© 2001 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 30, 62-66,
2001
© 2001 Oxford University Press
Findings From Recent National Surgical Adjuvant Breast and Bowel Project Adjuvant Studies in Stage I Breast Cancer
Affiliations of authors: B. Fisher, D. L. Wickerham, N. Wolmark, National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA; J.-H. Jeong, S. Anderson, Department of Biostatistics, University of Pittsburgh; J. Dignam, NSABP and Department of Health Studies, University of Chicago, IL; E. Mamounas, Cancer Center, Aultman Hospital, Canton, OH.
Correspondence to: Bernard Fisher, M.D., National Surgical Adjuvant Breast and Bowel Project, 4 Allegheny Center, Suite 602, Pittsburgh, PA 15212 (e-mail: bernard.fisher{at}nsabp.org).
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ABSTRACT |
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 TopNotes Abstract IntroductionPatients With Estrogen Receptor...PatientsWith Estrogen Receptor...Women With Estrogen Receptor...Radiation Therapy and/or TAM...Summary and CommentsReferences |
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Before 1989, credible information about the treatment of breast cancer was derived mainly from randomized clinical trials that enrolled women with either metastatic (stage IV); locally advanced (stage III); or primary, operable, axillary lymph node-positive (stage II) disease. This report provides information from six recent National Surgical Adjuvant Breast and Bowel Project (NSABP) trials involving lymph node-negative (stage I) patients. Findings from NSABP B-13 demonstrated, through 14 years of follow-up, improvements in disease-free survival (DFS) and overall survival from methotrexate and fluorouracil (MF), regardless of age, in women with estrogen receptor (ER)-negative tumors. Results from NSABP B-19, which was conducted with similar patients, demonstrated, through 8 years, a greater overall DFS and survival advantage with cyclophosphamide and MF (CMF) than that observed with MF. Findings from NSABP B-23, in which patients similar to those in B-13 and B-19 were randomly assigned to receive CMF plus placebo, CMF plus tamoxifen (TAM), doxorubicin (Adriamycin) and cyclophosphamide (AC) plus placebo, or AC plus TAM, demonstrated no difference in relapse-free survival (RFS) or overall survival among the four groups through 5 years, either for all patients or relative to age. NSABP B-14, which was carried out in women with ER-positive tumors, compared the outcomes of those who received either placebo or TAM. Through 14 years, superior DFS and overall survival advantages, as well as a reduction in contralateral breast cancer, were observed with TAM. No additional benefit resulted from TAM administration beyond 5 years. Findings from NSABP B-20, a second study conducted in patients with ER-positive tumors, showed, after 8 years, both a DFS and an overall survival advantage from TAM plus either MF or CMF over that achieved with TAM alone. A recent meta-analysis in women with negative lymph nodes and either ER-negative or ER-positive tumors of less than or equal to 1 cm in size was conducted using patients from five NSABP trials. After 8 years, the RFS in women with ER-negative tumors was greater in the group treated with surgery and chemotherapy than in those who underwent surgery alone. In women with ER-positive tumors, RFS and overall survival advantages were observed from the addition of chemotherapy to TAM when that treatment regimen was compared with TAM alone. In addition, evidence has been presented from NSABP B-21, a trial evaluating radiation therapy (XRT) and/or TAM for the prevention of ipsilateral breast tumor recurrence (IBTR) after lumpectomy in women with tumors less than or equal to 1 cm. Findings have shown that XRT is superior to TAM and that XRT + TAM is superior to XRT alone for preventing IBTR. The findings demonstrate that chemotherapy and/or hormonal therapy is effective for the management of women with negative axillary lymph nodes and either ER-negative or ER-positive tumors. Because it also has been proven effective in women with tumors less than or equal to 1 cm, such therapy might also be considered in the treatment of that patient population.
