Re: Locoregional Radiation Therapy in Patients With High-Risk Breast Cancer Receiving Adjuvant Chemotherapy: 20-Year Results of the British Columbia Randomized Trial

The paper of Ragaz et al. ( 1 ) provides important level 1 evidence that the improvement in overall survival from the addition of postmastectomy radiotherapy to systemic therapy in axillary lymph node-positive patients, previously reported ( 2 ) , is sustained up to 20 years. Ragaz et al. rightly identify the applicability of the results of their trial to clinical practice as a critical question. It is particularly relevant to the ongoing debate on the role of postmastectomy radiation therapy in women with one to three positive axillary lymph nodes. However, the findings may not necessarily be extrapolated to contemporary practice, because the radiotherapeutic technique, adjuvant chemotherapy, and hormonal therapy used in the Canadian study ( 1 ) have changed. Currently, there are relatively few centers that would attempt comprehensive lymph node irradiation, including the internal mammary chain, as in the Canadian trial. In addition, the dose to the heart is likely to be substantially lower, particularly with the use of planning involving three-dimensional computed tomography. The Canadian trial ( 1 ) used the combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as the standard chemotherapy. CMF has now largely been replaced by anthracycline-containing chemotherapy in premenopausal patients with axillary lymph node-positive disease. Although the proportional reduction in risk of locoregional recurrence from postmastectomy radiation therapy may remain constant for different levels of risk, there are few data on the cardiac sequelae of patients receiving concurrent or sequential anthracycline-containing adjuvant regimes combined with postmastectomy radiation therapy. The survival benefits reported by Ragaz et al. ( 1 ) in the group with one to three positive lymph nodes (57% versus 50% for the group receiving radiation therapy versus the group not given radiation therapy, respectively) is more modest than in patients with four or more positive lymph nodes (31% versus 17% for group receiving radiation therapy and group not given radiation therapy, respectively). In addition, it is possible that the 23 patients who had positive axillary lymph nodes but who lacked information on the number of lymph nodes involved could have skewed the first set of analyses. The trade-off among locoregional control, survival, and toxicity of postmastectomy radiation therapy for intermediate-risk breast cancer patients with one to three involved axilllary lymph nodes needs to be examined by use of contemporary radiotherapy and systemic therapy in the context of a large randomized phase III trial. The international SUPREMO (i.e., Selective Use of Postoperative Radiotherapy after Mastectomy) (BIG 2–04) trial ( 3 ) , recently funded by the United Kingdom Medical Research Council, will address this issue. In the biological substudy (TRANS-SUPREMO), tissue microarrays will be developed from the entire study population of 3700 patients to determine the immunohistochemical signatures associated with risk, relapse, and resistance to radiation therapy. We would therefore concur with the view of Whelan and Levine ( 4 ), in their accompanying editorial, that the highest level of evidence from randomized trials should determine clinical practice and that decisions on therapy should not ideally be, as they are at present, based on the subgroup analyses in the Canadian trial ( 1 ) and the larger Danish trial ( 5 ) .

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