investigate the association between patient characteristics, including race and socioeconomic characteristics (education, employment status, and insurance), and the selection of chemotherapy regimen.
The data for this study were collected through the Awareness of Neutropenia in Chemotherapy Study Group Registry, a prospective observational multicenter study of cancer patients starting chemotherapy for solid tumors and lymphoma. Beginning in March 2002, patient participants were enrolled at 115 sites within the United States. Sites were stratified by geographic region and patient volume. The Coordinating Center for this study was located at the University of Rochester (Rochester, NY) and received approval from the University's institutional review board (IRB) to direct this multicenter registry. In addition, each site received either central IRB (n = 105) or local IRB (n = 20) approval to participate in the study.
Patient Selection
Data Collection
Standard Chemotherapy Regimens
Analyses The use of nonstandard chemotherapy regimens was examined according to patient and disease characteristics.  2 tests were used to assess significant differences in the use of nonstandard regimens for categoric covariates. The Kruskal-Wallis test was used to investigate the association between continuous measures and the use of a nonstandard regimen. Multivariate logistic regression was performed to identify factors independently associated with the use of a nonstandard regimen. Age, comorbidity, and race were chosen to be incorporated into the model a priori, and additional variables were included into a multivariate model based on the results of the univariate analysis. Robust SEs were used to account for multiple patients from the same practice site. Clinically important interactions were checked and significant interactions are reported. Covariates in the model were checked for collinearity. All variables were evaluated for missing values. Missing observations were either grouped with the most relevant category or a special group labeled "missing" was created when patients with the absent values differed from the existing categories. All tests of significance were two sided; P < .05 was considered to be significant. The analyses were done in SAS version 9.1.3 (SAS Institute Inc, Cary, NC).
Patient Characteristics Between March 2002 and March 2005, 957 participants treated at 101 sites who met eligibility criteria were enrolled. Patient characteristics are listed in Table 2.
Use of Nonstandard Adjuvant Chemotherapy Regimens Of the 957 participants, 845 (88%) were treated with a standard chemotherapy regimen, and 112 (12%) were treated with a nonstandard regimen. A single-agent regimen was administered to 33 patients. The 24 regimens classified as nonstandard are shown in Table 3. Of the 24 different nonstandard regimens, 12 (50%) contained an anthracycline and 14 (58%) contained a taxane. Five (21%) contained both an anthracycline and a taxane. Most data were complete, with missing data on race for five participants (0.5%), missing data on employment status for 11 participants (1.1%), missing data on employment type for 24 participants (2.5%), and missing data on education for 49 participants (5.1%).
Univariate analyses. The clinical and demographic characteristics of patients treated with standard regimens were compared with those treated with nonstandard regimens (Table 4). In univariate analyses, patients with less than a high school education were three times more likely to receive a nonstandard regimen compared with patients with a college education (20% v 6%; P = .0002). Black patients were more likely to receive a nonstandard regimen compared with whites (19% v 11%; P = .047). Other factors associated with nonstandard chemotherapy regimens were higher stage disease (P < .0001), age  70 years (P = .001), Medicaid insurance (P = .048), employment other than full time (P = .045), job category (P = .025), and geographic location (P = .021). Patients with unknown hormone receptor status were more likely to receive a nonstandard regimen compared with patients whose receptor status was known (30% v 11%; P = .001). Comorbidity was not associated with receipt of nonstandard chemotherapy. In the analysis of single-agent regimens, 9% of women with stage III disease received single-agent therapy compared with 0.4% with stage I disease and 2.8% with stage II disease (P < .0001). Women with Medicaid were more likely to receive single-agent chemotherapy (11.5%) compared with 5.2% of the women with Medicare and 2.7% with third-party payer insurance (P = .002). Women who were older than 70 years were more likely to receive a single agent than women who were younger than age 70 years (9.8% v 2.9%; P = .001).
