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Originally published as JCO Early Release 10.1200/JCO.2005.03.6178 on December 12 2005 © 2006 American Society of Clinical Oncology.
Axillary Surgery: Clinical Judgment RequiredUniversity of California San Francisco, San Francisco, CA The Halsted radical mastectomy included an en bloc resection of axillary contents. Now, more than a century later, there is little controversy about the use of breast-conserving surgical treatments in place of mastectomy, while the routine use of axillary dissection, or at least axillary sampling, has persisted despite the fact that it is the greatest source of morbidity from breast surgery. Is it time to abandon this procedure all together, at least in some patients? Halsted and his successors removed and/or irradiated lymph nodes because they thought that breast cancer always spreads regionally before metastasizing distantly, and that all regional disease had to be removed to improve survival. The National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated in trial B04 that this is not the case.1 One thousand seventy-nine patients without clinical evidence of axillary adenopathy were randomly assigned to simple mastectomy, a radical mastectomy with lymph node dissection, or simple mastectomy with radiation therapy to the chest wall and axilla. Sixty-eight (19%) of the patients randomly assigned to receive no surgery or radiotherapy to the axilla eventually developed positive axillary nodes. This was about half of the rate expected from the incidence of positive nodes in the radical mastectomy arm of the study, and proved that disease left behind can be kept in check or eradicated by the body's own defense mechanisms. It was possible to remove the axillary recurrence in all but one of the 68 patients, thus removing the argument that axillary recurrences cannot be managed surgically. Most importantly, with 25 years of follow-up, no significant survival differences have emerged. There have been no randomized trials of similar or larger size addressing the role of axillary surgery without axillary radiotherapy subsequent to NSABP B04.
In this issue of the Journal of Clinical Oncology, the International Breast Cancer Study Group (IBCSG)2 reports the result of a trial in which older patients (defined as those Because of the small size of this study, champions of axillary node dissection are not likely to feel this issue is resolved. The authors of the IBCSG trial performed a predictive power calculation and concluded that if the trial had been fully accrued as originally designed, there would have been less than 3% chance of observing a statistically significant improvement in disease-free or overall survival from node dissection. However, this does not rule out the possibility that a meta-analysis that combines the results of this trial with NSABP B04, and the few other small trials addressing this question, will show some small but statistically significant advantage for axillary node dissection. For example, there have been nine randomized trials, including NSABP B04, in which breast surgery plus axillary dissection was compared with the same surgery plus axillary radiotherapy and no node dissection. Most of these trials did not employ systemic therapy, and none demonstrated a significant survival advantage for the arm in which axillary dissection was employed. However, an overview of six of these studies suggested there was a survival advantage for this group.3 Thus, we are likely to face the common dilemma we have encountered with so many other therapeutic issues surrounding the treatment of breast cancer: a small benefit that can be demonstrated only with large numbers of patients in a meta-analysis performed many years after the completion of the studies that are no longer completely relevant because of the introduction of new treatments. The prognostic information provided by node dissection has also been an important factor in keeping this procedure alive, and the IBCSG study is unusual in that the decision to use tamoxifen without chemotherapy was based on criteria that did not include nodal status. While it is true that no other prognostic information is as significantly associated with important outcomes, including survival as the number of histologically involved lymph nodes, nodal status has no predictive value.4,5 Physicians often fail to understand that the proportional effects of (or benefits from) adjuvant systemic therapy are the same in those with node-positive and node-negative tumors. This could be because treatment guidelines are still promulgated separately for nodal subsets. The argument is frequently made that each systemic therapy must be evaluated separately in patients with node-positive and node-negative breast cancer,6 but this categorization of treatments by nodal subsets is an historical artifact. The first trials of adjuvant chemotherapy were performed in patients with positive lymph nodes because the therapy was toxic and the benefits were unknown. Patients in higher risk categories were more likely to accept this toxicity and uncertainty. Now that these therapies are of proven benefit in all treatment groups and the estimate of the size of the benefit can be made based on calculated risk of recurrence using factors such as