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© 2001 American Society for Clinical Oncology
Bone Metastases in Breast Cancer: How to Prevent?Centre Hospitalier Universitaire VaudoisLausanne, Switzerland To the Editor:I read with interest the recent article by Colleoni et al1 (for the International Breast Cancer Study Group [IBCSG]) in the December issue of the Journal of Clinical Oncology. In this retrospective review of data from 6,792 patients who participated in several randomized IBCSG trials (I to VII), the authors wanted to identify patient populations at high risk for bone metastases at any time after diagnosis of operable breast cancer to target the most potential beneficiaries of bisphosphonate prophylaxis. They concluded that bisphosphonates to prevent bone metastases may have a major impact on the outcome and may be most efficiently studied in populations with several involved axillary nodes at the time of presentation and in populations with local or regional relapse. I do not agree with their conclusion for two reasons. First, even if there is some evidence that bisphosphonates improve survival in breast cancer by decreasing the number of bone metastases (follow-up period of 36 months),2 there is also evidence that they may have a negative effect on disease-free and overall survival by increasing the development of nonskeletal metastases.3 Second, even accepting the beneficial effect of bisphosphonates in terms of survival, one should not overlook the most important adjuvant treatment in terms of locoregional control (and therefore bone metastases), which is radiation therapy. The IBCSG trials have nearly always excluded adjuvant radiation therapy (except breast irradiation in patients with tumorectomy) even in patients with four or more involved nodes, patients with tumors 4 cm or larger, patients with extranodal extension, or those with inadequate axillary dissections (< 10 nodes). In the IBCSG I-VII studies, only 10.6% of the patients had breast irradiation (tumorectomy patients), and no patient among the 6,792 patients had regional irradiation. Only 18.7% of those patients were node negative; 49.4% had one to three positive nodes, and 31.9% had four or more positive nodes. Among the patients with first locoregional recurrence (n = 1,220), the most relevant observation was the high 10-year cumulative incidence (36.7%) of bone metastases. The results of recent randomized trials4-6 as well as recent meta-analyses7,8 show clearly that, after mastectomy, postoperative locoregional radiation therapy improves locoregional control and survival in women with node-positive breast cancer who received adjuvant systematic therapy. Thus, for such patients included in IBCSG trials, radiation therapy may be the best modality in the prophylaxis of bone metastases; and the role of bisphosphonates should be assessed particularly in patients receiving adjuvant radiation therapy. REFERENCES
1.
Coleoni M, O’Neill A, Goldhirsch A, et al: Identifying breast cancer patients at high risk for bone metastases. J Clin Oncol 18: 3925-3935, 2000
2.
Diel IJ, Solomayer EF, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339: 357-363, 1998 3. Saarto T, Blomqvist C, Virkkunen P, et al: No reduction of bone metastases with adjuvant clodronate treatment in node-positive breast cancer patients. Proc Am Soc Clin Oncol 18: 128a, 1999 (abstr 489)
4.
Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337: 949-955, 1997
5.
Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337: 956-962, 1997 6. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBcG 82c randomised trial. Lancet 353: 1641-1648, 1999[Medline]
7.
Whelan TJ, Julian J, Wright J, et al: Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18: 1220-1229, 2000
8.