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INTRODUCTION |
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TopNotesAbstractIntroductionPatients With Estrogen Receptor...PatientsWith Estrogen Receptor...Women With Estrogen Receptor...Radiation Therapy and/or TAM...Summary and CommentsReferences |
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At a National Institutes of Health (NIH) consensus conference convened in 1985, data on adjuvant chemotherapy and endocrine therapy that had been obtained from randomized trials conducted during the 1970s and early 1980s were evaluated. It was concluded that there was inadequate information to justify recommending therapy other than surgery for women with negative axillary lymph nodes (1). By 1990, however, findings from studies conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and by other investigators warranted a second conference on the treatment of early-stage breast cancer. Meeting participants concluded that "the rate of local and distant recurrence following local therapy for lymph node-negative breast cancer is decreased by both adjuvant combination of cytotoxic chemotherapy and by adjuvant tamoxifen" (2). It was also noted that patients with tumors of less than or equal to 1 cm had an excellent prognosis and would not require adjuvant systemic therapy outside of clinical trials. Participants acknowledged, however, that the completed studies were not large enough, nor the follow-up long enough, to allow for an accurate estimation of the interactions between menopausal status or steroid receptor positivity and the effects of adjuvant therapy in lymph node-negative patients. They also noted that there were too few patients with estrogen receptor-negative tumors to permit an evaluation of the benefit of tamoxifen, that the follow-up was too short for meaningful mortality data to be obtained, and that not enough information was available to permit a determination of the effects of combination chemotherapy plus tamoxifen in patients with negative lymph nodes. Since the 1990 conference, findings from six NSABP trials using 11 620 patients with primary (stage I) breast cancer and negative axillary lymph nodes have provided information to address these issues. Numerous reports of the results from these studies have either been published or are currently in press. Highlights of the most recent findings from the studies were presented at the November 2000 NIH consensus conference on adjuvant therapy for breast cancer. This report provides an overview of that presentation.
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PATIENTS WITH ESTROGEN RECEPTOR-NEGATIVE TUMORS AND NEGATIVE AXILLARY LYMPH NODES |
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TopNotesAbstractIntroductionPatients With Estrogen Receptor...PatientsWith Estrogen Receptor...Women With Estrogen Receptor...Radiation Therapy and/or TAM...Summary and CommentsReferences |
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Worth of Adjuvant Chemotherapy
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 trial, women were randomly assigned to receive either surgery and no chemotherapy or surgery followed by 12 courses (1 year) of methotrexate and sequentially administered 5-fluorouracil (MF) followed by leucovorin. Findings through 14 years of follow-up demonstrated that the improvements in overall disease-free survival and survival from MF, previously reported after 5 (3) and 8 (4) years, have persisted (P<.0001 in the former and P = .02 in the latter; Fig. 1
). A similarly statistically significant disease-free survival benefit was observed for women aged less than or equal to 49 years and for those aged greater than or equal to 50 years (P = .005 in the former and P = .001 in the latter). A slight but not statistically significant difference in overall survival (P = .3) was observed in women aged less than or equal to 49 years, while a statistically significant overall survival benefit was observed in those aged greater than or equal to 50 years (P = .02). There was no evidence of an interaction between treatment group and age (e.g., P = .34) for overall survival. The risk ratios (and 95% confidence intervals [CIs]) relative to overall survival were 0.82 (95% CI = 0.56 to 1.17) for women aged less than or equal to 49 years and 0.59 (95% CI = 0.38 to 0.92) for those 50 years of age or older.
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A second trial, NSABP B-19, was conducted to determine whether the alkylating agent cyclophosphamide contributed an additional benefit when administered with MF. Over a 6-month period, patients received either six courses of MF, as given in B-13, or six courses of cyclophosphamide and MF (CMF), as is conventionally used to treat breast cancer. Through 8 years, just as first reported after 5 years (4), greater overall disease-free survival and survival advantages (P = .0003 and P = .03, respectively) were obtained from treatment with CMF (Fig. 2
). Those advantages were most evident in women aged less than or equal to 49 years (P = .0004 and P = .007, respectively). In women aged greater than or equal to 50 years, there was a small but nonsignificant advantage in both disease-free survival (P = .2) and overall survival (P = .8). As was observed above with regard to the B-13 study, there was no evidence of a statistically significant interaction between treatment and age group relative to disease-free survival (P = .22) and overall survival (P = .08). For women aged less than or equal to 49 years, the risk ratio was 0.59 (CI = 0.44 to 0.87), and for those aged greater than or equal to 50 years, the risk ratio was 0.78 (CI = 0.56 to 1.1). Relative to overall survival, the risk ratio was 0.6 (CI = 0.42 to 0.87) for women aged less than or equal to 49 years and 0.96 (CI = 0.63 to 1.45) for those 50 years of age or older.
