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© 2002 American Society for Clinical Oncology Adjuvant Therapy for Breast Cancer: Practice Patterns of Community PhysiciansByFrom the National Cancer Institute, Bethesda, and Information Management Services, Inc, Silver Spring, MD. Address reprint requests to Linda C. Harlan, MD, Applied Research Program, National Cancer Institute, 6130 Executive Blvd, EPN 4005, Bethesda, MD 20892; email: lh50w{at}nih.gov
PURPOSE: We evaluated the use of adjuvant therapy for breast cancer using the National Institutes of Health (NIH) Consensus Development Conference statements as guideposts for assessing how rapidly community physicians adopt recommended therapies.
PATIENTS AND METHODS: Women with stage I through IIIA breast cancer diagnosed in 1987 through 1991 and in 1995 were randomly sampled from the population-based National Cancer Institute Surveillance, Epidemiology, and End-Results program. A total of 8,106 women were included in the study with younger women,
RESULTS: After adjusting for clinical and nonclinical factors, the use of 1985 recommendations for adjuvant therapy in women with node-positive disease was already high at 80% in 1987 and increased slightly to 84% by 1995. Use of combined multidrug chemotherapy plus tamoxifen increased. In contrast, the use of 1990 recommendations for adjuvant therapy for node-negative disease was slightly less than 13% in 1987 and increased markedly to 57% by 1995. For women with node-negative tumors CONCLUSION: Community physicians began prescribing adjuvant chemotherapy and hormonal therapy in advance of publication of the NIH consensus statement in 1990. Adoption of recommended treatments for node-negative disease has been less complete compared with node-positive tumors, perhaps reflecting the more complex nature of the clinical trials data or the smaller anticipated benefit from adjuvant therapy for this disease subset.
DURING THE PAST TWO decades, clinical research has brought about major changes in surgical and adjuvant therapy for early-stage breast cancer. The initial positive results from clinical trials of adjuvant chemotherapy and hormonal therapy after primary treatment of local disease have encouraged the expansion of adjuvant approaches to other subsets of women with resectable breast cancer.1,2 As results from clinical trials accumulated on the postoperative treatment of early-stage breast cancer, the National Cancer Institute (NCI) disseminated this information through announcements and conferences that were intended to guide treatment. In the 1980s, based on clinical trials and reviews, adjuvant chemotherapy with a combination of drugs was recognized as standard care for premenopausal women with axillary node involvement, whereas tamoxifen was recommended for node-positive, receptor-positive tumors in postmenopausal women.1,3 Indeed, this standard was confirmed by the 1985 National Institutes of Health (NIH) Consensus Development Conference statement.4 In May 1988, the NCI issued a clinical alert advising the use of combination chemotherapy for node-negative patients with tumors greater than 3 cm in size and estrogen receptornegative based on new clinical trials results.5 The NIH Consensus Development Conference in June 1990 concluded that adjuvant therapy also provided benefits for women with early-stage, node-negative breast cancer.6 The 1995 Clinical Announcement provided information on the use of 5 years of tamoxifen, compared with a longer duration, and suggested that 5 years should be the standard outside of clinical trials.7,8 Despite the potential for results from clinical trials to change morbidity and mortality from breast cancer, several studies suggest that the transfer of findings from the research setting into community practice has been disappointing. Some suggest that physicians do not necessarily rely on evidence from trials to make recommendations for breast cancer therapy, and clinical practice guidelines based on the research are not uniformly followed by many physicians.9-12 However, other studies have found more rapid incorporation of new clinical trials results into physician practices.13,14 Indeed, physicians may begin to incorporate new treatment regimens into their clinical practices after initial publications of clinical trials or after the publication of an important review of recent clinical trials. To assess recent trends in adoption of research results for adjuvant breast cancer therapy, we conducted a population-based study of women with early-stage breast cancer treated in community settings in diverse geographic locations throughout the United States. We sought to determine whether the percentage of women with early-stage breast cancer receiving adjuvant therapy had increased over the time period between 1987 and 1995 using NIH Consensus Development Conference statements and NCI announcements as reference standards. These standards are summarized in Fig 1.