Multivariate analyses. In multivariate analyses (Table 5), factors associated with nonstandard chemotherapy regimen were black race (P = .020), higher tumor stage (P < .0001), lower educational attainment (P = .024), and age 70 years (P = .032). Hormone receptor status was borderline significant (P = .050), with patients with unknown status more likely to receive nonstandard regimens. Geographic region, job category, employment status, and insurance were no longer significantly associated with nonstandard regimens. Nonsignificant factors included in the multivariate model did not confound the significant relationships observed. There was a statistically significant interaction between race and employment status. Black patients not employed full time were more likely to receive a nonstandard regimen (P = .004).
In this sample of 957 breast cancer patients treated with adjuvant chemotherapy, most patients were treated with a guideline-concordant chemotherapy regimen. The use of nonstandard regimens was associated independently with patient educational level, black race, and cancer stage. Comorbidity, which might be expected to influence selection of chemotherapy, was not associated with receipt of nonstandard regimens. As with most observational studies, unobservable differences between those receiving standard versus nonstandard regimens are very likely to play a role in the patterns of care we observed. In addition, unobserved differences in the practices treating the patients are likely to play a role as well. The results of this study are consistent with other studies that document differences in breast cancer adjuvant therapy in vulnerable populations. In addition to disparities in receipt of adjuvant chemotherapy among women of low SES14,15 and black race,15-17,26 previous studies have demonstrated that chemotherapy doses are more likely to be reduced intentionally in black women27 and women of lower SES,27,28 and that black women are more likely to discontinue chemotherapy early.29 The interaction between black race and lack of full-time employment in this study highlights the difficulty encountered when attempting to disentangle the effects of race and SES. The reason for the association between disease stage and nonstandard regimen is unclear and deserves additional study in other patient samples. It is possible that physicians harbor uncertainty about the best regimens for the treatment of higher stage disease and are more willing to administer unconventional regimens to those patients they deem to be at highest risk of recurrence. The more frequent use of single-agent regimens in women with stage III disease, however, contradicts this hypothesis, given that single-agent regimens are generally considered less aggressive, and clinical trials of single-agent therapy (for example, paclitaxel in the Cancer and Leukemia Group B study C40101) were being conducted only in women with stage I disease at the time patients were being enrolled onto our study. Practice guidelines, when followed, may improve quality of care by reducing unwarranted variations in care.30,31 Equating practice guidelines with quality of care, however, may lead to erroneous conclusions, given that physician discretion and patient preferences may lead to selection of therapy that is not concordant with guidelines.31,32 In addition, practice guidelines may not be updated to reflect advances in knowledge.33 In this study, the guidelines used to define a standard regimen in this study were contemporaneous with the study period (2002 to 2005). It is important to note that in our sample, most of the nonstandard regimens contained an anthracycline, a taxane, or both types of agents. In addition, several of these regimens have been or are being studied in clinical trials and may eventually be found to be superior to regimens currently considered standard. Differences in treatment are not synonymous with disparities in treatment.34,35 There is some evidence, for example, that cultural differences in patient preferences for health states may account, in part, for differences in the decision to administer adjuvant chemotherapy for the treatment of breast cancer.36 Nonetheless, the higher likelihood of nonstandard regimens in black women and in women with less education suggests that systematic differences in care are present according to these nonclinical factors.37 Given the other disparities in quality of care cited, and persistent outcome disparities in breast cancer among black women and in women of lower SES,38,39 attention to such patterns of care may reveal opportunities to address and eliminate such disparities.