Breast Radiotherapy after Lumpectomy — No Longer Always Necessary
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《新英格兰医药杂志》
Breast-conserving surgery followed by radiotherapy is the standard of care for women with small breast cancers who wish to avoid mastectomy. This approach achieves good local control, does not disturb the women's body image or impair survival,1 and has been an important step forward in the management of this disease.
Several trials have compared breast-conserving surgery plus postoperative radiotherapy with breast-conserving surgery alone, and all have shown an increased risk of local recurrence if radiotherapy is omitted but no difference in survival. One of the largest of these trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 study, which began in 1976 and included women with breast tumors up to 4 cm in diameter, showed that patients treated with lumpectomy alone had a rate of local recurrence of 39 percent after 20 years of follow-up, as compared with a rate of only 14 percent for those who also received radiotherapy.2 Standard practice has therefore been to provide radiotherapy after conservative surgery for all patients, making the goal of identifying women who may not need this additional treatment elusive.
Since these trials were started, imaging and tumor-localization techniques have improved, and the need for histologically clear resection margins to minimize the risk of local recurrence has been recognized. In addition, there is now widespread use of adjuvant medical therapy, including tamoxifen, which reduces the risk of local recurrence3 and improves survival. Against this changing background, two new trials reported in this issue of the Journal have reevaluated the need for radiotherapy after breast-conserving surgery.
The first trial, reported by Fyles and his Canadian colleagues, involved women 50 years of age or older.4 Despite the use of tamoxifen and a requirement of clear resection margins for all patients, the results reflect those of earlier trials. Women who did not receive breast radiotherapy had a significantly higher rate of local relapse at five years than those who did (7.7 percent vs. 0.6 percent), with no significant differences in the rates of distant relapse, overall survival, or death from breast cancer. The trial design could be called into question for including women with tumors as large as 5 cm in diameter and for not requiring a hormone-receptor–positive status as a criterion for eligibility. Even allowing for this approach, a planned analysis of women with estrogen-receptor–positive tumors no more than 2 cm in diameter still showed a significant and clinically relevant reduction in the rate of local relapse for those treated with radiotherapy; after eight years this rate was 3.6 percent in the group given tamoxifen plus radiotherapy and 15.2 percent in the group given tamoxifen alone. These results reinforce findings from another recent trial — the NSABP B-21 study — in which the addition of radiotherapy to lumpectomy and tamoxifen for tumors that were 1 cm in diameter or less significantly reduced the risk of local recurrence.5
The second Cancer and Leukemia Group B (CALGB) C9343 trial, reported by Hughes et al.,6 was more restrictive. It included only women 70 years of age or older who had tumors that were positive for estrogen receptors (or had an unknown receptor status) and were no greater than 2 cm in diameter. Such women represent a large subgroup (approximately 40,000 women annually) of patients with breast cancer in the United States on the basis of data from the Surveillance, Epidemiology, and End-Results Program,7 and results in this group have important implications concerning the use of medical resources. Paradoxically, women 70 years of age or older were specifically excluded from some of the earlier trials, including the NSABP B-06 trial. The CALGB trial also showed a significant increase in the five-year rate of local or regional recurrence among women treated with lumpectomy and tamoxifen alone, as compared with women who also received radiotherapy. In contrast to the results of other trials, however, the absolute difference was small (4 percent vs. 1 percent), and there were no significant differences in the subsequent need for mastectomy, the risk of distant metastases, or survival between the two groups.
Does this absolute difference in the rate of local recurrence of 3 percent matter clinically, when weighed against the cost of the use of additional resources and treatment-related adverse effects? An overview of 40 trials in this field has confirmed that local radiotherapy is associated with an increase in deaths from cardiac and other causes, which nullifies a long-term reduction in deaths from breast cancer.8 Modern radiotherapy techniques, including three-dimensional treatment planning and intensity-modulated radiotherapy, with cardiac shielding, can minimize the risk of cardiac irradiation in most patients.9 Some side effects persist, and the CALGB investigators reported an increased incidence of breast pain, fibrosis, breast edema, and poor cosmetic results in the group that received radiotherapy. In addition, breast radiotherapy is resource-intensive and time-consuming for the patient and may decrease the quality of life.10 There is, of course, the counterargument that not having radiotherapy may increase a woman's anxiety about the possibility of recurrence and could require more frequent follow-up. On balance, nevertheless, there are clear advantages in identifying subgroups in a large population of elderly women who do not require radiotherapy after lumpectomy and tamoxifen.