Data for the current analyses were obtained from the Patterns of Care Studies conducted within the Surveillance, Epidemiology, and End-Results (SEER) cancer registries. The SEER program obtains data on demographics, diagnosis, tumor characteristics, and treatment primarily through the hospital medical records, outpatient surgical centers, or pathology departments. With more individuals receiving treatment outside the hospital setting, the routine SEER data on the first course of treatment is not complete. Therefore, the Patterns of Care Studies are used for selected cancer sites because special data collection efforts are required to obtain details of therapy not found in the hospital record. The effort includes contacting the treating physician to obtain detailed information on radiation, chemotherapy, and hormonal therapy. From the SEER data for cases diagnosed in 1987 through 1991 and in 1995, women with early-stage breast cancer (stages I, II, and IIIA as defined by the American Joint Committee on Cancer) were identified. These cases were then stratified by age at diagnosis (< 51 and 51 and older), and a subset of cases was randomly selected from each of the two age groups. Women younger than 51 years old were oversampled to obtain more stable estimates of the therapy provided to younger breast cancer patients. We also oversampled African-American and Hispanic women diagnosed with breast cancer in 1995. Women residing in Los Angeles County were included only in the 1995 data because this registry did not join the SEER program until 1992. Models were run with the Los Angeles County registry data included and excluded from the analyses. There were no appreciable changes to the odds ratios for other variables included in the models, so we included the registry in our analyses. Women with a previous diagnosis of cancer (except for nonmelanoma skin cancers) were excluded from the study, as were women with simultaneous cancer diagnoses, because this might have altered the selection of therapy. A total of 8,106 women were included in these studies. We were interested in describing the use of adjuvant therapy. Therefore, patients who did not undergo surgery (n = 13) were excluded from the study. Another 369 women were enrolled onto clinical trials. We excluded them from our analysis because their treatment was dictated by the clinical trial protocol. Participation in clinical trials in our sample varied from a low of 1.3% in 1989 to a high of 4% in 1991. For the selected cases, the SEER registries reabstracted each womans medical records to verify tumor characteristics, treatment, as well as certain demographic information that might influence treatment. Demographic factors were categorized and included age (< 51, 51 to 64, and 65 and older), race (white, black, or other), marital status (married or other), and location of the tumor registry. In addition, the treating physician was contacted to determine if radiation therapy, chemotherapy, or hormonal therapy had been given. Because adjuvant therapy is often provided in the outpatient setting, the physician was asked to identify all drugs administered because this information was not always available in the hospital chart. The clinical determinants of treatment included axillary nodal status, number of positive nodes, estrogen receptor assay results, histologic tumor grade, and tumor size. Nodal status was determined from the pathologic findings for all dissected axillary or other regional lymph nodes and was reported as positive, negative, or unknown. Slightly more than 5.0% of cases (n = 320) had an unknown nodal status. Cases with unknown nodal status were excluded from the multivariate analyses of adjuvant therapy because nodal status was used to determine whether treatment was given according to NIH consensus statement recommendations. Estrogen receptor assays were classified as positive or negative based on the range set within the laboratory analyzing the surgical specimen. Cases with borderline values were considered receptor-positive. Tumor grade was recorded as the highest grade when multiple grades were given. Tumor size was based on the largest dimension of the primary tumor. When multiple masses were present, the largest measurement was recorded. Tumor size before the initiation of radiation therapy was used for patients receiving preoperative radiotherapy. We assigned women (n = 249) with negative nodes and unknown tumor size to the less than 1-cm tumor size category for the multivariate analysis. The multivariate analyses did not change appreciably with this group included or excluded, and they are included in the analysis presented. A univariate assessment of chemotherapy and tamoxifen and the previously mentioned clinical and demographic variables was performed. Multivariate analyses were performed to examine adoption of the recommendations from the NIH consensus statements and clinical alerts after adjustment for clinical and demographic factors. For women with positive nodes, recommended therapy was defined according to the 1985 NIH Consensus Development Conference statement (Fig 1). Recommended therapy for women with negative nodes was defined using the 1988 clinical alert and 1990 NIH Consensus Development Conference statement (Fig 1). All estimates were weighted to reflect the population from which the sample was drawn. The sample weights, calculated as the inverse of the sampling proportion for each sampling stratum (defined by age, race, stage, and registry location), were used to obtain estimates that are representative of all eligible early-stage breast cancer patients in the study areas. Because younger women were oversampled, an overall mean value will be different from the arithmetic average of each age group. We used the statistical software SUDAAN (Research Triangle Institute, Research Triangle Park, NC) for all analyses. This software allows for the use of sample weights and adjusts the SE appropriately. All tests were two-sided. Results of the logistic regression models are shown as adjusted percentages receiving the recommended therapy according to each of the independent variables. The logistic regression models were used to generate these estimates. The percentage in each group was then directly standardized to the distribution of the covariates among the weighted sample used in each model.15
Table 1 lists the number as well as the weighted percentage of cases in the study by year of diagnosis and selected demographic and clinical characteristics. The percentage of women with smaller tumors increased over time. The percentage of women with negative estrogen receptors did not vary appreciably over the time period nor did the percentage with unknown or unperformed receptor assays.
