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From the Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
Correspondence: Address correspondence to: Julia S. Wong, MD, Brigham and Women’s Hospital, Department of Radiation Oncology, 75 Francis St., Boston, MA 02115; Fax: 617-732-7347; E-mail: jwong{at}lroc.harvard.edu
Management of the clinically negative axilla in early-stage invasive breast cancer remains controversial. Before the advent of sentinel node biopsy, patients routinely underwent axillary lymph node dissection (ALND), which provided prognostic information, provided local control in the axilla, and was used to help guide adjuvant therapy recommendations. However, both node-negative and node-positive patients are now known to benefit from adjuvant systemic therapy,1,2 and it is unclear whether different regimens should be used based on the number of positive nodes. In addition, ALND is associated with morbidity, some of which can be long-term.3–5 Furthermore, the survival benefit of axillary treatment is not well established. Given these considerations, both clinicians and patients have expressed interest in avoiding ALND when feasible. Sentinel node biopsy continues to be increasingly popular as a less invasive option for obtaining axillary nodal information.
One alternative to ALND is axillary radiotherapy (RT). Axillary recurrences after ALND or axillary RT in clinically node-negative patients are uncommon. Randomized trials comparing ALND with axillary RT suggest that similar axillary local control can be obtained with either approach.6–8 Another alternative to ALND in patients undergoing breast-conserving therapy (BCT) is breast RT alone, which includes part of the lower axilla. One question that arises is, does the use of tangential breast RT contribute to local control in the axilla, in the absence of axillary dissection? Several investigators have reported retrospectively on axillary recurrence rates after BCT with tangential breast RT, without ALND, yielding reassuringly low axillary recurrence rates in the 0% to 5% range.9–12 In our experience, 92 patients with small tumors and clinically negative axillae received tangential RT without ALND.12 Sixty-two percent received adjuvant tamoxifen. No isolated regional nodal failures were observed at a median follow-up time of 50 months. In comparison, conservative breast surgery alone, without tangential breast or specific axillary RT and without ALND, resulted in a 4% rate of axillary recurrence in one study13 and a 23% rate of axillary recurrence in another.14 It therefore remains unclear how effective tangential breast RT is in reducing axillary recurrence.
In this issue of Annals of Surgical Oncology, Zurrida et al.15 contribute substantive evidence to this debate. In this trial, 435 clinically node-negative breast cancer patients, older than age 45 and with tumors <1.2 cm, underwent BCT consisting of breast-conserving surgery without ALND and were then randomized to breast RT only or to breast and axillary nodal RT. Approximately three quarters of the study population had tumors measuring 
1 cm. The primary end point was axillary recurrence rate. At a median follow-up time of 42 months, two patients (1%) in the breast RT-only arm and one patient (0.5%) in the breast and axillary RT arm developed axillary recurrences. There were no statistically significant differences in overall recurrence patterns, overall survival, or other untoward events. These results are interpreted as suggesting that low axillary failure rates can be achieved with either tangential (two-field) RT to the breast or with a more comprehensive RT approach fully including the axilla. The authors conclude that ALND "can be safely avoided in patients with very small invasive carcinomas." In considering this trial, we would like to provide further discussion of some issues related to RT technique, the low axillary recurrence rates observed, and the implications of the results.
Axillary RT typically refers to the use of a three-field (sometimes four-field) approach in which RT field(s) intended to encompass the supraclavicular and upper axillary nodes are matched to the superior border of the two tangential breast fields. While Zurrida et al.15 do not provide a detailed description of the RT technique used to treat the axilla in this trial, it is generally accepted that the upper axillary and supraclavicular nodes can be fully treated with this approach. However, the extent of the lower axilla included in the two tangential fields is less clear. To further complicate matters, a high tangents approach is sometimes used at some institutions, including ours, in which the field border of the tangential fields is extended superiorly in order to encompass more of the axilla.12 Before computed tomography–based radiotherapy treatment planning, many clinicians believed that the lower axillary nodes were usually included in the tangential fields, as clips from an ALND were seen within the field borders.16 However, computed tomography–based treatment planning indicates that the location of the axillary and supraclavicular nodes in relation to the RT fields is variable depending on patient anatomy and the precise details of the RT fields.17,18 In one study, level I axillary nodes were noted within the tangential fields in nine of nine patients,18 whereas less coverage of level I nodes was seen in reports from other investigators.19–21 Although these data on anatomy and dose are provocative, correlation between these observations and clinical outcome is required.
There are several possible explanations for the very low axillary recurrence rates observed in this trial. As the authors note, the rate of axillary nodal positivity does not necessarily correlate with axillary recurrence rates observed clinically. In the National Surgical Adjuvant Breast and Bowel Project B-04 trial,6,22 39% of patients with clinically negative nodes had histologically positive nodes at surgery, whereas only 18% of patients with clinically negative nodes who did not undergo ALND developed clinical evidence of axillary recurrence. In the present study, the authors estimate a 24% rate of axillary involvement. Given the size distribution of the primary tumors of these patients, it is possible that this estimate is generous. If the true incidence of axillary involvement is actually lower (perhaps 10% to 20%), this would correspond proportionally to a very low rate of anticipated axillary recurrence. Not reported in the series by Zurrida et al.15 is the frequency of lymphatic vessel invasion, a factor shown to be highly predictive of axillary nodal involvement.23 In addition, although axillary recurrences were rare with a median follow-up time of 42 months, more axillary recurrences will undoubtedly be observed with longer follow-up.
It is also worth considering the statistical power of the trial and its underlying assumptions. In the trial’s power statement, an axillary recurrence rate of 15% at 8 years was assumed for the arm that received no axillary RT. However, with the available follow-up, only 1% of patients in this arm developed an axillary recurrence, and, as stated by the authors, there was no ability to test the underlying hypothesis that axillary RT would be able to prevent the appearance of axillary metastases. Given this, we agree that the presented data suggest that breast RT alone yields comparable axillary control to breast and nodal RT in the absence of ALND in patients with very small carcinomas. Further follow-up and additional prospective studies are, we believe, necessary to be able to adequately address this question in the larger group of patients who are clinically node-negative. We are currently conducting a single-arm prospective trial of tangential breast RT after conservative surgery, in the absence of axillary dissection. Until these additional studies are completed, we feel it is reasonable based on the current information, including this trial, to omit specific axillary RT in clinically node-negative, older (perhaps older than 65 or 70 years) patients with small (up to 1.0 cm), estrogen receptor–positive cancers without lymphatic vessel invasion. Sentinel node biopsy is typically performed in younger patients and in patients with estrogen receptor–negative cancers to help determine adjuvant systemic therapy.
Received for publication December 27, 2001. Accepted for publication January 7, 2002.
REFERENCES
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  J. E. Gervasoni Jr., S. Sbayi, and B. Cady Role of lymphadenectomy in surgical treatment of solid tumors: an update on the clinical data. Ann. Surg. Oncol., September 1, 2007; 14(9): 2443 - 2462. [Abstract] [Full Text] [PDF]
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