The long natural history of breast cancer is a further issue here, and the median follow-up of approximately five years in both these trials could certainly lead to an underestimate of the final difference between therapies. In the NSABP B-06 trial, 19 percent of local relapses after lumpectomy alone occurred 5 to 10 years after treatment, and a further 9 percent occurred after 10 years.2 In the Canadian trial, even in the subgroup with a good prognosis, the rate of local relapse rose from 5.9 percent after five years to 15.2 percent after eight years for women treated with tamoxifen alone. For women over 70 years of age, however, this is likely to be less of an issue, since breast cancer in this age group is biologically less aggressive7 and is associated with a lower risk of local recurrence after breast-conserving surgery11 and with less time at risk.
Adjuvant endocrine therapy is improving with the availability of the aromatase inhibitors. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial showed that, as compared with tamoxifen, anastrozole resulted in a greater reduction in the risk of local recurrence as well as of systemic disease after a median follow-up of a mere 33 months,12 and similar benefits in local control have been reported with the use of exemestane13 and letrozole14 after 2 and 5 years of tamoxifen therapy, respectively. These findings raise the real possibility that treatment with aromatase inhibitors could further reduce the risk of local recurrence in the absence of radiotherapy.
Against this background, what course should we recommend to older women with small, hormone-receptor–positive breast tumors who have undergone lumpectomy? The Canadian trial indicates that women under the age of 70 years should still receive radiotherapy in addition to tamoxifen. This is frustrating advice, because although it is clear that the majority of women treated with lumpectomy and tamoxifen alone would not have a relapse, we still cannot confidently predict which women will be in the majority. We are entering an era in which the use of molecular markers, gene-expression profiles, and other molecular prognostic indicators is being investigated as a means of individualizing adjuvant medical therapies,15 and there is no reason why the same approach should not be applied to radiotherapy. Future trials of radiotherapy should be required to include tissue biopsy for prospective molecular analyses and informed consent for this type of research.
In contrast to the Canadian study, the CALGB trial offers persuasive data that women 70 years of age or older who have estrogen-receptor–positive cancers up to 2 cm in diameter can now be offered lumpectomy and tamoxifen alone without additional radiotherapy. For many women, the mere 3 percent increase in the risk of local recurrence with no concomitant decrease in survival is likely to be an entirely acceptable tradeoff, even in view of the fact that the risk of recurrence may increase further with time or perhaps be reduced by treatment with an aromatase inhibitor rather than tamoxifen. Other women will undoubtedly still want radiotherapy. Women who have just received a diagnosis of early breast cancer rightly have their own strong views about treatment, and in this context, it is of interest that 57 percent of those eligible for the Canadian trial declined to enroll. The CALGB trial provides new data that will help women and their health care providers make informed choices about treatment.
Source Information
From the Institute of Cancer Research and Breast Unit, Royal Marsden Hospital, London.
References
Morrow M, Harris JR. Local management of invasive breast cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the breast. 2nd ed. Philadelphia: Lippincott Williams & Williams, 2000:515-61.
Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-1241.
Buchholz TA, Tucker SL, Erwin J, et al. Impact of systemic treatment on local control for patients with lymph node-negative breast cancer treated with breast-conservation therapy. J Clin Oncol 2001;19:2240-2246.
Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 2004;351:963-970.
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 2002;20:4141-4149.
Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004;351:971-977.
Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000;92:550-556.
Early Breast Cancer Trialists' Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355:1757-1770.
Landau D, Adams EJ, Webb S, Ross G. Cardiac avoidance in breast radiotherapy: a comparison of simple shielding techniques with intensity-modulated radiotherapy. Radiother Oncol 2001;60:247-255.
Whelan TJ, Levine M, Julian J, Kirkbride P, Skingley P. The effects of radiation therapy on quality of life of women with breast carcinoma: results of a randomized trial. Cancer 2000;88:2260-2266.
Veronesi U, Luini A, Del Vecchio M, et al. Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 1993;328:1587-1591.
The ATAC (Arimidex, Tamoxifen Alone or in Combination) 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 2002;359:2131-2139.
