One to three versus four or more positive nodes and postmastectomy radiotherapy: time to end the debate.

The role of postmastectomy radiotherapy (PMRT) has been controversial for decades, accounting for countless presentations, debates, and papers. It was reasonably clear from the beginning that PMRT improved locoregional control. Much of the controversy has had to do with whether PMRT improved survival. The evidence is now strong that PMRT does indeed improve survival, both from individual studies and from reviews and meta-analyses. The Gebski et al analysis is particularly significant because, unlike many meta-analyses, this study controlled for the quality of the radiotherapy. The more recent studies demonstrate an absolute survival benefit of approximately 5% to 10% and approximately 66% to 75% relative reduction in locoregional recurrence. There should no longer be much doubt in the minds of oncologists as to the value of PMRT. Controversy continues to exist, however, as to the clinical characteristics of patients who would benefit significantly from PRMT. Because the risk of locoregional recurrence increases with the number of positive axillary lymph nodes, a widely adopted approach has been to apply PMRT only in patients with four or more positive axillary nodes, and not to those with one to three positive nodes. The rationale for this approach is nicely summarized in a prior Journal of Clinical Oncology editorial. If one believes that the ratio between locoregional failures avoided and breast cancer deaths prevented is approximately four to one, the group with four or more positive node group will enjoy the largest benefits in both locoregional control and survival. We have a number of concerns with this thesis, however. First, though this approach seems logical, it is not supported by the available data. In the Overgaard and Ragaz studies (Table 1), the absolute magnitude of the overall survival benefit afforded by PMRT is similar in the patients with one to three versus four or more positive lymph nodes. Many have criticized these studies for the degree of axillary surgery (median number of recovered nodes, seven in Overgaard and 11 in Ragaz), compared with a larger number of recovered nodes in some other studies. To address this criticism, a recent analysis from the Danish trials considered the subset of 1,152 node-positive patients with eight or more nodes removed (ie, median). The overall 15-year survival rate was increased by 9% in patients with either one to three positive nodes or four or more positive nodes, with a disconnect between improvement in local control and survival. Although the patients with four or more positive nodes had a far greater improvement in local control with RT than did the group with one to three nodes, the survival benefits were similar in both groups. The explanation advanced by the authors seems plausible. Improvements in locoregional control will yield survival benefits only if there is systemic tumor control as well. Because patients with four or more positive axillary nodes are likely, on average, to harbor a higher systemic subclinical disease burden than those with one to three positive nodes, improvements in locoregional control will be less likely to translate into a survival benefit in the four or more node group. Thus, the ratio between locoregional failures avoided and breast cancer deaths prevented may not be constant across patient subgroups. Further, as the efficacy of systemic therapy increases, the impact of PMRT on survival may also increase. In this regard, local and systemic therapies are synergistic rather than competitive. Second, some argue that a more complete axillary dissection would have moved most of the patients with one to three positive nodes in the Overgaard and Ragaz studies into the group with four or more positive nodes. This issue has been studied by several investigators. Danforth et al and Saha et al found that 64% to 71% of patients with one to three positive nodes after limited level I dissection (median, 10 nodes) would remain in the group with one to three positive nodes with a more complete dissection. Using mathematical models based on clinical data, Kiricute et al and Iyer et al computed that approximately 50% of patients with two positive nodes after limited dissection will remain in the group with one to three positive nodes with a more complete dissection. Thus, approximately 50% to 70% of the patients in the group with one to three positive nodes from the original Overgaard and Ragaz studies would likely remain in the same group with a more complete dissection. Thus, the often-heard suggestion that most of the patients with one to three nodes in the Overgaard and Ragaz studies would have had four or more nodes with a more complete dissection is not consistent with the data. Third, the subsetting of patients into groups with one to three versus four or more positive nodes is an artificial distinction originating in the early days of adjuvant systemic therapy for breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) was perhaps the first to do this, with initial benefits from adjuvant chemotherapy observed only in those with four or more positive lymph nodes. Later studies demonstrated the utility of systemic therapy in patients with one to three, or even zero, involved nodes. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 13 MAY 1 2008