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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3483-3484 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.1751
Completion Axillary Lymph Node Dissection for Breast Cancer: Immediate Versus Delayed Versus NoneVirginia Commonwealth University, Medical College of Virginia School of Medicine and the Massey Cancer Center, Richmond, VA Axillary lymph node dissection (ALND) for women with breast cancer was relegated to the status of a mere staging procedure long ago. More recently, even this role has been reduced because sentinel lymph node (SLN) biopsy has been shown to predict which patients will or will not have positive nodes in the axilla with a high degree of accuracy.1-5 The main advantages of SLN biopsy over standard ALND are more accurate staging and decreased morbidity, especially lymphedema and arm dysfunction.6-8 The benefits of replacing ALND with SLN biopsy are undeniable, but this transition has also raised new questions. Although the SLN by itself will indicate the nodal status (positive or negative), it has been routine for most women with positive sentinel nodes to undergo a completion ALND (cALND), even though other nodes may contain metastases in only 40% of these patients.2,9 The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial was designed to determine whether cALND was beneficial in patients with positive SLN, but was terminated because of poor accrual; so the question of SLN biopsy alone compared with cALND remains open in this group of patients.8,10 Meanwhile, a number of variables and methods have been described to help determine the likelihood of finding positive non-SLNs, which may influence patients’ and doctors’ decisions about whether a cALND is worthwhile.11,12 The role of cALND in patients with micrometastases remains particularly unsettled.13,14 In most centers, SLN are routinely sent to pathology for intraoperative assessment, with cALND being performed immediately if metastases are identified. False-negative results intraoperatively lead to the need for a secondary or delayed cALND procedure, which has generally been assumed to be less desirable. However, in this issue of Journal of Clinical Oncology, John Olson and colleagues report that among 1,003 patients enrolled in the ACOSOG Z0010 and Z0011 trials, short-term morbidities were actually higher with immediate cALND compared with delayed cALND, and late quality of life indicators were not different between the two approaches.15 A number of different histopathologic methods have been advocated for intraoperative SLN assessment, with the goal of maximizing sensitivity to avoid the need for a second operation, while not sacrificing specificity. Fortunately, the false-positive rates reported have been extremely low, so that unnecessary cALND occurs only rarely, but false-negative rates may be as high as 50%, resulting in the need for delayed cALND.16-20 The results reported by Olson and colleagues force us to ask—if immediate cALND is not better, then why bother with intraoperative examination of SLNs? The quick answer is that avoidance of a second operation (and a second anesthetic) has rather obvious benefits not measured in this study, such as decreased patient anxiety, lower costs, less time away from work, and less delay to the start of adjuvant therapy. Moreover, because the ACOSOG trials did not include women having total mastectomies, these results do not necessarily apply to such patients, where the consequences of re-operation may be greater, particularly in women who have undergone immediate reconstruction. Potential consequences of a second operation in those patients include damage to the blood supply to a free flap, infection of a prosthetic implant, and a much more difficult ALND because of the presence of a flap or tissue expander. In the post-SLN era, the need for cALND in all patients with positive SLN is now being challenged,13,21 and the main argument in favor of delayed cALND is that it allows for a discussion of the pros and cons with the patient before proceeding. This is analogous to the abandonment of frozen section examination of breast biopsies and immediate mastectomy for cancers; when there is equipoise between the options to consider, then the patient should have a chance to have input rather than agreeing to hypothetical procedures. This may be particularly important for patients with micrometastases in SLN or other factors that may predict a low likelihood of having other positive nodes. A number of such variables, such as tumor size, grade, lymphovascular invasion (LVI), estrogen receptor (ER) status, and method of detection of micrometastases have been described in the past few years.11,14,22,23 For patients who are judged to have a low likelihood of having positive non-SLN or in those who have overriding concerns about the consequences of an ALND, the data presented in the Olson et al article make it reasonable to omit intraoperative examination of the SLN selectively, chancing a second procedure. Fortunately, the same factors that predict low risk of positive non-SLN are often associated with a lower likelihood of a positive SLN, so that the frequency of having to reoperate on these patients should be low.24 But why not take this approach in everyone electing a SLN biopsy? The answer to this question is also articulated in the data presented here from the ACOSOG trials: identifying positive SLNs on intraoperative pathology and performance of an immediate cALND was associated with a much higher likelihood of finding positive non-SLN (43% v 27%) and a greater number of positive non-SLN (median, 2 v 1). This is also consistent with the finding that patients undergoing immediate cALND had, on average, larger tumors and more ER-negative tumors. All of these findings are consistent with the fact that finding SLN metastases on intraoperative examination is likely to be associated with larger tumor burden and larger foci of tumor (macrometastases) in the SLN. These, in turn, would be expected to be associated with a greater chance of finding metastases in non-SLN. If it is potentially harmful to leave behind positive nodes in the axilla (which has not been established with certainty), then the high likelihood of positive non-SLN in patients with SLN metastases detected by touch prep or frozen section make it reasonable to examine SLN intraoperatively and to proceed with cALND at the initial operation. But for patients or surgeons who have doubts about the risk/benefit ratio of cALND, especially for those patients whose tumor characteristics are associated with a low likelihood of a positive SLN or positive non-SLN, it is also reasonable to forego intraoperative SLN examination.
