the Applied Research Program
    Surveillance Research Program
    Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda
    Information Management Systems, Silver Spring, MD

    ABSTRACT

    PURPOSE: We describe trends in the use of chemotherapy and hormonal therapy by nodal and estrogen receptor (ER) status in women with early-stage breast cancer.

    METHODS: Cases were randomly sampled from the population-based Surveillance, Epidemiology and End Results (SEER) program and physician verified treatment was examined. A total of 9,481 women, aged 20 years and older, diagnosed with early-stage breast cancer in 1987 to 1991, 1995, and 2000 were included in the study.

    RESULTS: The use of chemotherapy plus tamoxifen increased between 1995 and 2000 for women with node-negative, ER-positive breast cancer  1 cm (8% to 21%). Nearly 23% of women with node-negative and ER-positive tumors  1 cm received no adjuvant therapy. The use of chemotherapy alone increased to nearly 60% in women with node-negative, ER-negative tumors  1 cm (48% to 59%). However, in 2000, 16% of women with node-positive and ER-negative tumors received no adjuvant therapy and an additional 6% received tamoxifen alone. The influence of age can clearly be seen. Chemotherapy is given much less often in women 70 years or older.

    CONCLUSION: The results from SEER areas across the United States suggest that physicians quickly responded to publications and guidelines regarding breast cancer therapy. The lack of definitive findings from clinical trials on the use of adjuvant therapy in women 70 years and older may explain the lower use in this group of women.

    INTRODUCTION

    Guidelines for the use of adjuvant therapy in the treatment of early-stage breast cancer have evolved over time. The first National Institutes of Health (NIH) Consensus Development Conference on adjuvant therapy for early stage breast cancer, held in 1985, led to recommendations for two groups of women with node-positive breast cancer: (1) chemotherapy for premenopausal women and postmenopausal women with an estrogen receptor (ER) –negative tumor and (2) tamoxifen for postmenopausal women with ER-positive tumors.1 The 2000 NIH Consensus Development Conference recommended the use of polychemotherapy regardless of nodal, menopausal, or hormone receptor status for most women diagnosed with early-stage breast cancer and indicated there was a statistically significant improvement in survival with the use of anthracycline-containing regimens.2 Adjuvant hormonal therapy was recommended for most women whose tumors express ER, but not advised for women with negative ER tumors. A recent meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reporting on 15-year survival found continued improvement in long-term survival among women with early-stage breast cancer who were treated with anthracycline-based chemotherapy followed by 5 years of tamoxifen.3 The EBCTCG reported, as have others,2 that no conclusions could be drawn about the use of this regimen in women 70 years and older since their representation in clinical trials has been minimal. Given these findings, it is important to identify women who fail to receive adjuvant therapy and examine the use in women 70 years and older.

    Data through 1995 from the National Cancer Institute (NCI) Patterns of Care (POC) population-based studies have previously been reported.4 In the current analysis, we describe the use of adjuvant therapy for patients with early-stage breast cancer diagnosed in 2000, examine adjuvant therapy by nodal and ER status, and discuss changes over time and the impact of age on receipt of therapy.

    METHODS

    The NCI's Surveillance, Epidemiology and End Results (SEER) program, a population-based cancer registry system, obtains data primarily from medical records within hospitals, outpatient surgical centers, pathology centers, and free-standing radiology centers. The SEER registries collect data on all cancer cases within their defined geographic region. The routine data collection includes detailed information on demographics, diagnosis, and tumor characteristics. The registries maintain active follow-up of all cases. Treatment information is also collected. However, adjuvant therapy is often incomplete because much of it is given in the outpatient setting. This is particularly true for hormonal therapy. Therefore, NCI supplements the routine SEER data by annually conducting POC studies that re-abstract data and collect detailed information on adjuvant therapy that is not found in those facility records.

    Details of the data collection methods for the POC studies have been described elsewhere.4 Women diagnosed in each of the years 1987 to 1991, 1995, and 2000 with American Joint Committee on Cancer stages I through IIIA breast cancer were stratified by age at diagnosis (younger than age 51 and 51 and older), stage, race/ethnicity, and registry, and a random sample was selected. Women 50 years and younger and non-Hispanic black women and Hispanic women were oversampled in 1995 and 2000 to obtain more stable estimates. Women with a previous diagnosis of cancer other than nonmelanoma skin cancers, a simultaneous cancer diagnosis, or who were younger than 20 years, were ineligible for the study. A total of 9,481 women were included in all years of these studies.

    Participating SEER registries re-abstracted the hospital record of the selected patients to verify tumor characteristics, treatment provided, and demographic information. Each patient's treating physician was contacted to determine whether adjuvant therapy had been given and, if so, which agents were administered. Information on the agents given, but not dose or duration, was collected. If the physician contacted was not the treating physician, he/she was asked to provide the name of the treating physician and that physician was then contacted.