Katz A, Strom EA, Buchholz TA, et al: Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol 18: 2817-2827, 2000
Response
European Institute of OncologyMilan, Italy In Reply:Our article describing identification of populations at high risk for bone metastases1 stimulated Dr Ozsahin to raise two interesting issues, though neither is directly related to the data or conclusions of our study. First, we agree that the role of biphosphonates in preventing bone metastases remains controversial. Second, the role of postmastectomy radiation therapy in improving local control of disease and reducing subsequent metastases has been supported by the recent overview,2 and this may also apply to metastases to bone, although that information is not available from the overview. A statistically significant reduction of new bone (and also visceral) metastases was observed with the clodronate treatment in one study on 302 patients.3 A second study on 1,079 patients with primary breast cancer demonstrated a clinically relevant reduction in the incidence of bony lesions with oral clodronate when compared with placebo (RR = 0.51; 95% confidence interval, 0.30 to 0.88; P = .012).4 A third study conducted on 282 patients and presented with a 5-year follow-up showed that the use of oral clodronate did not improve overall outcome and did not have a beneficial effect on the incidence of bone metastases.5 As shown in our paper,1 long-term high incidence of bone relapse can be predicted especially after estrogen receptor–positive primaries, suggesting that a more prolonged follow-up might be required to better define the role of bisphosphonates. Therefore, we concluded that there is enough evidence to support further well-designed studies on the effects of these compounds, especially within a subpopulation at high risk of bone metastases, a conclusion that is entirely in agreement with the American Society of Clinical Oncology guidelines for the use and research on bisphosphonates in breast cancer.6 Available results from the Early Breast Cancer Trialists’ Collaborative Group on the effects of radiotherapy for patients with early breast cancer indicated that radiotherapy was associated with a reduced risk of death caused by breast cancer (ratio of survival at 20 years, 0.911; SE, 0.017; 2P = .0001) but an increased risk of death from other causes (ratio of survival, 1.061; SE, 0.02; 2P = .0003).2 The balance between these favorable and unfavorable effects was related to absolute risk and patient age.2 Three recent trials have shown that postmastectomy irradiation added to a chemotherapy regimen containing cyclophosphamide, methotrexate, and fluorouracil (CMF)7,8 or tamoxifen9 improved disease-free and overall survival. The CMF regimens used in the Danish and Canadian trials were altered from the classical CMF regimen first reported as an effective adjuvant therapy almost 30 years ago. Several randomized trials have shown that departure from the classical CMF regimen compromises its efficacy in metastatic breast cancer,10 as we have previously commented.11,12 In the second trial by the Danish Group, tamoxifen was given for the duration of 1 year, clearly a suboptimal systemic therapy. Further clinical trials now being conducted in Europe and the United States may help to clarify the role of radiation therapy after mastectomy. Radiotherapy is clearly indicated if it is still possible in patients with excised local recurrence. Meanwhile, it is reasonable to investigate the role of bisphosphonates in combination with optimal systemic treatment and with radiation therapy, if the risk of local recurrence and patient age suggest the probability of net benefit.2 An efficacy study of this question will be facilitated by selection of a study population at increased risk of bone metastasis. The definition of such a population was the purpose of our article. REFERENCES 1. Colleoni M, O’Neill A, Goldhirsch A, et al: Identifying breast cancer patients at high risk for bone metastases. J Clin Oncol 18: 3925-3935, 2000 2. Early Breast Cancer Trialists’ Collaborative Group: Favourable and unfavourable effects on long term survival of radiotherapy for early breast cancer: An overview of the randomized trials. Lancet 355:1757-1770, 2000 3. Diel IJ, Solomayer EF, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339: 357-363, 1998 4. Powles TJ, McCloskey E, Paterson A, et al: Adjuvant clodronate will reduce the incidence of bone metastases in patients with primary operable breast cancer. Twenty-First Annual San Antonio Breast Cancer Symposium, San Antonio TX, December 12-15, 1998 (abstr)
5.
Saarto T, Blomqvist C, Virkkunen P, et al: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-Year results of a randomized controlled trial. J Clin Oncol 19: 10-17, 2001
6.
Hillner BE, Ingle JN, Berenson JR, et al: American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. J Clin Oncol 18: 1378-1391, 2000 7. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337: 949-955, 1997 8. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast. N Engl J Med 337: 956-962, 1997 9. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Dansish Breast Cancer Cooperative Group DBCG 82c randomized trial. Lancet 353: 1641-1648, 1999 10. Engelsman E, Klijn JC, Rubens RD, et al: "Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: An EORTC Breast Cancer Cooperative Group phase III trial (10808). Eur J Cancer 27: 966-970, 1991
11.
Goldhirsch A, Colleoni M, Coates AS, et al: Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: Are all CMFs alike? Ann Oncol 9: 489-493, 1998 12. Goldhirsch A, Coates AS, Colleoni M, et al: Radiotherapy and chemotherapy in high-risk breast cancer. N Engl J Med 338: 330, 1998 (letter)
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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