the tumor size and factors that reflect the aggressiveness of the tumor, such as histologic grade, mitotic activity, and microarrays, it is not necessary to know the nodal status for most patients.7,8 The important predictive factors are hormone receptor and HER2/neu status of the tumor and patient age or menopausal status. It is time we begin weaning ourselves from this dependence on nodal status for making decisions regarding the appropriate adjuvant therapy for each patient. A step along the way to this goal has been the introduction of sentinel lymph node biopsies (SLNB). In most cases, axillary lymph node dissection is not undertaken if the sentinel node is negative. It has been shown in a randomized trial that the use of the SLNB does decrease the complications of axillary surgery, but this was limited largely to the patients whose sentinel lymph node was negative, and who, therefore, had no further axillary node surgery.9 For example, among patients without involved lymph nodes, 24% randomly assigned to axillary lymph node dissection (ALND) had a postoperative axillary seroma compared to 11% of these patients who had only SLNB (P = .01). Among those with positive nodes, 12% of those randomly assigned to ALND and 20% of those with a SLNB followed by ALND had a seroma (P = .3). The development of paresthesias at any time in the first 12 months following surgery was 48% and 23% (P < .001) for node-negative patients randomly assigned to ALND and SLNB, respectively. For node-positive patients the corresponding incidence of sensory findings was 45% and 48% (P = .8). This suggests that clinical judgment should be employed in the use of SLNB as well. It is likely that other prognostic factors, especially tumor size, might identify those patients with a high likelihood of extensive nodal involvement (eg, those with > four positive nodes) for whom the use of adjuvant radiotherapy is indicated, and the use of SLNB followed by ALND when the sentinel node is positive might be limited to this group at high risk of local recurrence since this is the group for which it has been shown that this additional treatment has clear benefit.10 The emerging evidence on axillary lymph node surgery, including sentinel lymph node biopsy, suggests that in many patients with breast cancer, the toxicity of these procedures, albeit mild, cannot be justified by either survival benefits or prognostic information gained. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Author Contributions
REFERENCES
1. Fisher B, Jeong JH, Anderson S, et al: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567-575, 2002 2. International Breast Cancer Study Group: A randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: First results of International Breast Cancer Study Group (IBCSG) Trial 10-93. J Clin Oncol 24:337-344, 2006 3. Orr RK: The impact of prophylactic axillary node dissection on breast cancer survival—A Bayesian meta-analysis. Ann Surg Oncol 6:109-116, 1999[Abstract] 4. Early Breast Cancer Trials Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 5. Henderson IC, Patek AJ: The relationship between prognostic and predictive factors in the management of breast cancer. Breast Cancer Res Treat 52:261-288, 1998[CrossRef][Medline] 6. Giordano SH, Duan Z, Kuo Y, et al: The impact of CALGB 9344 on adjuvant taxane (T) use for breast cancer (BC). Proceedings Amer Soc Clin Oncol 24:16S, 2005 (abstr 669) 7. Sotiriou C, Neo SY, McShane LM, et al: Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 100:10393-10398, 2003 8. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 9. Purushotham AD, Upponi S, Klevesath MB, et al: Morbidity after sentinel lymph node biopsy in primary breast cancer: Results from a randomized controlled trial. J Clin Oncol 23:4312-4321, 2005 10. Recht A, Edge SB, Solin LJ, et al: Postmastectomy radiotherapy: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1539-1569, 2001
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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60 years of age) who were to be treated with tamoxifen regardless of nodal status were randomly assigned to receive clearance of the axillary lymph nodes or no surgical intervention in the axilla after either mastectomy or lumpectomy. Among those randomly assigned to axillary clearance, 28% were node-positive. Radiotherapy was not recommended for patients treated with mastectomy; 60% of those treated with breast-conserving therapy (33% of all patients in the study) had radiotherapy. There was significantly more restriction in arm movement and arm pain during the first few months after treatment among those randomly assigned to axillary clearance, but these differences were small and not significant after longer follow-up, and there were no differences in overall quality of life parameters. There were no differences in disease-free or overall survival, but there were only 473 patients in the study and the median follow-up was just 6.6 years. This study was originally designed to be much larger, but because of poor accrual the study goals were amended to focus on quality-of-life issues. It seems plausible that the poor accrual reflects a lack of uncertainty by the patients and physicians involved in this trial about the value of axillary node dissection in this patient population. 
