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Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2750-2756 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.3028 Use and Outcomes of Adjuvant Chemotherapy in Older Women With Breast Cancer
From the Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston; and the Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX Address reprint requests to Sharon H. Giordano, MD, MPH, M.D. Anderson Cancer Center, PO Box 301439, Unit 1354, Houston, TX 77230; e-mail: sgiordan{at}mdanderson.org
PURPOSE: This study was undertaken to determine patterns and outcomes of adjuvant chemotherapy use in a population-based cohort of older women with primary breast cancer.
PATIENTS AND METHODS: Women were identified from the Surveillance, Epidemiology, and End Results–Medicare-linked database who met the following criteria: age RESULTS: A total of 41,390 women met study criteria, of whom 4,500 (10.9%) received chemotherapy. The use of adjuvant chemotherapy more than doubled during the 1990s, from 7.4% in 1991 to 16.3% in 1999 (P < .0001), with a significant shift toward anthracycline use. Women who were younger, white, with lower comorbidity scores, more advanced stage disease, and estrogen receptor (ER) –negative disease were significantly more likely to receive chemotherapy. Chemotherapy was not associated with improved survival among women with lymph node–negative (LN) disease or LN-positive, ER-positive disease (hazard ratio [HR], 1.05; 95% CI, 0.85 to 1.31). However, among women with LN-positive, ER-negative breast cancer, chemotherapy was associated with a significant reduction in breast cancer mortality (HR, 0.72; 95% CI, 0.54 to 0.96). A similar significant benefit of chemotherapy was seen in the subset of women age 70 years or older (HR, 0.74; 95% CI, 0.56 to 0.97). CONCLUSION: In this observational cohort, chemotherapy was associated with a significant reduction in mortality among older women with ER-negative, LN-positive breast cancer.
Adjuvant chemotherapy clearly improves survival for women with early-stage breast cancer.1 Women age 50 to 69 years with breast cancer will achieve a 20% proportional reduction in the risk of recurrence and an 11% proportional reduction in the risk of death if they receive adjuvant polychemotherapy.1 However, there are limited data on the benefit of chemotherapy in women age 70 years or older. A recent report found that older and younger women derived similar benefits from more aggressive versus less aggressive chemotherapy regimens, suggesting that adjuvant chemotherapy may have a role in the treatment of healthy older women.2 Treatment guidelines from St Gallen3 and the National Comprehensive Cancer Network4 do not set an upper age limit for the use of chemotherapy, but acknowledge that comorbid conditions and life expectancy must be considered in chemotherapy decisions. Because of many factors, including the lack of data, patient comorbidities, and concerns over toxicity, older women are less likely to be treated with adjuvant chemotherapy.5-7 Furthermore, limited information is available on the types of adjuvant chemotherapy regimens that are being used to treat older breast cancer patients in the community.8 Because of the more significant role of patient comorbidities in older patients and the possibility of increased toxicities, especially among patients treated with anthracyclines, the choice of chemotherapy regimens may be quite different in younger versus older patients.9 Given the lack of a clear standard for adjuvant chemotherapy for breast cancer in older women, we wished to determine patterns of chemotherapy use in a population-based cohort of older women. In addition, because the benefit of adjuvant chemotherapy in older women is uncertain, we evaluated the association between chemotherapy use and survival.
Data Source We used the Surveillance, Epidemiology, and End Results (SEER) –Medicare-linked database for this study. The SEER program is a national population-based tumor registry that collects information on incident cancer cases. Medicare is the primary health insurer for 97% of the US population age 65 years or older. Under an agreement between the National Cancer Institute and the Center for Medicaid and Medicare Services, individuals listed in SEER who are eligible for Medicare have been linked to their Medicare records. Of persons who are reported by SEER as diagnosed with cancer at age 65 or older, 93% were matched with their Medicare enrollment records. At present, cancer patients diagnosed through 1999 have been linked, and their Medicare claims are available through 2002. Patient demographics, dates of diagnosis, extent of disease, and surgical treatment are available through the SEER registry data and are found in the SEER-Medicare Patient Entitlement and Diagnosis Summary File (PEDSF). Education and poverty are provided as census tract-level variables and are defined as the percentage of individuals living in a census tract with less than 12 years education or living below the poverty level. The use of specific chemotherapy drugs can be ascertained through Common Procedural Terminology J codes in the SEER-Medicare Outpatient, Physician/Supplier, and Durable Medical Equipment files.