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Worth of Chemotherapy Plus Tamoxifen
The NSABP initiated the B-23 study because of contradictory information about the propriety of using tamoxifen (TAM) with chemotherapy and because of uncertainty about the relative worth of doxorubicin (Adriamycin; Pharmacia Upjohn, Peapack, NJ) and cyclophosphamide (AC) and CMF for the treatment of such patients. Women (n = 2008) were randomly assigned to receive CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given over 6 months; four cycles of AC were administered over 63 days. A first report of findings from that study (5) demonstrated (Fig. 3) no statistically significant difference in either relapse-free survival or overall survival among the four groups through 5 years, either for all patients (P = 1.0 and P = .8, respectively) or for those aged less than or equal to 49 or greater than or equal to 50 years (data not shown). Because of the low incidence of contralateral breast cancer in all groups of lymph node-negative patients in the B-23 study (i.e., 3% through 5 years), it is not possible to estimate the efficacy of administering TAM to such patients for the express purpose of reducing the incidence of contralateral breast tumors.
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PATIENTSWITH ESTROGEN RECEPTOR-POSITIVE TUMORS AND NEGATIVE AXILLARY LYMPH NODES |
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TopNotesAbstractIntroductionPatients With Estrogen Receptor...PatientsWith Estrogen Receptor...Women With Estrogen Receptor...Radiation Therapy and/or TAM...Summary and CommentsReferences |
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Worth of TAM
NSABP B-14, a randomized, double-blind, placebo-controlled trial initiated in 1982, involved more than 2800 randomly assigned and 1200 registered TAM-treated patients. The aim of that study was to determine the effectiveness of TAM in patients with negative axillary lymph nodes. A significant advantage from TAM was first reported in 1989 after 5 years of follow-up (6). The disease-free survival and overall survival benefits have persisted through 14 years of follow-up (P<.001 and P = .002, respectively; Fig. 4) overall, as well as for women less than or equal to 49 years of age (P<.001 and P = .01, respectively) and for those aged greater than or equal to 50 years (P<.001 and P = .04, respectively). TAM therapy was also associated with a statistically significant reduction in contralateral breast cancer (6,7), but no additional benefit was observed from the administration of TAM beyond 5 years (8,9).
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Worth of Chemotherapy plus TAM
NSABP B-20, a study that involved more than 2300 women, was aimed at testing the hypothesis that the addition of either MF or CMF to TAM would result in a greater benefit than that which could be achieved with TAM alone. After 8 years, as was previously shown after 5 years of follow-up (10), there continue to be significant disease-free survival and overall survival advantages from the use of TAM plus chemotherapy (84% versus 77%, P = .001, for disease-free survival; 92% versus 88%, P = .018, for overall survival) (Fig. 5). That benefit was evident for both age groups, although more so for women aged less than or equal to 49 years than for those aged greater than or equal to 50 years.
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WOMEN WITH ESTROGEN RECEPTOR-NEGATIVE OR ESTROGEN RECEPTOR-POSITIVE TUMORS OF LESS THAN OR EQUAL TO 1 CM |
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TopNotesAbstractIntroductionPatients With Estrogen Receptor...PatientsWith Estrogen Receptor...Women With Estrogen Receptor...Radiation Therapy and/or TAM...Summary and CommentsReferences |
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In an attempt to resolve uncertainty about the treatment and prognosis of patients with negative axillary lymph nodes and either estrogen receptor (ER)-negative or ER-positive tumors of less than or equal to 1 cm, data obtained from five NSABP randomized trials were obtained and analyzed collectively (11). The 8-year relapse-free survival rates for women with ER-negative tumors of less than or equal to 1 cm treated with surgery alone or with surgery and chemotherapy (MF or CMF) were 81% and 90%, respectively (P = .06) (data not shown). Overall survival rates were similar in both groups (93% and 91%, respectively; P = .65). In women with ER-positive tumors of less than or equal to 1 cm who were treated with surgery alone, the 8-year relapse-free survival rate was 86%; the relapse-free survival rate was 93% after TAM was administered (P = .01) (data not shown) and 95% for women treated with TAM and chemotherapy (MF or CMF). When compared with the benefit achieved with the administration of TAM alone, the benefit achieved from the addition of chemotherapy to TAM approached statistical significance (P = .07). Overall survival rates among women in the three groups were 90%, 92% (P = .41), and 97% (P = .01), respectively.