Adjuvant therapy for women diagnosed with early-stage breast cancer increased substantially between 1987 and 1995 (Table 2). Only approximately 36% of women diagnosed in 1987 received adjuvant therapy. By 1995, this percentage had nearly doubled to 64%. The use of multidrug chemotherapy alone increased almost seven percentage points. Tamoxifen use increased substantially during this time from 20% to 34%. The use of multidrug chemotherapy plus tamoxifen more than doubled and increased from 5% to 12%. Age differentials in adjuvant therapy are listed in Table 3 according to nodal status.
Node-Positive Tumors By 1987, the first year of data from our study, use of adjuvant therapy for node-positive breast cancer was already high (Table 3). When examined by age, nearly 80% or greater of women younger than 51 years received adjuvant therapy, with slightly less use in women older than age 50 years. Particularly notable was the increase in concurrent use of tamoxifen and combination chemotherapy in all age groups from 1987 to 1995. However, the use of chemotherapy and the use of concurrent tamoxifen and chemotherapy were much less among women older than 65 years, whereas use of tamoxifen alone was much higher in this age group for all years. When examined by age and tumor size, nearly 70% or more of women in each age group received some adjuvant therapy, regardless of tumor size (data not shown). Estrogen receptor status did influence treatment in certain age groups. In younger women, age 51 or younger, chemotherapy was administered to a similar percentage of women with node-positive tumors regardless of receptor status (data not shown). However, women older than 50 years with estrogen receptornegative tumors were less likely to receive tamoxifen compared with women with receptor-positive tumors. In 1995, slightly more than 33% of women older than 65 years with positive nodes and estrogen receptornegative tumors received tamoxifen and multidrug chemotherapy, and nearly 15% received tamoxifen alone (data not shown). Women age 50 to 64 with estrogen receptornegative tumors were more likely to receive chemotherapy than a similar age group with estrogen receptorpositive tumors. Using a logistic regression model, we found that the recommended adjuvant therapy did not increase appreciably over the 9-year period in women with node-positive breast cancer after adjusting for age, race, geographic area, estrogen receptor status, tumor grade, tumor size, and number of positive nodes (Table 4). A comparison of 1987 to 1989 data with each of the successive time periods (1991 to 1992 and 1995) demonstrated no statistically significant differences; likewise, comparisons between 1990 to 1991 and 1995 showed no appreciable increase (data not shown). There were no differences by race, grade, or number of positive nodes. However, younger women were treated more often with guideline therapy than were older women, as were those with tumors sized 1 to 3 cm or receptor-positive disease. The adjusted percentage of women receiving the recommended adjuvant therapy was 73% for women age 51 to 64 and 63% for women age 65 and older.
Node-Negative Tumors During 1987, less than 17% of women with node-negative breast cancer were receiving adjuvant therapy. By 1995, treatment had increased such that adjuvant therapy was given to more than 62% of women younger than 65 years and to 51% in women older than 65 years (Table 3). Women younger than 51 years received chemotherapy considerably more often than older women, whereas the older group received tamoxifen more frequently. The 1990 NIH Consensus Development Conference suggested that women with node-negative tumors less than 1 cm in size had an excellent prognosis and did not require adjuvant therapy outside of clinical trials.16 In 1990, nearly 32% of this group was receiving some form of adjuvant therapy (Table 5). This percentage dropped in 1991 to approximately 27% but increased to nearly 40% in 1995, predominately because of the increased use of tamoxifen. In 1995, slightly less than 33% of women with node-negative tumors less than 1 cm in size received tamoxifen alone. Over the same period, use of multidrug chemotherapy also declined from a high of 12% in 1989 to 4.0% in 1995. Use of tamoxifen and multidrug chemotherapy together in this group of women with tumors less than 1 cm remained low and only increased to slightly less than 3% by 1995.