Study Population Adjuvant chemotherapy use within a year of diagnosis was identified through the Common Procedural Terminology J codes in SEER-Medicare files. To be considered adjuvant chemotherapy, claims had to begin within 4 months of diagnosis. The included codes were J8510, J8520, J8521, J8530 to J8999, and J9000 to J9999.8,10-12 We excluded the codes of J9202 (goserelin), J9209 (mesna), 9212 to 9214 (interferon), and 9217 to 9218 (leuprolide acetate) because these drugs are not cytotoxic chemotherapeutic agents. The chemotherapy regimen was identified by the combination of specific agents that were used in the chemotherapy. Chemotherapy was classified as an anthracycline-based regimen if J codes for doxorubicin or mitoxantrone were present and was classified as being based on cyclophosphamide, methotrexate, and fluorouracil (CMF) if J codes were present for methotrexate and fluorouracil with or without codes for cyclophosphamide, given that oral cyclophosphamide was not reimbursed by Medicare through all the years in this study. If J codes for other chemotherapy drugs were found in addition to CMF, the combination was still classified as a CMF-based regimen. If patients were given both anthracycline and CMF chemotherapy, they were included with the group who received anthracycline-based chemotherapy. Using ICD-9 (clinical modification) diagnosis and procedure codes, comorbidity conditions during 1 year before diagnosis of breast cancer were searched from Medicare inpatient, outpatient, and physician claim data. Comorbidity score was calculated using Klabunde’s adaptation of the Charlson comorbidity index from the macro provided by National Cancer Institute.13-15
Statistical Analyses
A total of 41,390 women age 65 years or older with stage I to III breast cancer were identified, of whom 4,500 (10.9%) were treated with adjuvant chemotherapy. During the 1990s, the percentage of patients who received chemotherapy significantly increased, from 7.4% in 1991 to 16.3% in 1999 (P < .001; Table 1). This increase in chemotherapy use was seen despite significant time shifts toward older patient age at diagnosis (P < .001) and earlier stage of disease (P = .007). The use of chemotherapy varied greatly by patient stage but increased significantly within each stage of disease (Fig 1). Patient characteristics are shown in Table 2, by receipt of adjuvant chemotherapy. Patients who received chemotherapy tended to be younger, in good health, have more advanced-stage disease, and have estrogen receptor–negative cancer when compared with those women who did not receive chemotherapy.
A multivariate analysis was performed to determine which factors were associated with chemotherapy use among older women with breast cancer (Table 3). The use of chemotherapy decreased with increasing patient age, so that women age 75 to 79 years and women age 80 years or older were approximately four times and 20 times less likely, respectively, to receive chemotherapy than women 65 to 69 years old. Women treated in 1999 were four times more likely (odds ratio, 4.00; 95% CI, 3.40 to 4.70) to receive chemotherapy than women treated in 1992. Older black women were less likely to receive adjuvant chemotherapy when compared to non-Hispanic white women (odds ratio, 0.74; 95% CI, 0.61 to 0.89). Clinical factors strongly influenced the use of adjuvant chemotherapy: women who had more advanced-stage disease, a higher number of involved axillary lymph nodes, high-grade tumors, estrogen receptor–negative tumors, and lower Charlson comorbidity scores were more likely to receive chemotherapy.
We evaluated the different chemotherapy regimens that these women received. Overall, 52.5% of women received chemotherapy with a CMF-based regimen, 41.3% received chemotherapy with an anthracycline-based regimen (including anthracycline and taxane combinations), 1.4% received chemotherapy with other taxane regimens, and 4.8% received chemotherapy with other combinations. The use of different regimens changed over the time course of this study. These changes are illustrated in Figure 2. The use of anthracycline-based chemotherapy increased from 26.7% of older women receiving chemotherapy in 1991 to 56.5% in 1999 (P < .001). Chemotherapy with CMF-based regimens decreased from 66.2 to 37.4% over the same time period. Figure 2 also demonstrates the striking increase in the use of adjuvant taxanes in older women during the 1990s. By 1999, 30.4% of older women received a taxane as a component of their adjuvant chemotherapy regimen.