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RADIATION THERAPY AND/OR TAM FOR THE PREVENTION OF IPSILATERAL BREAST TUMOR RECURRENCE AFTER LUMPECTOMY IN WOMEN WITH TUMORS OF LESS THAN OR EQUAL TO 1 CM |
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TopNotesAbstractIntroductionPatients With Estrogen Receptor...PatientsWith Estrogen Receptor...Women With Estrogen Receptor...Radiation Therapy and/or TAM...Summary and CommentsReferences |
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Since the first report of results obtained from an NSABP trial (B-06) about the role of lumpectomy and breast irradiation for breast cancer, the question arose as to whether there were cohorts of women who did not require radiation therapy and whether such therapy might be replaced with TAM. NSABP B-21 was implemented to address that issue. Women with ER-positive or ER-negative tumors less than or equal to 1 cm (n = 1009) were randomly assigned to either TAM alone, radiation therapy plus placebo, or radiation therapy plus TAM. Recently reported results (12) have demonstrated a rate (per 1000 patients per year) of ipsilateral breast tumor recurrence (IBTR) of 23.3 for women who received TAM, 11.7 for those who received radiation therapy plus placebo, and 3.4 for those who received radiation therapy plus TAM.
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SUMMARY AND COMMENTS |
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TopNotesAbstractIntroductionPatients With Estrogen Receptor...PatientsWith Estrogen Receptor...Women With Estrogen Receptor...Radiation Therapy and/or TAM...Summary and CommentsReferences |
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The findings presented in this report demonstrate a significant benefit from 1 year of MF therapy in patients with ER-negative tumors and negative axillary lymph nodes. The benefit from 6 months of MF therapy was not as good as that observed with 6 months of conventional CMF therapy. There was, however, no significant difference in outcome between women who received 6 months of CMF and those who received 2 months of AC. When TAM was given with either chemotherapy regimen, there was no significant advantage over that achieved from chemotherapy alone.
In women with ER-positive tumors and negative lymph nodes who received TAM therapy, a prolongation of disease-free survival and overall survival was present through 14 years of follow-up. Evidence of a reduction in IBTR and recurrences at other local and distant sites, as well as in tumor occurrence in the contralateral breast, persisted. These benefits were attained with a relatively low incidence of side effects. Study data demonstrate the worth of administering CMF with TAM to this cohort of patients.
These NSABP findings demonstrating the worth of adjuvant therapy for the treatment of patients with lymph node-negative breast cancer have been amply confirmed by the findings presented in the 1998 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis (13). In its report, the EBCTCG noted, through 10 years, a 10.4% absolute benefit in relapse-free survival for patients under 50 years of age and a 5.7% absolute benefit in relapse-free survival in those patients aged 50–69 years, all of whom had received polychemotherapy. Similarly, a 5.7% and a 6.4% improvement in overall survival was noted in the two age groups, respectively, as a result of polychemotherapy.
The prognosis of women with ER-negative or ER-positive tumors of less than or equal to 1 cm and negative lymph nodes was somewhat better than that which has been reported for women with larger tumors. The prognosis was not, however, sufficiently favorable to dismiss the consideration of systemic therapy as an option for certain women with tumors of less than or equal to 1 cm. However, a cutoff point in the array of tumor sizes below 10 mm that would justify omission of systemic therapy remains to be established.
After lumpectomy for the treatment of women with tumors of less than or equal to 1 cm, the administration of radiation therapy and TAM prevents IBTR to a greater extent than does radiation therapy alone. TAM alone has been found to be inferior to radiation therapy in that regard.