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Melony E.S. Sorbero, Amgen; Jeffrey Crawford, Amgen Stock: N/A Honoraria: Jeffrey Crawford, Amgen; David C. Dale, Amgen; Gary H. Lyman, Amgen, GlaxoSmithKline Research Funds: David C. Dale, Amgen; Gary H. Lyman, Amgen, GlaxoSmithKline Testimony: N/A Other: N/A
Conception and design: Jennifer J. Griggs, Melony E.S. Sorbero, Debra A. Wolff, Jeffrey Crawford, David C. Dale, Gary H. Lyman Provision of study materials or patients: Gary H. Lyman Collection and assembly of data: Eva Culakova, Marek S. Poniewierski, Debra A. Wolff, Jeffrey Crawford, Gary H. Lyman Data analysis and interpretation: Jennifer J. Griggs, Eva Culakova, Melony E.S. Sorbero, Debra A. Wolff, Jeffrey Crawford, David C. Dale, Gary H. Lyman Manuscript writing: Jennifer J. Griggs, Eva Culakova, Melony E.S. Sorbero, Debra A. Wolff, Gary H. Lyman Final approval of manuscript: Jennifer J. Griggs, Eva Culakova, Melony E.S. Sorbero, Marek S. Poniewierski, Debra A. Wolff, Jeffrey Crawford, David C. Dale, Gary H. Lyman
Supported by Amgen Inc (data collection only), through the Awareness of Neutropenia in Chemotherapy (ANC) Study Group. Amgen played no role in the data collection, study design, or interpretation of data. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology–v. 2.2006. http://www.nccn.org/professionals 2. Eifel P, Axelson JA, Costa J, et al: National Institutes of Health Consensus Development Conference Statement: Adjuvant therapy for breast cancer, November 1-3, 2000. 17:1-23 3. Goldhirsch A, Wood WC, Gelber RD, et al: Meeting highlights: Updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 21:3357-3365, 2003 4. Hébert-Croteau N, Brisson J, Latreille J, et al: Compliance with consensus recommendations for systemic therapy is associated with improved survival of women with node-negative breast cancer. J Clin Oncol 22:3685-3693, 2004 5. Lash TL, Silliman RA, Guadagnoli E, et al: The effect of less than definitive care on breast carcinoma recurrence and mortality. Cancer 89:1739-1747, 2000[CrossRef][Medline] 6. Lash TL, Clough-Gorr K, Silliman RA: Reduced rates of cancer-related worries and mortality associated with guideline surveillance after breast cancer therapy. Breast Cancer Res Treat 89:61-67, 2005[CrossRef][Medline] 7. Owusu C, Lash TL, Silliman RA: Effect of undertreatment on the disparity in age-related breast cancer-specific survival among older women. Breast Cancer Res Treat 102:227-236, 2007[CrossRef][Medline] 8. Harlan LC, Greene AL, Clegg LX, et al: Insurance status and the use of guideline therapy in the treatment of selected cancers. J Clin Oncol 23:9079-9088, 2005 9. Potosky AL, Harlan LC, Kaplan RS, et al: Age, sex, and racial differences in the use of standard adjuvant therapy for colorectal cancer. J Clin Oncol 20:1192-1202, 2002 10. Potosky AL, Saxman S, Wallace RB, et al: Population variations in the initial treatment of non-small-cell lung cancer. J Clin Oncol 22:3261-3268, 2004 11. Giordano SH, Hortobagyi GN, Kau SW, et al: Breast cancer treatment guidelines in older women. J Clin Oncol 23:783-791, 2005 12. Lathan CS, Neville BA, Earle CC: The effect of race on invasive staging and surgery in non-small-cell lung cancer. J Clin Oncol 24:413-418, 2006 13. Mandelblatt JS, Kerner JF, Hadley J, et al: Variations in breast carcinoma treatment in older Medicare beneficiaries: Is it black or white? Cancer 95:1401-1414, 2002[CrossRef][Medline] 14. Silliman RA, Demissie S, Troyan SL: The care of older women with early-stage