Axillary Management in Early Clinically Node-Negative Breast Cancer

The evidence base for axillary lymph node management contains important gaps and ambiguities, but regional node irradiation (RNI) is likely important in reducing the risk of distant metastasis in high-risk breast cancer, reported Elizabeth A. Mittendorf, MD, PhD, of the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center in Houston.

Dr. Mittendorf reviewed clinical trial data guiding axillary management at the 33rd Annual Miami Breast Cancer Conference, held March 10–13 in Miami Beach, Florida. She reviewed findings from the ACOSOG Z0011, EORTC AMAROS, NCIC-CTG MA.20, and EORTC 22922 trials.

“Data strongly suggest that RNI is an important component of distant metastasis risk reduction in high-risk breast cancer,” said Dr. Mittendorf. Patients with clinically node-negative (cN0) disease and negative sentinel lymph nodes (SLNs) experience an axillary nodal recurrence rate of less than 1%, and do not benefit from axillary lymph node dissection (ALND) or nodal irradiation.

“Patients with clinically node-negative, T1-2 tumors, with 1–2 positive SLNs, and patients with micrometastatic disease in the SLN, do not benefit from ALND,” she said. “Patients with macrometastatic disease in the SLN can be treated with ALND or axillary radiotherapy.”

When a patient has one to three positive lymph nodes, Dr. Mittendorf advised clinicians to consider RNI “when other adverse pathologic factors are present,” including young age, high tumor grade, large primary tumor, or estrogen receptor (ER)-negative tumors.

ACOSOG Z0011 enrolled patients undergoing breast-conserving surgery (BCS) for cN0, T1-2 breast cancer; sentinel lymph node dissection (SLND) was performed on 1 to 2 SLNs. Patients were stratified by age, ER status, and tumor size, and then randomized to undergo ALND or no ALND, before undergoing breast radiotherapy.

ALND was not associated with statistically significant differences from SLND alone for 5-year overall survival (OS), 5-year disease-free survival (DFS), or 5-year locoregional recurrence–free survival (LRRFS). Notably, however, ALND was associated with significantly increased rates of lymphedema.

“Z0011 was a surgery trial, not a radiation trial,” Dr. Mittendorf noted. “The primary finding was that routine ALND is not necessary after positive SLND-that finding stands.”

Variability of radiotherapy field design in the Z0011 trial “means that no conclusions can be drawn about whether radiotherapy to the axilla and other regional nodes was necessary or beneficial,” she cautioned.

In contrast, the EORTC AMAROS trial investigated ALND vs radiation in SLN-positive patients, testing the hypothesis that axillary radiotherapy provides local control and survival “comparable to ALND with fewer side effects in women with a positive SLN,” said Dr. Mittendorf. Patients undergoing either breast-conserving therapy or mastectomy were eligible to enroll in AMAROS.

Five-year OS and DFS were not statistically different between the ALND and SLND plus axillary radiotherapy study arms, but 5-year lymphedema rates were significantly lower (11% vs 23%) in the latter.

“In Z0011 and AMAROS, lymphedema rates were 23% for ALND and 14% for axillary radiotherapy,” Dr. Mittendorf concluded. “Based on Z0011, I would suggest that 82% of the patients enrolled on AMAROS could have avoided both ALND and axillary radiotherapy.”

The MA.20 and EORTC 22922 trials offer some insight into radiotherapeutic management of the supraclavicular and internal mammary nodes, Dr. Mittendorf said.

MA.20 enrolled women undergoing BCS and ALND with node-positive or node-negative plus T3 or high-risk T2 breast cancer, and randomized participants to receive either 50 Gy whole-breast irradiation (WBI) or WBI plus RNI. The primary endpoint, 10-year OS, was not different between study arms, but 10-year DFS, LRRFS, and distant DFS were each superior in the WBI plus RNI group.

However, MA.20 interpretation requires important caveats, including accrual that began in 2000, before SLND was the standard of care. “SLND was undertaken in only 39% of patients,” Dr. Mittendorf noted. There are also limited data regarding lymph node metastases, with unknown percentages of clinically node-positive metastases and macrometastases. Chemotherapy was also “inferior” in MA.20, Dr. Mittendorf said: “Only 25% of patients received a taxane in addition to an anthracycline.”

EORTC 22922 included women undergoing BCS or mastectomy for axillary node-positive or central/medial breast tumors, assigning them to receive radiotherapy to the breast/chest wall only, or with supraclavicular and internal mammary node irradiation. That study found smaller survival effect sizes and larger confidence intervals than MA.20 for more vs less radiotherapy, Dr. Mittendorf noted (possibly due to a lower-risk patient population).

MA.20 and EORTC 22922 have received a lot of attention but it is unclear that they have changed clinical practice. “It was important that the data be published but important details are unknown,” said Dr. Mittendorf.