We next calculated Cox models to determine whether adjuvant chemotherapy in older women was associated with any change in breast cancer survival among women with lymph node–negative and lymph node–positive breast cancer. A significant interaction was seen between estrogen receptor status and chemotherapy use. Thus, the analyses are stratified by estrogen receptor status and by the presence or absence of axillary lymph node involvement. Results of Cox models are shown in Table 4. Among women with lymph node–negative disease, chemotherapy use was not significantly associated with risk of death from breast cancer for either women with estrogen receptor–positive or –negative disease. Similarly, among women with lymph node involvement, no benefit from chemotherapy was apparent among women with estrogen receptor–positive disease. However, among women with lymph node–positive and estrogen receptor–negative disease, chemotherapy use was associated with a lower hazard of death from breast cancer (hazard ratio, 0.72; 95% CI, 0.54 to 0.96). The benefit was similar for women treated with anthracycline versus nonanthracycline chemotherapy. Chemotherapy was also associated with improvements in overall survival only for women with lymph node–positive, estrogen receptor–negative breast cancer (hazard ratio, 0.65; 95% CI, 0.52 to 0.82).
There was no significant interaction between chemotherapy and patient age. Because of the lack of data from randomized controlled trials on the benefit of chemotherapy in women age 70 years or older, we also looked specifically at this cohort of 32,734 women. A similar benefit from chemotherapy was seen, with a hazard ratio of 0.74 (95% CI, 0.56 to 0.97; P = .026) for breast cancer deaths among women age 70 years or older with lymph node–positive and estrogen receptor–negative breast cancer. Women 70 years or older with lymph node–negative or estrogen receptor–positive disease had no apparent benefit from adjuvant chemotherapy.
In this study, we found that chemotherapy for breast cancer is associated with improved survival among older women with lymph node–positive, estrogen receptor–negative breast cancer. This benefit of chemotherapy was independent of patient age, and a similar improvement in survival was seen in a subset of women age 70 years or older as was seen in women age 65 years or older. No benefit of chemotherapy was apparent in women with lymph node–negative breast cancer or among women with lymph node–positive and estrogen receptor–positive breast cancer, who would be at a lower risk of recurrence and death from breast cancer. Our findings are consistent with the study by Elkin et al18 in this issue. The authors examined a population of older women with estrogen receptor–negative breast cancer, and reported improved survival among those women who received chemotherapy. Our results are also concordant with recently published data by Muss et al,2 which indicate that older women achieve a reduction in risk of both breast cancer recurrence and death from intensive chemotherapy regimens. Although the study by Muss et al provided convincing evidence generated from randomized clinical trials on the benefit of chemotherapy in older women, only 159 of the patients (2%) were age 70 or older. Similarly, the Oxford overview has shown that women age 50 to 69 benefit from adjuvant chemotherapy, but had an insufficient number of patients age 70 years or older to determine the benefit of chemotherapy in women older than 70 years of age.19 Our data, although observational, suggest that women older than 70 with high-risk disease may benefit from adjuvant chemotherapy. In this study, we only observed a benefit from chemotherapy among women with estrogen receptor–negative breast cancer. The importance of estrogen receptor status in response to chemotherapy is being recognized with increasing frequency. In an analysis of more than 6,000 lymph node–positive patients treated during the last 20 years on Cancer and Leukemia Group B trials, Berry et al20 showed that adjuvant chemotherapy had a consistently greater impact on those patients with estrogen receptor–negative than estrogen receptor–positive disease. We similarly found that the benefit of chemotherapy differed by estrogen receptor status. We also found no beneficial effect of chemotherapy on node-negative tumors. Although our data on the benefit of chemotherapy in lymph node–positive, estrogen receptor–negative older women are compelling, the lack of an effect seen in the other subsets cannot definitively rule out any benefit from chemotherapy in these patient populations. However, our findings are consistent with the Oxford overview, which demonstrated a decreasing benefit of chemotherapy with increasing patient age.19 We have also shown that the use of adjuvant chemotherapy in older women has more than doubled during the 1990s, despite time trends toward earlier stage disease and older age at diagnosis. This increase was seen within each stage of breast cancer. These trends likely reflect both increasing use of adjuvant chemotherapy for all breast cancer patients21 and a greater willingness to offer chemotherapy to older patients. In 1990, the National Institutes of Health Consensus Statements found insufficient evidence to recommend adjuvant chemotherapy in older women.22 Yet over time, there has been increasing recognition that healthy older women may reap benefit from chemotherapy. The changes in the St Gallen Guidelines reflect this shift: the 2001 guidelines eliminate the category of "elderly" because it was believed to be "arbitrary and not useful."3,23 Our study shows that treatment changes have occurred not