The group of patients in whom the value of cALND seems to be most in doubt are those patients with micrometastases (ie, foci of tumor < 2 mm in diameter).13,14 Although this was not addressed in the ACOSOG study, one would expect that these are also the patients most likely to have a falsely negative report on intraoperative pathology. Therefore, they are least likely to have an immediate cALND, and most of these patients will have the opportunity to weigh the balance between the morbidity and potential benefit of a second operation. One could therefore argue that we should only want to detect metastases What does this all mean for more sensitive molecular assays for tumor deposits in SLN, such as the GeneSearch assay (Veridex, Warren, NJ)? The main advantage of this approach is not to miss positive SLN intraoperatively so that immediate cALND can be performed, avoiding a second operation.25 For most patients with palpable breast cancers, the increased accuracy of a molecular assay may be worthwhile because a significant proportion of those women will have non-SLN metastases, even if the SLN harbors only micrometastases. But with the threshold for a positive result set to detect metastases down to 0.2 mm, some patients who may have a low likelihood of having other nodes positive would have an immediate cALND. If a second operation may be potentially harmful, then this is worthwhile. But some of these patients (and their surgeons), particularly those with micrometastases or tumor characteristics associated with a small chance (perhaps < 10%) of having positive non-SLN, may have preferred not to have a cALND. If, as suggested by the results presented in this issue by Olson and colleagues, a second operation is "not so bad," then perhaps we should be more careful about committing such borderline patients (those with small tumors, no LVI, and SLN metastases between 0.2 and 2 mm in size) to a cALND at the first operation as a result of using such a sensitive assay. Immediate and delayed cALND may have similar rates of resulting morbidity, but both may compromise quality of life more than no ALND. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Harry D. Bear, Genentech, Genomic Health Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
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Houvenaeghel G, Nos C, Mignotte H, et al: Micrometastases in sentinel lymph node in a multicentric study: Predictive factors of non-sentinel lymph node involvement. J Clin Oncol 24:1814-1822, 2006 15. Olson JA, McCall LM, Beitsch P, et al: Impact of immediate vs. delayed axillary node dissection on surgical outcomes in breast cancer patients with positive sentinel nodes: Results from the American College of Surgeons Oncology Group (ACOSOG) trials Z0010 and Z0011. J Clin Oncol 26:3530-3535, 2008 16. Treseler P: Pathologic examination of the sentinel lymph node: What is the best method? Breast J 12:S143-S151, 2006[CrossRef][Medline] 17. Forbes RC, Pitchford C, Simpson JF, et al: Selective use of intraoperative touch prep analysis of sentinel nodes in breast cancer. Am Surg 71:955-960, 2005[Medline] 18. Tew K, Irwig L, Matthews A, et al: Meta-analysis of sentinel node imprint cytology in breast cancer. Br J Surg 92:1068-1080, 2005[CrossRef][Medline] 19. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2 mm in size intraoperatively because cALND may be most justified in these patients. 