    Women treated on a clinical trial (n = 432; 3.3%), women who did not have surgery to the primary site (n = 33; 0.4%), or women who were diagnosed with Paget's disease (n = 1) were excluded from the current analysis. Patients with tumors less than 1 cm at diagnosis (n = 1,169; 15.5%) and tumors with unknown size (n = 469; 4.3%) were excluded from the analysis of adjuvant therapy. Chemotherapy in these analyses includes multiagent chemotherapy only. Women with ER values reported as borderline were categorized as receptor positive and those with an unknown ER status (n = 1,180; 16.9%) were excluded from the analysis of adjuvant therapy.

    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 group, race/ethnicity, and registry), were used to obtain estimates that are representative of all eligible early-stage breast cancer patients in the study areas. Because young women were oversampled, an overall mean value will be different from the arithmetic average of each stage group. We used SUDAAN statistical software (1997, Research Triangle Institute, Research Triangle Park, NC), which allows for the use of sample weights and adjusts the SEs appropriately.5 All tests are two-sided.

    RESULTS

    Over time there has been a decrease in the percent of women diagnosed with positive lymph nodes and an increase in those with tumors smaller than 1 cm (Table 1). The percentage of women with unknown histologic grade decreased markedly from nearly 70% in 1987 to slightly less than 7% in 2000.

    The percentage of women with node-positive tumors 1 cm and larger receiving chemotherapy, with or without tamoxifen, was greater than 70% irrespective of their ER status (Table 2). When examined by ER status, women with positive nodes and ER-positive tumors had a significant increase in the use of combination chemotherapy and tamoxifen between 1995 and 2000. There was an associated decrease in the use of either chemotherapy or tamoxifen alone. The percentage of women with node-positive, ER-positive tumors and who received tamoxifen alone has decreased significantly over time from 47% in 1987 to 14% in 2000. The use of chemotherapy plus tamoxifen has increased dramatically in that same time period from 21% to 57%, a statistically significant increase. This shift included a nearly two-fold increase between 1995 and 2000.

    Chemotherapy and tamoxifen therapy for women with node-positive, ER-negative tumors has shown dramatic changes over time; both increasing and decreasing (Table 2). Surprisingly, in 2000, 16% of these high-risk patients received no adjuvant therapy, while another 6% received tamoxifen alone. There was also a nonsignificant increase from 6% to 10% in the percentage of women with node-positive, ER-negative breast cancer receiving no adjuvant therapy.

    The percentage of women with node-negative, ER-positive breast cancer receiving chemotherapy plus tamoxifen also increased significantly between 1995 and 2000. Women with node-negative, ER-negative tumors experienced a nonsignificant increase in the receipt of chemotherapy alone from 1995 to 2000. However, 10% of these women received both tamoxifen and chemotherapy and an additional 6% received tamoxifen alone. In 2000, women with ER-positive tumors were equally likely to receive tamoxifen whether their lymph nodes were positive or negative.

    In 2000, adjuvant therapy was received less frequently by women 70 years and older. In this oldest age group of women with node-negative tumors 1 cm or greater, 37% received no adjuvant therapy compared with 14% of women younger than 50 years, a statistically significant difference, and 23% of women 50 to 69 years of age, a nonsignificant difference (Fig 1). While there was a statistically significant increase between 1991 and 1995 in the percentage of women 70 years and older with node-positive tumors 1 cm or greater receiving both chemotherapy and tamoxifen, there was a nonsignificant decrease between 1995 and 2000 (Fig 2) .

    The type of adjuvant therapy given also varied by age group. In 2000, more than 90% of women younger than 50 years with ER-negative tumors received chemotherapy with or without tamoxifen; 72% of women aged 50 to 69 years, and 30% of women 70 years and older received chemotherapy with or without tamoxifen (data not shown). Fewer women in all age groups with ER-positive tumors received chemotherapy.

    The use of anthracycline-based multiagent therapies as a proportion of all chemotherapies increased dramatically over time. In 1987, fewer than 15% of women with negative lymph nodes and 25% of women with positive lymph nodes, who were younger than 50 years and who received chemotherapy, received anthracycline (Table 3). By 2000, there was a statistically significant increase in the percentage of anthracycline-based therapy with more than 80% of women younger than 70 years with positive lymph nodes and more than 70% with negative lymph nodes receiving anthracycline. Women 70 years and older were significantly less likely to receive anthracycline agents; only 19% of women with node-negative and 10% of women with node-positive who received chemotherapy received this regimen in 2000.

