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© 2002 American Society for Clinical Oncology
A Trial of Two QuestionsCancer Care Ontario Hamilton Regional Cancer Center, McMaster University, Hamilton, Ontario, Canada THE NATIONAL Surgical Adjuvant Breast and Bowel Project (NSABP) B-21 trial addresses two important questions for women with node-negative, less than 1 cm breast cancer who have undergone breast-conserving surgery (BCS): (1) Is breast irradiation really necessary if adjuvant tamoxifen alone is administered? And (2) do such women who are treated with breast irradiation gain additional benefit from adjuvant tamoxifen? On the surface, the answer would seem to be yes to both questions. But as is often the case in medical decision making, the answer is "It depends." There are now six published randomized trials evaluating the role of breast irradiation after BCS.1-6 All of these studies have demonstrated that breast irradiation substantially reduces the risk of recurrence of cancer in the breast, thereby increasing the likelihood of breast conservation. Since the publication of the first of these trials,1,2 there has been interest in identifying patients in whom the risk of local recurrence is so low that breast irradiation is not required. Trials have evaluated the need for breast irradiation when surgery is more extensive,3,4 when tumors are small (< 2 cm),3,4,6 and when adjuvant systemic therapy is used.5 Despite some early positive results,7,8 with longer follow-up investigators were unable to identify a group of patients in whom radiation could be avoided.3,4
Fisher et al9 have now evaluated the need for breast irradiation when the tumor is small ( When this trial was developed, available data suggested that size was a major determinant of local recurrence. Thus, investigators selected the smallest tumors to study the group at lowest risk for local failure. Other studies have examined different factors that are predictive of a decreased risk for local recurrence after BCS, such as age more than 50 years,2-4 low or moderate grade,2,10 wide margin of excision,11 absence of lymphatic/vascular vessel invasion10,11 and favorable histopathology.3,10,11 These studies have been unable to identify a low-risk group of patients who would not benefit from breast irradiation. These results are consistent with those of NSABP B-21 and support breast irradiation as standard treatment after BCS.
At the time this trial was conceived, practice guidelines did not advocate adjuvant systemic therapy for women with node-negative tumors
Should a woman with node-negative breast cancer and a tumor The NSABP has done its part. With a number of landmark studies over the last 20 years, including B-21, the NSABP has provided accurate estimates of the benefits and risks of both breast irradiation1 and adjuvant tamoxifen.30-33 Because of the inclusion of many centers and physicians in these studies, these data are likely to be generalizable to patients who are seen every day in our clinics. The information from the NSABP trials can be used as a basis for communicating with women the various treatment options that are available. For breast irradiation, patients should be informed not only about the benefits of reduction in local recurrence but also the side effects of therapy, such as fatigue, skin irritation, breast discomfort, poor cosmetic outcome, and the need to attend daily treatments for up to 5 to 6 weeks.34 Given the benefits observed in the B-21 trial, previous research suggests the majority of women are likely to choose breast irradiation, even without measurable survival benefits.27 The choice of adjuvant tamoxifen in addition to breast irradiation is more complex. Women and their physicians will need to consider not only the reduction in local recurrence but the additional benefits of reduction of distant recurrence, contralateral breast cancer, and fractures, weighed against the risks of thromboembolic events, uterine cancer, and the other side effects of tamoxifen.30-33 Given that a significant proportion of women with breast cancer will want to avoid recurrence, a number are likely to choose adjuvant therapy.21,35,36 Until now, treatment decision making from the perspective of individual patients and their physicians has been discussed. As women at lower risk are offered new therapies, we will, in some instances based on health insurance groups and publicly funded health care, have to decide as a society if we can afford to offer such treatments. These decisions are likely to be more difficult, but approaches similar to decision aids performed on a wide representative sample can help inform such decisions.37