Models that included all women with node-negative tumors were constructed to determine factors associated with the use of guideline therapy (Table 4). Over time, there was a statistically significant increase in the percentage of women who received the recommended therapy. The increase occurred primarily between the time period 1987 to 1989 and the two later periods, 1990 to 1991 and 1995, with no clear additional increase between 1990 to 1991 and 1995, and persisted after adjusting for age, race, geographic region, receptor status, tumor grade, and tumor size.
Chemotherapeutic Drugs
Measurement of chemotherapy and tamoxifen use in a United States population-based setting provides feedback on the ability of research results to modify clinical practice. In this community-based study, we found that by 1987, the first year of our study, penetration of adjuvant therapy had reached levels of nearly 80% in women with node-positive breast cancer, with no further statistically significant changes occurring between 1987 and 1995. It would seem that results from clinical trials and the 1985 NIH Consensus Development Conference recommendations for the treatment of node-positive breast cancer had already been implemented by much of the community by 1987. We recognize that using the NIH Consensus Development Conference statements or clinical announcements as reference points for assessing practice patterns may not be ideal. It is certainly possible that other publications may have influenced community practice. However, although individual trials may be influential, it is likely that confirmatory trials are required before a major shift in practice patterns occurs. That is why we elected to use the Consensus Conference statements and clinical announcements as they occur once there is sufficient literature to support a change in therapy. An alternate reference point that might have been selected are the publications performed by the Early Breast Cancer Trialists Collaborative Group (EBCTCG), a statistical center based in Oxford, England, that has performed meta-analyses of adjuvant therapy for breast cancer. In December 1988, the EBCTCG published an analysis of 61 randomized trials of the use of cytotoxic therapy and tamoxifen and mortality.3 They concluded that tamoxifen reduced mortality in women age 50 years and older and cytotoxic therapy reduced mortality in women younger than 50 years. The sample size was insufficient to adequately address the use of these therapies in women with node-negative breast cancer. Using the 1988 publication as a reference point, our data do not suggest that a major shift occurred at this time in the therapy of women with node-positive breast cancer. However, this is most likely due to the fact that the data from the EBCTCG meta-analyses were presented at the 1985 NIH Consensus Conference and influenced the resulting Consensus Development Conference statement. It is noteworthy that in women older than 50 years with node-negative breast cancer, there was a substantial increase in the use of adjuvant therapy in the year after the 1988 meta-analysis, which suggests that community physicians might have applied the findings from node-positive breast cancer to the women at lower risk. An example of publications that may have influenced trends unrelated to Consensus Conferences statements or clinical announcements occurred in 1989. There was a substantial decrease in the use of tamoxifen in women of all ages with node-positive breast cancer. The decreased use of tamoxifen coincided with reports of endometrial cancers being associated with this drug.17 Other studies have also attempted to assess trends in patterns of care. In a hospital-based study, Guadagnoli et al14 found that in a sample of women diagnosed in Minnesota and Massachusetts between September 1993 and September 1995 with lymph nodepositive breast cancer, more than 90% of premenopausal women received chemotherapy. Approximately 92% of postmenopausal women with node-positive, estrogen receptorpositive tumors in that study received hormonal therapy, chemotherapy, or both. In contrast to the 1995 data from our study, the percentage receiving these treatments in the hospital-based studies are somewhat higher. Potential reasons for this difference may be explained by the inclusion in our study of a geographically diverse, population-based sample of all women within SEER diagnosed with early-stage breast cancer. Geographic differences in treatment practices have been noted by others.11,12 Our sample also included a substantial number of African-American women, Hispanic women, and women of other races, whereas the other study included primarily white women. Although there were no significant differences by race after adjusting for other factors, there was a trend for African-American women to receive less adjuvant therapy. Racial and ethnic minority groups have been shown to have less access to medical care.18,19 Despite these methodologic differences, the percentage receiving either chemotherapy or hormonal therapy was quite high and surprisingly similar between the two studies. Although there were no increases in the percentage of women with node-positive tumors receiving recommended therapy between 1987 and 1995, there were changes in the specific chemotherapeutic drugs that were administered. In 1987, among a subset of women receiving chemotherapy, more than 84% of the node-positive patients received CMF or CMF plus vincristine and prednisone. By 1995, the use of anthracycline-containing regimens increased to 42% in women receiving adjuvant chemotherapy. Similar trends are seen in women with node-negative breast cancer, although the use of CMF remains greater. Several clinical trials have reported anthracycline-containing regimens as a preferable treatment modality. The 1988 publication by the EBCTCG3 did cite a small survival advantage for anthracycline-containing adjuvant regimens based on a meta-analysis of 11 randomized trials. Our data suggest that United