just among the thought leaders in the field, but, more importantly, among the community physicians who are providing medical care to older breast cancer patients. The patterns of chemotherapy use are encouraging because the use of chemotherapy seems to parallel our findings on outcome; that is, both estrogen receptor negativity and lymph node involvement were strongly associated with the use of adjuvant chemotherapy. For example, among women age 70 to 80 with comorbidity scores of 0 to 1 who had lymph node–positive, estrogen receptor–negative breast cancer, 66% were treated with adjuvant chemotherapy. As has been previously demonstrated, we found that the use of adjuvant chemotherapy decreased markedly with increasing patient age, even after adjustment for comorbidities.5-7 The use of chemotherapy was also less common in older black women than in non-Hispanic white women, which is consistent with well-documented patterns of undertreatment of black women.6,12 We found significant geographic variability in the use of chemotherapy. These geographic differences are important to recognize because they could be influenced by appropriate educational interventions. The major limitation in using observational data to study treatment outcomes is selection biases that are not adequately measured and controlled for in the multivariate models.24 With respect to chemotherapy outcomes, two major selection biases would tend to produce opposite effects. The first is that chemotherapy is more likely to be administered to patients with more aggressive tumors. This is shown in Table 3, for example, with higher tumor stage and histologic grade associated with greater likelihood of chemotherapy. However, tumor stage and grade only partially capture the variation in aggressiveness of tumors. Clinicians and patients may be using more subtle prognostic variables when deciding on choice of therapy. The second bias is that patients with comorbidity are less likely to receive chemotherapy (Table 3). Once again, no comorbidity measure based on administrative data could completely capture the variance in patient health status.24 In addition to controlling for measurable confounders in the multivariate survival analyses, we can also assess the impact of these biases by looking at the comparative effects of chemotherapy on cancer-specific survival versus all-cause survival. In general, selection biases on tumor aggressiveness would tend to increase cancer-specific mortality in the chemotherapy group, whereas selection biases on comorbidity would tend to decrease all-cause mortality in the chemotherapy group. It would be difficult to construct an argument whereby selection biases were responsible for the selective effect of chemotherapy on cancer-specific survival in patients with lymph node–positive, estrogen receptor–negative disease, a finding that is in accord with the Cancer and Leukemia Group B data mentioned previously. In this regard, our results are analogous to the observational studies showing a beneficial effect on survival in patients with stage III but not stage II colon cancer, and are consistent with data from clinical trials.25,26 Other limitations of this study include the use of administrative claims, which were generated for billing rather than for research purposes, to ascertain chemotherapy administration. However, given issues of reimbursement as well as the penalties for Medicare fraud, physicians’ offices have strong incentives to bill accurately. The specific drugs were identified by Common Procedural Terminology J codes, which are required for reimbursement. However, for chemotherapy administered to hospitalized patients, these codes are unavailable. Thus, to some extent, we may have under-ascertained chemotherapy use or could have obtained a biased representation of the chemotherapy regimens in use. However, adjuvant chemotherapy for breast cancer rarely is given to patients ill enough to require hospitalization. We also were not able to determine whether patients received a full course of chemotherapy at standard doses, and incomplete therapy may be an important component of undertreatment.27 Our findings may not be completely generalizable because patients in SEER sites tend to be more urban and affluent than the rest of the US population.28 Despite these limitations, we have been able to examine chemotherapy use and outcomes in a population-based cohort of more than 41,000 older women. We have shown more that a doubling in the use of adjuvant chemotherapy in women during the 1990s, although by 1999 only 16% of older women received chemotherapy. Because the life expectancy of a 70-year-old woman is approximately 15 years,29 many patients with stage II or III breast cancer were likely undertreated. Our results, in conjunction with the Cancer and Leukemia Group B analyses2 and the study by Elkin et al,18 would lead us to conclude that women older than 65 years who are in relatively good health with lymph node–positive, estrogen receptor–negative breast cancer should be offered chemotherapy. In addition, our results add some support to those who urge caution in the routine use of chemotherapy in older women with good-prognosis tumors. Given that half of all new cases of breast cancer occur in this older population, it is critical to continue to generate evidence on which to base therapeutic decisions. One can only speculate that had these 4,500 women been included in a randomized trial of adjuvant chemotherapy, we would have conclusive evidence of the value of adjuvant chemotherapy regimens in older patients in the United States.
The authors indicated no potential conflicts of interest.
