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Originally published as JCO Early Release 10.1200/JCO.2004.06.974 on September 27 2004 © 2004 American Society of Clinical Oncology.
Postmastectomy Radiation Therapy: Who Needs It?
1 British Columbia Cancer Agency–Vancouver Island Centre and University of British Columbia, Victoria, British Columbia Canada Three recent trials1-3 demonstrating that adjuvant postmastectomy radiation therapy (PMRT) not only reduced locoregional failure (LRF) but also improved 10- to 15-year breast cancer–specific and overall survival have rekindled debates regarding which breast cancer patients should receive PMRT.4-7 Several guidelines have been published,8-10 and there is also evidence that the use of regional nodal radiation therapy (RT) has increased since 1997.11 The guidelines generally agree that PMRT is indicated in patients with four or more positive nodes, but also conclude that additional research is required to define its role in patients with one to three positive nodes. There are two reasons to consider the use of PMRT: to optimize locoregional control and to improve survival. More than 30 randomized trials of PMRT have shown a remarkably consistent, two-thirds to three-quarters relative risk reduction in LRF, independent of tumor or nodal characteristics, age, treatment era or dose, and fractionation.12-14 The absolute locoregional control benefit of PMRT is greater when the risk of recurrence is higher. Prospective PMRT trials,1-3 retrospective analyses of systemic therapy trials,15-18 and institutional or population-based series19-21 have demonstrated that there are factors, including higher nodal tumor burden, advanced tumor size, and young age, that are associated with increased LRF. Confirmation of these factors is reported in this issue of the Journal of Clinical Oncology by Taghian et al, who review the experience of 5,758 mastectomy-treated patients with node-positive breast cancer in five National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials.18 The incidence of LRF (with or without simultaneous distant failure) was nearly 25% or greater for patients with four or more positive nodes, tumor size greater than 5 cm, fewer than six nodes recovered at axillary dissection, or patient age younger than 40 years. Higher LRF rates occurred among patients with combinations of these risk factors. The LRFs occurred early, with a median time of 2 years to isolated local failure (ILF), and 71% occurred within 4 years. The majority of ILFs occurred on the chest wall (57%) or in the supraclavicular fossa (23%). Isolated axillary failure was relatively uncommon (12% of ILFs), but a median of 16 axillary nodes were dissected and examined.18 Recognizing the importance of the extent of nodal involvement, guidelines recommend PMRT for patients with four or more positive nodes, primarily to reduce LRF.8-10 PMRT reduces the LRF risk of 25%, to 6% to 8%, providing an absolute benefit for 17 to 19 women for each 100 treated. In patients with one to three positive nodes, Taghian et al found a 10-year LRF rate of 13%. In this group of patients, PMRT will reduce the LRF risk to 3% to 4%, which represents an absolute benefit for 9 to 10 women for each 100 treated. The risks of serious adverse effects are modest.9, 10 Contemporary conformal RT techniques, which limit normal tissue exposure,22, 23 create the potential to improve the therapeutic ratio of PMRT. The major remaining controversy surrounding PMRT is in the selection of which patients warrant treatment primarily for a survival benefit. Clinical trials and meta-analyses demonstrate that the ratio between the number of LRFs avoided and breast cancer deaths prevented is approximately 4:1 to 5:1.1-3, 12-14 A similar ratio is seen in trials of RT after breast-conserving surgery,24-26 and in one meta-analysis of axillary surgery extent.27 An absolute reduction in LRF of 20% can therefore be expected to confer an improvement in breast cancer–specific survival of 4% to 5%.1-3, 12-14, 24-26 Based on the ratio of 4:1 to 5:1, one can estimate that if the 10-year LRF risk is less than 10%, then only one to two women will realize a survival benefit for each 100 treated with PMRT. Many women may find that the cost, inconvenience, and morbidity of RT outweigh this small improvement in 10-year survival. On the other hand, if the baseline 10-year LRF risk is 25%, PMRT would produce an absolute risk reduction of 16% to 18% and an absolute survival improvement of 4% to 5%, increasing the likelihood that patients and physicians would choose treatment. As a result, PMRT is not routinely indicated when the LRF is less than 10%, but it is justified when the LRF exceeds 25%. Between a CRF of 10% and 25%, the decision to use PMRT requires a more delicate balancing of each patient's priorities and preferences. Data presented by Taghian et al18 and others1-3, 15-17, 19-21 are helpful in identifying groups of patients with 10-year LRF risks of 25% and higher. A caveat in determining the applicability of the study by Taghian et al to current clinical practice is that the results were derived from a database of clinical trials that primarily investigated the optimal use of different anthracycline-based chemotherapy regimens, when the NSABP did not permit the use of PMRT.18 Compared with population-based or institutional series, many more patients in the NSABP experience were premenopausal or younger than 50 years, and only 1.9% had fewer than six axillary nodes dissected.18 Patients judged by their oncologists to have indications for PMRT or to be unsuitable for one of the chemotherapy arms of the randomized trials, might not have been offered trial participation. During these trials, in British Columbia for example, PMRT was recommended to patients with one to three positive nodes if the involved node(s) were bulky, represented 50% or more of the nodes dissected, or if there was significant extranodal extension.11 Such patients would not have been offered participation in a clinical trial in which PMRT was not permitted. The greater proportion of younger women and possible exclusion of patients deemed by their oncologists to have indications for PMRT introduces some uncertainties in generalizing the reported LRF estimates to patients considering PMRT today. Further research is required to define the role of PMRT in patients with one to three positive nodes. A North American Intergroup trial designed to directly address this issue, in which patients were randomly assigned to PMRT or observation, was prematurely closed due to lack of accrual. A European trial of internal mammary and supraclavicular RT recently completed accrual.28 An ongoing trial in North America and Australia randomly assigns patients after breast-conserving surgery to RT to the breast or the breast plus regional nodes.29 The nodal treatment volume varies according to the number of positive nodes and number of nodes removed. Although not directly applicable to the postmastectomy setting, this study may provide insight into regional recurrence patterns related to RT use and treatment region in women with one to three positive nodes. Until mature data from such prospective randomized trials of locoregional RT are available, the data reported by Taghian et al18 will help clinicians and patients who face the complex task of appraising the benefits and risks of curative locoregional therapy. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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