I will briefly comment on two points discussed by Pierce and Lichter in their thorough review: (1) the recently published Oxford overview analysis of locoregional therapies , and (2) which patients may benefit from postmastectomy radiotherapy.
Clinical Relevance of Meta-Analysis
Overview, or meta-analysis, is a valuable statistical tool, but its clinical relevance rests on the often dubious assumption that the similarities between trials are more important than their frequently drastic differences relative to patient populations and treatment techniques . For example, the global results of the Oxford overview resulted ther mixing together trials employing breast-conserving surgery, simple mastectomy without axillary dissection, modified radical mastectomy, or radical mastectomy and either orthovoltage or megavoltage radiotherapy, without regard to the relative effectiveness of these various treatments in preventing locoregional relapse. (Other problems of analysis and presentation in this overview have been described in more detail elsewhere .) Thus, the finding, in the combined trials, of a 1.1% absolute reduction in overall mortality for patients given more "aggressive" locoregional therapy (ie, more extensive surgery and/or the addition of radiotherapy to surgery), as compared with "control" patients, is irrelevant. The benefits of treating patients in specific clinical situations with particular therapies cannot be estimated from such an exercise.
A more relevant grouping of trials for our present purpose would include only studies in which patients were treated by modified radical mastectomy and multiagent chemotherapy and were randomized to receive or not receive megavoltage radiotherapy. The Oxford overview included four such studies, in which patients were exclusively or predominantly histologically node-positive (the Danish BCG 82b, Vancouver, Helsinki, and BMFT 03 Germany trials). The odds reduction in mortality for the irradiated patients in these four combined trials was 20.8% ± 9% (P = .02). In absolute terms, 18.8% of the 1,064 irradiated patients died during the period of observation, as compared with 22.5% of the 1,072 control patients. This reduction in overall mortality is very similar in size to that obtained from other commonly accepted oncologic therapies .
Which Patients Should Be Treated?
The second issue focuses on which patients should receive postmastectomy radiation therapy. Although some patient groups are demonstrably at high risk of locoregional (and distant) failure following surgery, radiotherapy may also benefit patients with lower risks. This would be analogous to the effects of systemic therapy. That is, all patient subgroups appear to benefit to a similar degree when the proportional reduction in recurrence is considered, but absolute differences in outcome are substantially greater for patients at higher risk (eg, patients with positive axillary nodes) than for those at lower risk (those with negative nodes) .
In particular, it is premature to conclude that patients with one to three positive nodes should not participate in a trial of postmastectomy radiotherapy or be considered for such treatment outside of a trial. In an update of the British Columbia trial, which was published too late to be incorporated into the Pierce-Lichter review, the use of radiotherapy resulted in an increase in the 12-year distant disease-free survival rate for both patients with one to three positive nodes (68%, as compared with 54% in controls [P = .06], or a proportional reduction of 30%) and those with four or more positive nodes (41% vs 19% [P = .06], or a proportional reduction of 27%) . (Survival and relapse-free survival rates were not reported for these subgroups, however.)Definitive Recommendations Require More Data
I agree with Pierce and Lichter that definitive recommendations regarding the indications for postmastectomy radiotherapy cannot be made at present. At present, I, too, routinely recommend such treatment only for patients with large (over 5 cm) or locally advanced tumors, four or more positive axillary lymph nodes, or involved chest wall margins . However, it should be recognized that these criteria may be unduly restrictive. We desperately need more subgroup analyses and complete publication of the randomized trials that have already been conducted. We may find that the distant disease-free and overall survival advantages of using postmastectomy radiotherapy in patients with one or three positive nodes equals or exceeds the benefits of giving chemotherapy to node-negative patients or radiotherapy following breast-conserving surgery .