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081-1092.
Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793-1802.
Van de Vijver MJ, He YD, van't Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347:1999-2009.(Ian E. Smith, M.D., and G)
Several trials have compared breast-conserving surgery plus postoperative radiotherapy with breast-conserving surgery alone, and all have shown an increased risk of local recurrence if radiotherapy is omitted but no difference in survival. One of the largest of these trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 study, which began in 1976 and included women with breast tumors up to 4 cm in diameter, showed that patients treated with lumpectomy alone had a rate of local recurrence of 39 percent after 20 years of follow-up, as compared with a rate of only 14 percent for those who also received radiotherapy.2 Standard practice has therefore been to provide radiotherapy after conservative surgery for all patients, making the goal of identifying women who may not need this additional treatment elusive.
Since these trials were started, imaging and tumor-localization techniques have improved, and the need for histologically clear resection margins to minimize the risk of local recurrence has been recognized. In addition, there is now widespread use of adjuvant medical therapy, including tamoxifen, which reduces the risk of local recurrence3 and improves survival. Against this changing background, two new trials reported in this issue of the Journal have reevaluated the need for radiotherapy after breast-conserving surgery.
The first trial, reported by Fyles and his Canadian colleagues, involved women 50 years of age or older.4 Despite the use of tamoxifen and a requirement of clear resection margins for all patients, the results reflect those of earlier trials. Women who did not receive breast radiotherapy had a significantly higher rate of local relapse at five years than those who did (7.7 percent vs. 0.6 percent), with no significant differences in the rates of distant relapse, overall survival, or death from breast cancer. The trial design could be called into question for including women with tumors as large as 5 cm in diameter and for not requiring a hormone-receptor–positive status as a criterion for eligibility. Even allowing for this approach, a planned analysis of women with estrogen-receptor–positive tumors no more than 2 cm in diameter still showed a significant and clinically relevant reduction in the rate of local relapse for those treated with radiotherapy; after eight years this rate was 3.6 percent in the group given tamoxifen plus radiotherapy and 15.2 percent in the group given tamoxifen alone. These results reinforce findings from another recent trial — the NSABP B-21 study — in which the addition of radiotherapy to lumpectomy and tamoxifen for tumors that were 1 cm in diameter or less significantly reduced the risk of local recurrence.5
The second Cancer and Leukemia Group B (CALGB) C9343 trial, reported by Hughes et al.,6 was more restrictive. It included only women 70 years of age or older who had tumors that were positive for estrogen receptors (or had an unknown receptor status) and were no greater than 2 cm in diameter. Such women represent a large subgroup (approximately 40,000 women annually) of patients with breast cancer in the United States on the basis of data from the Surveillance, Epidemiology, and End-Results Program,7 and results in this group have important implications concerning the use of medical resources. Paradoxically, women 70 years of age or older were specifically excluded from some of the earlier trials, including the NSABP B-06 trial. The CALGB trial also showed a significant increase in the five-year rate of local or regional recurrence among women treated with lumpectomy and tamoxifen alone, as compared with women who also received radiotherapy. In contrast to the results of other trials, however, the absolute difference was small (4 percent vs. 1 percent), and there were no significant differences in the subsequent need for mastectomy, the risk of distant metastases, or survival between the two groups.
Does this absolute difference in the rate of local recurrence of 3 percent matter clinically, when weighed against the cost of the use of additional resources and treatment-related adverse effects? An overview of 40 trials in this field has confirmed that local radiotherapy is associated with an increase in deaths from cardiac and other causes, which nullifies a long-term reduction in deaths from breast cancer.8 Modern radiotherapy techniques, including three-dimensional treatment planning and intensity-modulated radiotherapy, with cardiac shielding, can minimize the risk of cardiac irradiation in most patients.9 Some side effects persist, and the CALGB investigators reported an increased incidence of breast pain, fibrosis, breast edema, and poor cosmetic results in the group that received radiotherapy. In addition, breast radiotherapy is resource-intensive and time-consuming for the patient and may decrease the quality of life.10 There is, of course, the counterargument that not having radiotherapy may increase a woman's anxiety about the possibility of recurrence and could require more frequent follow-up. On balance, nevertheless, there are clear advantages in identifying subgroups in a large population of elderly women who do not require radiotherapy after lumpectomy and tamoxifen.