Supported in part by National Institutes of Health Grant No. 1K07 CA 109064-01 (to S.H.G) and the Center on Population Health and Health Disparities Grant No. P50CA105631. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Cancer 89:561-573, 2000[CrossRef][Medline] 7. DeMichele A, Putt M, Zhang Y, et al: Older age predicts a decline in adjuvant chemotherapy recommendations for patients with breast carcinoma: Evidence from a tertiary care cohort of chemotherapy-eligible patients. Cancer 97:2150-2159, 2003[CrossRef][Medline] 8. Du X, Goodwin JS: Increase of chemotherapy use in older women with breast carcinoma from 1991 to 1996. Cancer 92:730-737, 2001[CrossRef][Medline] 9. Du XL, Osborne C, Goodwin JS: Population-based assessment of hospitalizations for toxicity from chemotherapy in older women with breast cancer. J Clin Oncol 20:4636-4642, 2002 10. Health Care Financing Administration: HCFA Common Procedure Coding System (HCPCS): National Level II Medicare Codes. Los Angeles, CA, Practice Management Information Corp, 1994 11. American Medical Association: Physicians’ Current Procedural Terminology: CPT 94. Chicago, IL, American Medical Association, 1993 12. Du X, Goodwin JS: Patterns of use of chemotherapy for breast cancer in older women: Findings from Medicare claims data. J Clin Oncol 19:1455-1461, 2001 13. 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] 14. Romano PS, Roos LL, Jollis JG: Adapting a clinical comorbidity index for use with ICD-9-CM administrative data: Differing perspectives. J Clin Epidemiol 46:1075-1079, 1081-1090, 1993[CrossRef][Medline] 15. National Cancer Institute: SEER-Medicare: Calculation of Comorbidity Weights. http://healthservices.cancer.gov/seermedicare/program/comorbidity.html 16. Stokes M, Davis C, Koch G: Categorical Data Using the SAS System. Cary, NC, SAS Institute Inc, 2000 17. Grambasch PM, Therneau T: Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81:515-526, 1994 18. Elkin EB, Hurria A, Mitra N, et al: Adjuvant chemotherapy and survival in older women with hormone receptor–negative breast cancer: Assessing outcome in a population-based observational cohort. J Clin Oncol 24:10.1200/JCO.2005.03.6053 19. 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. Berry D, Cirrincione C, Henderson IC, et al: Effects of improvements in chemotherapy on disease-free and overall survival of estrogen-receptor negative, node positive breast cancer: 20-year experience of the CALGB and U.S. Breast Intergroup. Breast Cancer Res Treat 88:29-41, 2004[CrossRef][Medline] 21. Mariotto A, Feuer EJ, Harlan LC, et al: Trends in use of adjuvant multi-agent chemotherapy and tamoxifen for breast cancer in the United States: 1975-1999. J Natl Cancer Inst 94:1626-1634, 2002 22. NIH Consensus Conference: Treatment of early-stage breast cancer. JAMA 265:391-395, 1991 23. Glick JH, Gelber RD, Goldhirsch A, et al: Meeting highlights: Adjuvant therapy for primary breast cancer. J Natl Cancer Inst 84:1479-1485, 1992 24. Wen SW, Hernandez R, Naylor CD: Pitfalls in nonrandomized outcomes studies: The case of incidental appendectomy with open cholecystectomy. JAMA 274:1687-1691, 1995 25. Schrag D, Rifas-Shiman S, Saltz L, et al: Adjuvant chemotherapy use for Medicare beneficiaries with stage II colon cancer. J Clin Oncol 20:3999-4005, 2002 26. Iwashyna TJ, Lamont EB: Effectiveness of adjuvant fluorouracil in clinical practice: A population-based cohort study of elderly patients with stage III colon cancer. J Clin Oncol 20:3992-3998, 2002 27. Lyman GH, Dale DC, Crawford J: Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: A nationwide study of community practices. J Clin Oncol 21:4524-4531, 2003 28. Nattinger AB, McAuliffe TL, Schapira MM: Generalizability of the surveillance, epidemiology, and end results registry population: Factors relevant to epidemiologic and health care research. J Clin Epidemiol 50:939-945, 1997[CrossRef][Medline] 29. Arias E, Smith B: Deaths: Preliminary data for 2001. Natl Vital Stat Rep 51:1-44, 2003[Medline] Submitted April 7, 2005; accepted November 17, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
65 years, stage I to III breast cancer, and diagnosis between 1991 and 1999. Adjuvant chemotherapy use was ascertained by Common Procedural Terminology J codes. Logistic regression analysis was performed to determine factors associated with chemotherapy use. Multivariate Cox proportional hazards models were used to calculate the hazard of death for women with and without chemotherapy. 