Is this the final word on the role of breast irradiation and adjuvant therapy in "low-risk" patients? Probably not. It is possible that eventually a group of patients with a relatively low absolute benefit from breast irradiation will be identified such that some of these patients may choose not to receive radiation. Indeed, two trials were recently completed in which the need for breast irradiation in addition to tamoxifen was evaluated in women with node-negative breast cancer who were more than 50 years old38 and REFERENCES
1. Fisher B, Anderson S, Redmond CK, et al: Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 333: 1456-1461, 1995
2. Clark RM, Whelan T, Levine M, et al: Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: An update. J Natl Cancer Inst 88: 1659-1664, 1996
3. Liljegren G, Holmberg L, Bergh J, et al: 10-year results after sector resection with or without postoperative radiotherapy for stage 1 breast cancer: A randomized trial. J Clin Oncol 17: 2326-2333, 1999
4. Veronesi U, Marubini E, Mariani L, et al: Radiotherapy after breast-conserving surgery in small breast carcinoma: Long-term results of a randomized trial. Ann Oncol 12: 997-1003, 2001 5. Forrest AP, Stewart HJ, Everington D, et al: Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial. Lancet 348: 708-713, 1996[CrossRef][Medline] 6. Holli K, Saaristo R, Isola J, et al: Lumpectomy with or without postoperative radiotherapy for breast cancer with favourable prognostic features: Results of a randomized study. Br J Cancer 84: 164-169, 2001[CrossRef][Medline]
7. The Uppsala-Örebro Breast Cancer Study Group: Sector resection with or without postoperative radiotherapy for stage 1 breast cancer: A randomized trial. J Natl Cancer Inst 82: 277-282, 1990
8. Veronesi U, Luini A, Del Vecchio M, et al: Radiotherapy after breast-conserving surgery in women with localized cancer of the breast. N Engl J Med 328: 1587-1591, 1993
9. Fisher B, Bryant J, Dignam JJ, et al: Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 20: 4141-4149, 2002 10. Fisher ER, Anderson S, Tan-Chiu E, et al: Fifteen-year prognostic discriminants for invasive breast carcinoma. Cancer 91: 1679-1687, 2001[CrossRef][Medline] 11. Schnitt SJ, Hayman J, Gelman R, et al: A prospective study of conservative surgery alone in the treatment of selected patients with stage 1 breast cancer. Cancer 77: 1094-1100, 1996[CrossRef][Medline]
12. Goldhirsch A, Wood WC, Senn HJ, et al: Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 87: 1441-1445, 1995 13. The Steering Committee on Clinical Practice: Guidelines for the care and treatment of breast cancer: Adjuvant systemic therapy for women with node-negative breast cancer. CMAJ 158: S43-S51, 1998
14. Fisher B, Dignam J, Tan-Chiu E, et al: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93: 112-120, 2001
15. Lippman ME, Hayes DF: Adjuvant therapy for all patients with breast cancer? J Natl Cancer Inst 93: 80-82, 2001
16. Mirchandani D, Muggia F: Re: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93: 1420-1421, 2001 17. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351: 1451-1467, 1998[CrossRef][Medline] 18. Loprinzi CL, Ravdin RM, de Laurentiis M, et al: Do American oncologists know how to use prognostic variables for patients with newly diagnosed primary breast cancer? J Clin Oncol 12: 1422-1426, 1994[Abstract] 19. O’Connor AM, Llewellyn-Thomas HA, Sawka C, et al: Physicians’ opinions about decision aids for patients considering systemic adjuvant therapy for axillary-node negative breast cancer. Patient Educ Couns 30: 143-153, 1997[CrossRef][Medline] 20. Siminoff LA, Fetting JH, Abeloff MD: Doctor-patient communication about breast cancer adjuvant therapy. J Clin Oncol 7: 1192-1200, 1990[Abstract] 21. Ravdin PM, Siminoff IA, Harvey JA: Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy. J Clin Oncol 16: 515-521, 1998[Abstract] 22. Degner LF, Kristjanson L, Bowman D, et al: Information needs and decisional preferences in women with breast cancer. JAMA 277: 1485-1492, 1997[Abstract] 23. Levine MN, Gafni A, Markham B, et al: A bedside decision instrument to elicit a patient’s preference concerning adjuvant chemotherapy for breast cancer. Ann Intern Med 117: 53-58, 1992[Medline]
24. Ravdin PM, Siminoff LA, Davis GJ, et al: Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 19: 980-991, 2001