The long natural history of breast cancer is a further issue here, and the median follow-up of approximately five years in both these trials could certainly lead to an underestimate of the final difference between therapies. In the NSABP B-06 trial, 19 percent of local relapses after lumpectomy alone occurred 5 to 10 years after treatment, and a further 9 percent occurred after 10 years.2 In the Canadian trial, even in the subgroup with a good prognosis, the rate of local relapse rose from 5.9 percent after five years to 15.2 percent after eight years for women treated with tamoxifen alone. For women over 70 years of age, however, this is likely to be less of an issue, since breast cancer in this age group is biologically less aggressive7 and is associated with a lower risk of local recurrence after breast-conserving surgery11 and with less time at risk.
Adjuvant endocrine therapy is improving with the availability of the aromatase inhibitors. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial showed that, as compared with tamoxifen, anastrozole resulted in a greater reduction in the risk of local recurrence as well as of systemic disease after a median follow-up of a mere 33 months,12 and similar benefits in local control have been reported with the use of exemestane13 and letrozole14 after 2 and 5 years of tamoxifen therapy, respectively. These findings raise the real possibility that treatment with aromatase inhibitors could further reduce the risk of local recurrence in the absence of radiotherapy.
Against this background, what course should we recommend to older women with small, hormone-receptor–positive breast tumors who have undergone lumpectomy? The Canadian trial indicates that women under the age of 70 years should still receive radiotherapy in addition to tamoxifen. This is frustrating advice, because although it is clear that the majority of women treated with lumpectomy and tamoxifen alone would not have a relapse, we still cannot confidently predict which women will be in the majority. We are entering an era in which the use of molecular markers, gene-expression profiles, and other molecular prognostic indicators is being investigated as a means of individualizing adjuvant medical therapies,15 and there is no reason why the same approach should not be applied to radiotherapy. Future trials of radiotherapy should be required to include tissue biopsy for prospective molecular analyses and informed consent for this type of research.
In contrast to the Canadian study, the CALGB trial offers persuasive data that women 70 years of age or older who have estrogen-receptor–positive cancers up to 2 cm in diameter can now be offered lumpectomy and tamoxifen alone without additional radiotherapy. For many women, the mere 3 percent increase in the risk of local recurrence with no concomitant decrease in survival is likely to be an entirely acceptable tradeoff, even in view of the fact that the risk of recurrence may increase further with time or perhaps be reduced by treatment with an aromatase inhibitor rather than tamoxifen. Other women will undoubtedly still want radiotherapy. Women who have just received a diagnosis of early breast cancer rightly have their own strong views about treatment, and in this context, it is of interest that 57 percent of those eligible for the Canadian trial declined to enroll. The CALGB trial provides new data that will help women and their health care providers make informed choices about treatment.
Source Information
From the Institute of Cancer Research and Breast Unit, Royal Marsden Hospital, London.
References
Morrow M, Harris JR. Local management of invasive breast cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the breast. 2nd ed. Philadelphia: Lippincott Williams & Williams, 2000:515-61.
Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-1241.
Buchholz TA, Tucker SL, Erwin J, et al. Impact of systemic treatment on local control for patients with lymph node-negative breast cancer treated with breast-conservation therapy. J Clin Oncol 2001;19:2240-2246.
Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 2004;351:963-970.
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 2002;20:4141-4149.
Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004;351:971-977.
Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000;92:550-556.
Early Breast Cancer Trialists' Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355:1757-1770.
Landau D, Adams EJ, Webb S, Ross G. Cardiac avoidance in breast radiotherapy: a comparison of simple shielding techniques with intensity-modulated radiotherapy. Radiother Oncol 2001;60:247-255.
Whelan TJ, Levine M, Julian J, Kirkbride P, Skingley P. The effects of radiation therapy on quality of life of women with breast carcinoma: results of a randomized trial. Cancer 2000;88:2260-2266.
Veronesi U, Luini A, Del Vecchio M, et al. Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 1993;328:1587-1591.
The ATAC (Arimidex, Tamoxifen Alone or in Combination) 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 2002;359:2131-2139.
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081-1092.
Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793-1802.
Van de Vijver MJ, He YD, van't Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347:1999-2009.(Ian E. Smith, M.D., and G)