Although findings from almost all of the studies have demonstrated a benefit, they have all engendered controversy with regard to their clinical application. As the prognosis of both treated and untreated cohorts of patients becomes better, therapeutic decision making becomes more difficult. The question arises as to what proportion of women in a cohort can be justifiably "written off" because it has been decided that the group's prognosis is sufficiently good to preclude treatment of any of the patients, despite evidence that some of them stand to benefit from a therapy of demonstrated efficacy. It would be inappropriate to deny women the opportunity to receive therapy from which they might benefit, because so many women with invasive cancer die each year despite having received "effective" treatment or because they have received either inadequate treatment or no treatment at all. In the 1990s, the death rate from breast cancer fell by 2%–3% per year. That circumstance was, in large part, a result of more widespread use of adjuvant therapy and more timely detection of the disease. It is likely that the judicious use of such therapy to treat women with smaller tumors and negative lymph nodes will result in increased overall survival among all women with breast cancer. It is, of course, necessary that extensive investigation be mandatory in an attempt to identify prognostic and predictive factors that provide justification for either administering or withholding a particular therapy from an individual patient. The NSABP has implemented a new generation of clinical trials to evaluate hypotheses that have been formulated as a result of the accumulation of new biologic information and the development of new agents that may improve the outcome of breast cancer patients via endocrine (hormonal) manipulation. One such study, NSABP B-33, is evaluating the effect of estrogen deprivation resulting from use of the aromatase inhibitor exemestane. That study involves American Joint Committee on Cancer/TNM stage I and stage II postmenopausal breast cancer patients who have completed at least 5 years of TAM therapy. Another trial compares the worth of the pure antiestrogen Faslodex (AstraZeneca, Wilmington, DE) with or without chemotherapy versus TAM with or without chemotherapy in premenopausal and postmenopausal, clinically lymph node-negative breast cancer patients.
The NSABP is also interested in studies that evaluate luteinizing hormone-releasing hormone analogues such as Goserlin (AstraZeneca). Another NSABP trial, B-34, compares adjuvant clodronate therapy with placebo in early-stage breast cancer patients who receive either systemic chemotherapy and/or TAM, or no therapy. The principal aim of that study is to determine whether the second generation bisphosphonate (clodronate) will improve disease-free survival and reduce the incidence of skeletal metastases.
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NOTES |
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Supported by Public Health Service grants U10CA12027, U10CA69651, U10CA37377, and U10CA69974 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
E. Mamounas is a member of the Advisory Board for Breast Cancer for AstraZeneca and Pharmacia Oncology and is a member of the Speaker's Bureau for this advisory board.
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REFERENCES |
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TopNotesAbstractIntroductionPatients With Estrogen Receptor...PatientsWith Estrogen Receptor...Women With Estrogen Receptor...Radiation Therapy and/or TAM...Summary and CommentsReferences |
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1
Consensus conference. Adjuvant chemotherapy for breast cancer. JAMA 1985;254:3461–3.
2
NIH consensus conference. Treatment of early-stage breast cancer. JAMA 1991;265:391–5.
3 Fisher B, Redmond C, Dimitrov NV, Bowman D, Legault-Poisson S, Wickerham DL, et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 1989;320:473–8.[Abstract]
4
Fisher B, Dignam J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996;14:1982–92.
5
Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, et al. Tamoxifen and chemotherapy for axillary-node negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 2001;19:931–42.
6 Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989;320:479–84.[Abstract]
7
Fisher B, Redmond C. New perspective on cancer of the contralateral breast: a marker for assessing tamoxifen as a preventive agent. J Natl Cancer Inst 1991;83:1278–80.
8
Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996;88:1529–42.
9
Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001;93:684–90.
10
Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997;89:1673–82.
11
Fisher B, Dignam J, Tan-Chiu E, Anderson S, Fisher ER, Wittliff JL. Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary nodes. J Natl Cancer Inst 2001;93:112–20.
12
Wolmark N, Dignam J, Margolese R, Wickerham DL, Fisher B. The role of radiotherapy and tamoxifen in the management of node negative invasive breast cancer 
1.0 cm treated with lumpectomy: preliminary results of NSABP protocol B-21 [abstract]. Proc ASCO 2000;19:70a.
13 Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930–42.[CrossRef][Web of Science][Medline]
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