breast cancer: What is the role of surgeon gender? Med Care 37:1057-1067, 1999[CrossRef][Medline] 15. White J, Morrow M, Moughan J, et al: Compliance with breast-conservation standards for patients with early-stage breast carcinoma. Cancer 97:893-904, 2003[CrossRef][Medline] 16. Shavers VL, Harlan LC, Stevens JL: Racial/ethnic variation in clinical presentation, treatment, and survival among breast cancer patients under age 35. Cancer 97:134-147, 2003[CrossRef][Medline] 17. Pierce L, Fowble B, Solin LJ, et al: Conservative surgery and radiation therapy in black women with early stage breast cancer. Cancer 69:2831-2841, 1992[CrossRef][Medline] 18. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 20. Levine M: Clinical practice guidelines for the care and treatment of breast cancer: Adjuvant systemic therapy for node-positive breast cancer (summary of the 2001 update)—The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. CMAJ 164:644-646, 2001 21. British Columbia Cancer Agency: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Breast/ManagementAdjuvantSystemicTherapy.htm 22. Cancer Care Ontario: http://www.cancercare.on.ca/index_practiceGuidelines 23. Charlson ME, Pompei P, Ales KL, et al: A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 40:373-383, 1987[CrossRef][Medline] 24. Harris DM, Lippman ME, Morrow M, et al: Diseases of the Breast (ed 3). Philadelphia, PA, Lippincott Williams & Wilkins, 2004 25. DeVita VT, Hellman S, Rosenberg SA, Cancer: Principles and Practice of Oncology (ed 7). Philadelphia, PA, Lippincott Williams & Wilkins, 2004 26. Bickell NA, Wang JJ, Oluwole S, et al: Missed opportunities: Racial disparities in adjuvant breast cancer treatment. J Clin Oncol 24:1357-1362, 2006 27. Griggs JJ, Sorbero MES, Stark AT, et al: Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat 81:21-31, 2003[CrossRef][Medline] 28. Griggs JJ, Culakova E, Sorbero MES, et al: Effect of patient socioeconomic status and body mass index on the quality of breast cancer adjuvant chemotherapy. J Clin Oncol 25:277-284, 2007 29. Hershman D, McBride R, Jacobson JS, et al: Racial disparities in treatment and survival among women with early-stage breast cancer. J Clin Oncol 23:6639-6646, 2005 30. Smith TJ, Hillner BE: Ensuring quality cancer care by the use of clinical practice guidelines and critical pathways. J Clin Oncol 19:2886-2897, 2001 31. Walter LC, Davidowitz NP, Heineken PA, et al: Pitfalls of converting practice guidelines into quality measures: Lessons learned from a VA performance measure. JAMA 291:2466-2470, 2004 32. Cabana MD, Rand CS, Powe NR, et al: Why don't physicians follow clinical practice guidelines? A framework for improvement. JAMA 282:1458-1465, 1999 33. Shekelle PG, Ortiz E, Rhodes S, et al: Validity of the Agency for Healthcare Research and Quality clinical practice guidelines: How quickly do guidelines become outdated? JAMA 286:1461-1467, 2001 34. Rathore SS, Krumholz HM: Differences, disparities, and biases: Clarifying racial variations in health care use. Ann Intern Med 19:635-638, 2004 35. Braveman P: Health disparities and health equity: Concepts and measurement. Annu Rev Public Health 27:167-194, 2006[CrossRef][Medline] 36. Schleinitz MD, Depalo D, Blume J, et al: Can differences in breast cancer utilities explain disparities in breast cancer care? J Gen Intern Med 21:1253-1260, 2006[CrossRef][Medline] 37. Blackman DJ, Masi CM: Racial and ethnic disparities in breast cancer mortality: Are we doing enough to address the root causes? J Clin Oncol 24:2170-2178, 2006 38. Field TS, Buist DS, Doubeni C, et al: Disparities and survival among breast cancer patients. J Natl Cancer Inst Monogr 35:88-95, 2005 39. Newman LA, Mason J, Cote D, et al: African-American ethnicity, socioeconomic status, and breast cancer survival: A meta-analysis of 14 studies involving over 10,000 African-American and 40,000 White American patients with carcinoma of the breast. Cancer 94:2844-2854, 2002[CrossRef][Medline] Submitted December 6, 2006; accepted April 3, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