States oncologists are, on average, early adopters of new therapies, even before definitive results become available from adjuvant trials. We observed a steady increase in the percentage of women with node-negative breast cancer who received adjuvant therapy over the 8-year period. Between 1987 and 1988, even before the issuance of the NCI clinical alert or the publication of the analysis of 61 clinical trials, we observed a dramatic increase in the percentage of women younger than 65 years who received some form of adjuvant therapy. The increase was more gradual but constant in the older groups. Again, between 1990 and 1991, there was a substantial increase for the two younger age groups, with a much smaller increase in the women age 65 years and older. The increase in the observed use of NIH consensus statement recommendations between 1987 to 1989 and subsequent years 1990 to 1991 and 1995 remained after we adjusted for age, race, geographic location, receptor status, tumor grade, and tumor size. Our study illustrates that adjuvant therapy does differ according to a patients age. Among women with node-positive tumors, the adjusted percentage of women receiving therapy consistent with the 1985 Consensus Conference statement was 82% for women younger than 51 years, 73% for women age 51 to 64 years, and 63% for women age 65 years and older. It is possible that the lower levels and the slower increase in the use of consensus statement adjuvant therapy in the oldest group is due in part to a relative lack of clinical trials information on the effect of treatment in this age group. Using the SEER-Medicare data, Du and Goodwin20 reported that in 1991 and 1992 approximately 26% of women age 65 years and older with node-positive disease received chemotherapy. The Du and Goodwin study is not strictly comparable. That study included women with all stages of invasive breast cancer, examined only chemotherapy data obtained through the use of the Medicare claims data procedures codes, and included chemotherapy given through the first 6 months after diagnosis. Despite the differences in methodology, our results are similar (25.2% in 1990 and 17.2% in 1991). The adoption of recommended therapy in older women with negative nodes was slower and did not reach the same level as that of younger women. Du and Goodwin reported that about 5% of women with node-negative breast cancer received chemotherapy. This is somewhat higher than the percentage in our study, 3.4% and 2.8% in 1991 and 1992, respectively. However, only women with early-stage breast cancer were included in our study. The 1990 NIH Consensus Development Conference recommended no additional treatment for women with negative nodes and tumor sizes less than 1 cm. In 1995, 40% of women in this category were receiving adjuvant therapy, primarily tamoxifen. At the recent 2000 NIH Consensus Development Conference, it was recommended that women with positive lymph nodes or tumors larger than 1 cm, regardless of nodal status, be considered for cytotoxic chemotherapy and that women with receptor-positive tumors be given 5 years of tamoxifen.21 The therapy given to women with small tumors in 1995 and the increased use of adjuvant therapy in women with node-negative disease may reflect the early adoption by some physicians of node-negative trial results overall, extrapolated to this good prognosis subset.3 In considering adherence to recommended therapy, we did examine the influence of a limited number of clinical and demographic factors. Nodal status, tumor size, and estrogen receptor status had a clear effect on treatment choice, whereas tumor grade and number of positive nodes did not. For node-positive disease, the presence of estrogen receptorpositive disease was the only clinical factor significantly related to choice of treatment and was associated with a greater likelihood of patients being treated according to Consensus Conference statement recommendations. Among women with node-negative disease, women with larger tumors received the recommended therapy less often than did women with smaller tumors. Although compliance with Consensus Conference recommendations generally increased during our study, 27% of node-positive and 47% of node-negative breast cancer patients did not receive the recommended therapy in 1995. Better understanding of the factors that influence treatment decisions is required. We found that treatment decreases by approximately 10% for node-positive and node-negative disease for women age 65 years and older compared with younger women. Some of this difference may reflect more comorbid disease in older women. Comorbidity has been shown to explain some, but not all, of the decrement in the receipt of radiation for older breast cancer patients.12 The slower adoption and less frequent adherence to guideline recommendations in women with node-negative disease may reflect the relatively smaller survival advantage found for this subset in clinical trials. The 1992 EBCTCG22 analysis of the impact of cytotoxic drugs suggested the absolute improvement in 10-year survival for node-negative breast cancer patients was 4%. The absolute improvement in survival with tamoxifen was reported to be 3.5%.23 In addition, the guidelines from the 1990 Consensus Development Conference are somewhat complex and suggest that tumors less than 1 cm in size do not need further treatment, whereas adjuvant therapy should be considered for those with tumors 1 to 3 cm in size. Patients and physicians may weigh the risks and benefits of adjuvant therapy and decide that the potential risks and side effects outweigh the benefits. Specific subsets of patients for whom recommendations either are lacking or are less definitive include those with small node-negative tumors and older women. As both of these groups are likely to become predominant in future years because of improved screening and overall prolongation of life, further research regarding optimal adjuvant approaches for these subgroups is warranted.
