Management of Axillary Lymph Node Metastasis in Breast Cancer: Title and subTitle BreakMaking Progress

Less is more”—so goes the adage, and that certainly has been the case for breast cancer. Forty years ago, the standard treatment for this disease was the Halsted radical mastectomy, an aggressive operation that involved removal of not only the breast but also the adjacent musculature and axillary lymph nodes. Better understanding of breast cancer biology revealed that aggressive surgical therapy alone was inadequate. As treatment approaches evolved away from extensive surgery, axillary lymph node dissection (ALND) remained part of the treatment regimen to detect nodal disease. Axillary lymph node metastases were considered an indicator that systemic disease was present, identifying a need for chemotherapy.

Women with breast cancer have benefitted greatly from a series of carefully performed randomized controlled trials. Each successive trial showed that less surgery was better, in that outcomes were the same and less surgical intervention resulted in fewer surgical complications. In the first major study,¹ the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial, which began in 1971, 1765 women with breast cancer were randomized into 5 treatment groups. Those with palpable lymph nodes were randomized to receive a Halsted radical mastectomy or a total mastectomy (removal of the breast only without the underlying muscle or lymph nodes) along with regional radiation therapy. Women with breast cancer without palpable axillary lymph nodes were randomized into 1 of 3 study groups: Halsted radical mastectomy with ALND, total mastectomy with regional radiation treatment, or mastectomy alone with delayed ALND if nodal recurrences were observed. There was a 40% incidence of occult nodal metastasis in the radical mastectomy group. Despite an axillary recurrence failure rate of 19% in the total mastectomy group, the survival was similar between the groups after 25 years of follow-up.¹ In general, women with clinically palpable axillary lymph nodes had worse survival than those without clinically evident lymph nodes. Local treatment of occult cancer in axillary lymph nodes had no effect on overall survival.

Recognition of the waning utility of ANLD led to the development of sentinel lymph node dissection (SLND). This technique involves injecting dye into the primary tumor and selectively resecting lymph nodes that take up the dye and thus indicate that they are the nodes draining the tumor mass. SLND has supplanted ALND for staging the axilla in early breast cancer, because less aggressive axillary surgery results in less arm stiffness, pain, paresthesia, and risk of lymphedema. A recently published single-institution study² with 10-year follow-up randomized 516 patients with breast cancer to undergo both SLND and ALND or SLND alone with ALND only if the sentinel lymph nodes (SLNs) contained cancer; that study showed better arm mobility and less pain in the SLND-alone group. At a median follow-up of 102 months, the regional failure rate in the SLND-alone group was 0.77%. There was no significant difference in disease-free survival between the groups, suggesting that ALND is not beneficial.

Retrospective analyses add indirect evidence regarding the lack of utility of ALND. These studies are not definitive because, as with all retrospective evaluations, it is difficult to control for selection bias and treatment bias. In general, these analyses show low axillary recurrence rates in women with minimal axillary disease and with positive SLNs who did not have completion ALND.^{3 - 4} These patients tended to be older; had small, low-grade tumors with micrometastatic (<2 mm) nodal disease; and underwent breast conservation surgery. Predictors of non-SLN metastasis include tumor size, size of SLN metastatic deposit, number of SLNs involved, tumor lymphovascular invasion, and extranodal extension. In an effort to identify patients who might benefit from ALND, nomograms using these characteristics have been developed to predict who should undergo ALND.⁵ Despite increasing evidence disfavoring ALND, it remains part of widely recognized guidelines for breast cancer care.⁶ However, the apparent lack of utility of ALND has influenced clinicians treating breast cancer because the performance of ALND following SLND has declined.^{7 - 8}

In this issue of JAMA, Giuliano and colleagues from the American College of Surgeons Oncology Group⁹ report results of the Z0011 randomized trial comparing SLND alone with ALND in women with breast cancer and SLN metastasis. The results of this trial definitively showed that ALND is not beneficial. Women with breast cancer enrolled in the trial all had clinical T1 and T2 tumors, no palpable lymphadenopathy, and 1 or 2 SLNs containing metastases identified using hematoxylin-eosin staining. All patients underwent lumpectomy and received whole-breast irradiation therapy; postoperative systemic chemotherapy was not specified as part of the protocol but was received by 96% to 97% of women in the 2 treatment groups. Overall survival was the primary end point. Because observed survival was vastly better than survival predicted when the study was designed in the 1990s, accrual was closed in 2004.

The median number of lymph nodes removed was 17 in the ALND group and was only 2 in the SLND group. Twenty-seven percent of the ALND group had additional nodal metastases on ALND above and beyond those found with SLND alone. Despite this, the axillary recurrence rates for both groups were similar: 0.9% in the SLND group and 0.5% in the SLND group (P = .45).¹⁰ The 5-year overall survival was similar between the 2 groups (91.8% in the ALND group vs 92.5% in the SLND-alone group), with a median follow-up of 6.3 years. Survival was independent of lymph node status and was so good in both groups that longer follow-up has little likelihood of demonstrating any difference between the ALND and SLND groups.

When the investigators designed this trial, they anticipated 5-year survival of 80%. This was based on the already observed improvement in breast cancer survival in the 1990s compared with the 5-year overall survival of 60% and approximately 40% of patients with node positivity observed in the B-04 trial.¹ As a testament to improved breast cancer treatment, the Z0011 trial had a 5-year overall survival of more than 90%, with 100% of patients having positive nodes. One important difference might be that almost all of the patients in the Z0011 trial received adjuvant systemic therapy, which has been shown to reduce locoregional recurrence.¹¹ Additionally, all patients in the Z0011 trial received tangential-field whole-breast radiation therapy. This approach irradiates the SLND site, much of the level-I axilla, and a portion of level-II axilla.^{12 - 13} Together, adjuvant radiation and systemic therapy likely treated the low-volume nodal metastasis in this study.

The Early Breast Cancer Trialists' Collaborative Group projected that a greater than 10% reduction in locoregional recurrence rate could translate into a survival advantage after 15 years of follow-up.¹⁴ Consequently, complete axillary staging via removal of 10 or more axillary lymph nodes has been used to guide adjuvant therapy. The Z0011 trial^{9 - 10} includes patients with early breast cancer with low nodal tumor burden and low locoregional recurrence rates. In the ALND group, 13.5% of patients had 4 or more metastatic lymph nodes and would have been candidates for nodal irradiation based on the collaborative group's recommendations. The overall low regional failure rates between the groups in Z0011, coupled with equivalent overall survival between groups irrespective of the degree of axillary tumor burden, suggests that axillary node counts are not useful for guiding treatment decisions.

Giuliano and colleagues^{9 - 10} have made an important contribution to the surgical management of SLN metastasis in breast cancer. Following the lead of Fisher et al¹ and other clinical investigators, these randomized clinical trials have shown that less surgery combined with more radiation and chemotherapy have improved survival for women with breast cancer. Taken together, findings from these investigators provide strong evidence that patients undergoing partial mastectomy, whole-breast irradiation, and systemic therapy for early breast cancer with microscopic SLN metastasis can be treated effectively and safely without ALND.