    DISCUSSION

    The use of adjuvant therapy for women with early-stage, node-negative breast cancer in this population-based sample treated in a community setting has continued to increase in the 5 years between 1995 and 2000. The types of adjuvant therapies prescribed for women with breast cancers have changed, with the percentage of women receiving anthracyline-based chemotherapy increasing dramatically.

    As early as 1985, the NIH Consensus Development Conference recommendation was that women with node-positive breast cancer, who are at increased risk for recurrence or progression, receive chemotherapy if they had ER-negative tumors or were premenopausal.1 The 1998 EBCTCG publication reported that polychemotherapy for early-stage breast cancer provided significant benefit to women with positive as well as negative lymph nodes6 while the 2005 EBCTCG publication reported continued survival advantage for women younger than 70 years treated with chemotherapy.3 The NIH Consensus Development Conference recommending chemotherapy for breast cancer patients with negative as well as positive lymph nodes occurred in November, 2000.2 Between 1995 and 2000, we found an increase in the use of chemotherapy for women irrespective of nodal or ER status. Women with node-positive tumors were much more often given chemotherapy than women with node-negative tumors. However, over the 10 years from 1990 through 2000 there was no significant change in the percentage of women with positive nodes receiving adjuvant therapy. In 2000, the largest difference in the use of chemotherapy was seen between the women whose tumors were ER positive with positive or negative nodes, 75% and 26%, respectively. While the absolute values have changed over time, the striking differences between these two groups have not. Use of adjuvant therapy for women with positive nodes was already high in 1987. However, over time there has been a large increase in adjuvant therapy provided to women with node-negative, ER-positive and ER-negative tumors. It is interesting to note that by year, 1987 through 2000, and within nodal status the percentages of women who were untreated tends to be surprisingly similar by ER status. The differences appear to largely occur between positive and negative nodal status groups.

    The recommendations for tamoxifen have changed over time. Tamoxifen was recommended for postmenopausal women with node-positive, ER-positive tumors by the 1985 NIH Consensus Development Conference.1 In 1988, the NCI Clinical Alert also recommended tamoxifen for women with node-negative, ER-positive breast cancer.7 The recent EBCTCG publication reported a 31% decrease in mortality with the use of 5 years of tamoxifen.3 Age did not appear to influence these findings. By 1987, the use of tamoxifen in women with node-positive, ER-positive breast cancer was already high (68%). Between 1995 and 2000, we observed a significant decrease in the use of tamoxifen alone and an associated increase in the use of both tamoxifen and chemotherapy for these women. Between the clinical alert in 1988 and 2000 the use of tamoxifen alone doubled for women with node-negative, ER-positive tumors.

    As with the EBCTCG suggestion that further research was needed on the use of tamoxifen in women whose tumors did not express receptor protein, the 2000 Consensus Statement recommended tamoxifen only for women with receptor-positive tumors.8,2 Although the use of tamoxifen in women with ER-negative tumors has never been high, it did reach 43% in 1995 for women with positive nodes and ER-negative tumors. Before these publications and recommendations, physicians and patients may have decided that the benefits from chemotherapy for women with negative nodes and positive receptors did not outweigh the risks. Tamoxifen may have been given more often because of the perception of lower toxicity as compared with chemotherapy.

    In 1992, the EBCTCG reported that tamoxifen was beneficial for women over the age of 69, but data were insufficient to assess chemotherapy.8,9 In 1998 and again in 2005, the EBCTCG found insufficient numbers of women 70 years and older to assess the efficacy of chemotherapy.10,3 The 2000 NIH Consensus Development Conference reflected the limits of existing evidence, recommending polychemotherapy for most women with either node-negative or node-positive disease, and suggesting that data for women older than 70 years were insufficient to make a recommendation.2 Findings in the published literature of efficacy of chemotherapy and age are reflected in our data.10,9,6,11 Women older than age 69 years were much less likely to receive adjuvant therapy than were younger women. Moreover, if older women were given adjuvant therapy, it was less likely to be chemotherapy, alone or in combination with tamoxifen, and more likely to be tamoxifen alone, whether or not their tumors are ER positive. Even when the ERs were known to be negative, only 30% of women 70 years and older received chemotherapy while 26% received tamoxifen alone (data not shown). For these older women, there might be an expectation of an increase in the percentage refusing chemotherapy. However, there was no indication that they refused. When treatment was verified with the physicians, a category of refusal was available for the physician to mark. With evidence that tamoxifen was useful for these older women and with no clear clinical trials evidence that chemotherapy was beneficial in this age group, physicians and patients might have decided that tamoxifen would provide some benefit with fewer side effects than chemotherapy.