25. Sepucha KR, Belkora JK, Tripathy D, et al: Building bridges between physicians and patients: Results of a pilot study examining new tools for collaborative decision making in breast cancer. J Clin Oncol 18: 1230-1238, 2000
26. Molennar S, Sprangers MA, Rutgers EJ, et al: Decision support for patients with early-stage breast cancer: Effects of an interactive breast cancer CDROM on treatment decision, satisfaction, and quality of life. J Clin Oncol 19: 1676-1687, 2001 27. Whelan TJ, Levine MN, Gafni A, et al: Breast irradiation post-lumpectomy: Development and evaluation of a decision instrument. J Clin Oncol 13: 847-853, 1995[Abstract] 28. Whelan T, Sawka C, Levine M, et al: A randomized trial of a decision aid for the use of adjuvant chemotherapy in women with node-negative breast cancer. Proc Am Soc Clin Oncol 20: 237a, 2001 (abstr 946) 29. Ravdin PM, Siminoff L, Hewlett J, et al: Evaluation of impact of communication tool generated by the computer program Adjuvant!, on patients with early breast cancer and their doctors. Proc Am Soc Clin Oncol 20: 31a 2001 (abstr 119) 30. Fisher B, Costantino J, Redmond C, 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 320: 479-484, 1989[Abstract]
31. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90: 1371-1388, 1998 32. Dignam JJ, Fisher B: Occurrence of stroke with tamoxifen in NSABP B-24. Lancet 355: 848-849, 2000[Medline]
33. Day R, Ganz PA, Costantino JP, et al: Health-related quality of life and tamoxifen in breast cancer prevention: A report from the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Clin Oncol 17: 2659-2669, 1999 34. Whelan T, Levine M, Julian J, et al: The effects of radiation therapy on quality of life of women with breast cancer: Results of a randomized trial. Cancer 88: 2260-2266, 2000[CrossRef][Medline] 35. Coates AS, Simes RJ: Patient assessment of adjuvant treatment in operable breast cancer, in Williams CJ (ed): Introducing New Treatments for Cancer: Practical, Ethical, and Legal Problems. New York NY, John Wiley & Sons, 1992, pp 447-458 36. Lindley C, Vasa S, Sawyer WT, et al: Quality of life and preferences for treatment following systemic adjuvant therapy for early-stage breast cancer. J Clin Oncol 16: 380-387, 1998 37. Gafni A, Birch S: Guidelines for the adoption of new technologies: A prescription for uncontrolled growth in expenditures and how to avoid the problem. Can Med Assoc J 148: 913-917, 1993[Abstract] 38. Fyles A, McCready D, Manchul L, et al: Preliminary results of a randomized study of tamoxifen +/- breast radiation in T1/2 NO disease in women over 50 years of age. Proc Am Soc Clin Oncol 20: 24a, 2001 (abstr 92) 39. Hughes KS, Schnaper L, Berry D, et al: Comparison of lumpectomy plus tamoxifen with and without radiotherapy (RT) in women 70 years of age or older who have clinical stage 1, estrogen receptor positive (ER+) breast carcinoma. Proc Am Soc Clin Oncol 20: 24a, 2001 (abstr 93)
40. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89: 1673-1682, 1997 41. The ATAC Trialists’ Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 1002 42. Houghton J, Baum M, Rutqvist LE, et al: The ZIPP trial of adjuvant Zoladex in premenopausal patients with early breast cancer: An update at five years. Proc Am Soc Clin Oncol 19: 93a, 2000 (abstr 359) This article has been cited by other articles:
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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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1 cm) and the patient receives long-term endocrine therapy. After lumpectomy, 1,009 patients were randomly assigned either to tamoxifen alone, breast irradiation plus placebo, or breast irradiation plus tamoxifen. The risk of local recurrence at 8 years was 16.5% for patients treated with tamoxifen alone compared with 9.3% for breast irradiation alone. Given that tamoxifen is unlikely to have any effect on local recurrence in estrogen receptor (ER)–negative patients, when the analysis is limited to patients with ER-positive tumors, there is still a significantly lower rate of local recurrence with breast irradiation. In this population, the rate of local recurrence was 12.6% with tamoxifen alone compared with 5.4% with breast irradiation alone at 8 years (approximate event rates as determined from the yearly risk estimates assuming a constant hazard). These results suggest that the risk of local recurrence with tamoxifen alone is substantial and that radiation is more effective than tamoxifen in preventing local recurrence. 
70 years with primary tumors 