Supported by grant no. N01-PC-67005 to the Connecticut Department of Health, N01-PC-67006 to Emory University, N01-PC-67009 to Fred Hutchinson Cancer Research Center, N01-PC-65107 to Northern California Cancer Center, N01-PC-67008 to University of Iowa, N01-PC-67007 to University of New Mexico, N01-PC-67010 to University of Southern California, N01-PC-67000 to University of Utah, and N01-PC-65064 to Wayne State University from the National Cancer Institute, Division of Cancer Control and Population Sciences. This study was made possible through the efforts of the Principal Investigators and the cancer registry personnel at the participating SEER registries.
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Abrams JS: Five years versus ten years: Is the end in sight? J Natl Cancer Inst 93: 662-663, 2001 9. Kosecoff J, Kanouse DE, Brook RH: Changing practice patterns in the management of primary breast cancer: Consensus development program. Health Serv Res 25: 809-823, 1990[Medline] 10. Lazovich D, Solomon CC, Thomas DB, et al: Breast conservation therapy in the United States following the 1990 National Institutes of Health Consensus Development Conference on the treatment of patients with early stage invasive breast carcinoma. Cancer 86: 628-637, 1999[CrossRef][Medline] 11. Farrow DC, Hunt WC, Samet JM: Geographic variation in the treatment of localized breast cancer. N Engl J Med 326: 1097-1101, 1992[Abstract]
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Ballard-Barbash R, Potosky AL, Harlan LC, et al: Factors associated with surgical and radiation therapy for early stage breast cancer in older women. J Natl Cancer Inst 88: 716-726, 1996
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Johnson TP, Ford L, Warnecke R, et al: Effect of a National Cancer Institute clinical alert on breast cancer practice patterns. J Clin Oncol 12: 1783-1788, 1994 14. Guadagnoli E, Shapiro CL, Weeks JC, et al: The quality of care for treatment of early stage breast carcinoma: Is it consistent with national guidelines? Cancer 83: 302-309, 1998[CrossRef][Medline] 15. Korn EL, Graubard BI: Analysis of health surveys. New York, NY, John Wiley and Sons, 1999 16. Early stage breast cancer. Consens Statement 8:1-19, 1990 17. Fornander T, Rutqvist LE, Cedermark B, et al: Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 1: 117-120, 1989[Medline] 18. Hayward RA, Shapiro MF, Freeman HE, et al: Inequities in health services among insured Americans: Do working-age adults have less access to medical care than the elderly? N Engl J Med 318: 1507-1512, 1988[Abstract] 19. Freeman HE, Blendon RJ, Aiken LH, et al: Americans report on their access to health care. Health Aff 6: 6-8, 1987[CrossRef][Medline]
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Du X, Goodwin S: Patterns of use of chemotherapy for breast cancer in older women: Findings from Medicare claims data. J Clin Oncol 19: 1455-1461, 2001 21. National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development Conference statement: Adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst Monogr 93: 5-15, 2001 22. Early Breast Cancer Trialists Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 womenPart 2. Lancet 339: 71-85, 1992[Medline] 23. Early Breast Cancer Trialists Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 womenPart 1. Lancet 339: 1-15, 1992[Medline] Submitted June 11, 2001; accepted December 11, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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