    The 2005 EBCTCG reported that 6 months of anthracycline-based chemotherapy reduced the cause-specific death rate by approximately 38% in women younger than 50 years, and by 20% in women 50 to 69 years of age at diagnosis.3 The 2000 NIH Consensus Development Conference also stated there might be a "small but statistically significant improvement in survival" with the use of anthracycline-containing regimens.2 As a proportion of all multiagent chemotherapy, we found a significant increase in the use of anthracycline-based chemotherapy for women younger than 70 years between 1995 and 2000 that may have been in response to early publications of trial results. This increase occurred earlier for the youngest age group and for women with positive nodes. These women might be considered most at risk for recurrence or progression of disease. Cardiac complications are reported with these agents and may contribute to the low rate with increasing age of the patient.12

    The population included in the SEER program is generally representative of the United States. However, the SEER populations tend to be slightly more urban, with a larger number of foreign-born individuals than does the US population as a whole.13 Although physicians were asked to indicate whether a patient refused specific therapies, we do not have information on patient preference. The patient, while not directly refusing treatment, might have decided against adjuvant therapy after discussing the risks and benefits with her physician. In addition, we do not have information about the dose and duration of the therapy, which may have been less for older women. We also do not have data on the social support available to the patient, which may have influenced the therapy selected. Since this data was collected, new agents, such as aromatase inhibitors and monoclonal antibodies, have become available, and the use of the agents reported here along with the percentage of patients using them would be expected to change.

    The results from SEER areas across the United States suggest that physicians quickly responded to publications and guidelines regarding breast cancer therapy. The majority of women with early-stage breast cancer were receiving adjuvant therapy with a sharp increase in use of anthracycline agents between 1995 and 2000 as trial results were published. The efficacy of adjuvant therapy in women 70 years and older is unclear in the published reports and guidelines and that lack of certainty is reflected by lower rates of use in this subgroup of women. The use of tamoxifen in women whose tumors are ER negative should be expected to decrease following the more recent recommendations that do not advise the use of tamoxifen in women with ER-negative tumors.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Linda C. Harlan, Jeffrey Abrams, Rachel Ballard-Barbash

    Financial support: Linda C. Harlan

    Collection and assembly of data: Linda C. Harlan, Jennifer L. Stevens

    Data analysis and interpretation: Linda C. Harlan, Limin X. Clegg, Jeffrey Abrams, Jennifer L. Stevens, Rachel Ballard-Barbash

    Manuscript writing: Linda C. Harlan, Limin X. Clegg, Jeffrey Abrams, Rachel Ballard-Barbash

    Final approval of manuscript: Linda C. Harlan, Limin X. Clegg, Jeffrey Abrams, Jennifer L. Stevens, Rachel Ballard-Barbash

    Acknowledgment

    We thank the Surveillance, Epidemiology and End Result Program Registries for their contributions.

    NOTES

    Supported by funding from the following: contract numbers: N01-PC-35133, N01-PC-35135, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35141, N01-PC-35142, N01-PC-35143, N01-PC-35145.

    Results reported here have not been published elsewhere. The manuscript makes use of data published: Harlan LC, Abrams J, Warren J, Clegg L, Stevens J, Ballard-Barbash R: Adjuvant therapy for breast cancer: Practice patterns of community physicians. J Clin Oncol 20:1809-1817, 2000.

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

    REFERENCES

    National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development Conference statement: Adjuvant chemotherapy for breast cancer, September 9-11, 1985

    National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development Conference statement: Adjuvant chemotherapy for breast cancer, November 1-3, 2000

    Early Breast Cancer Trialists' Collaborative Group (EBCTCG): 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

    Harlan LC, Abrams J, Warren JL, et al: Adjuvant therapy for breast cancer: Practice patterns of community physicians. J Clin Oncol 20:1809-1817, 2002

    Shah BV, Barnwall BG, Bieler GS: SUDAAN. Research Triangle Park, NC: Research Triangle Institute; 1997

    Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998

    National Cancer Institute: Clinical alert form the National Cancer Institute. Breast Cancer Res Treat 12:3-5, 1988

    Early Breast Cancer Trialists' Collaborative Group: Systematic 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 women [part 1]. Lancet 339:1-15, 1992

    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 women [part 2]. Lancet 339:71-85, 1992

    Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998

    Muss HB. Factors used to select adjuvant therapy of breast cancer in the United States: An overview of age, race, and socioeconomic status. J Natl Cancer Inst Monogr 30:52-55, 2001

    Surveillance, Epidemiology, and End Results (SEER): Characteristics of the SEER Population Compared with the Total United States Population. Rockville, MD, National Cancer Institute, National Institutes of Health, 2003

    United States Food and Drug Administration: Adriamycin PI mock-up: Revised boxed warning to include risk of secondary leukemia per FDA request. http://www.fda.gov/cder/foi/label/2002/50467s64s67,50629s10s13lbl.pdf

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