Long-Term Study Finds Axillary Radiotherapy Safe and Effective After Positive Sentinel Node Biopsy
Following identification of a positive sentinel lymph node, surgical axillary lymph node dissection and axillary radiation therapy provide comparable locoregional control and survival, according to a 10-year follow-up of the large European Organisation for Research and Treatment of Cancer AMAROS trial.1 Axillary radiation therapy has the advantage of causing significantly less lymphedema than surgical clearance of these nodes.
Our new 10-year data show that axillary radiotherapy and axillary lymph node dissection provide excellent and comparable overall survival, distant metastasis–free survival, and locoregional control.— Emiel J.T. Rutgers, MD
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“Our new 10-year data show that axillary radiotherapy and axillary lymph node dissection provide excellent and comparable overall survival, distant metastasis–free survival, and locoregional control. Given that we previously published 5-year data from AMAROS showing significantly more lymphedema in the surgery arm, we believe that axillary radiotherapy should be considered a good option for patients who have a positive sentinel lymph node biopsy instead of surgical axillary lymph node dissection. Axillary radiation therapy can be considered a standard procedure in this setting,” stated Emiel J.T. Rutgers, MD, of the Netherlands Cancer Institute, Amsterdam, at the 2018 San Antonio Breast Cancer Symposium.
The sentinel lymph node is the most likely to harbor metastasis and can be identified and surgically removed by using tracers that mimic the route to cancer cells from the tumor site through the lymph vessels. If the sentinel node is negative, then patients do not need axillary lymph node dissection. However, if it is positive, axillary lymph node dissection is typically performed in the United States, but this surgery has side effects that can be persistent and troublesome to patients, most notably lymphedema and shoulder pain.
Other trials of unsuspicious nodes have shown that axillary radiation therapy provides good locoregional control, providing a rationale for the study. Between 2001 and 2010, AMAROS enrolled 4,806 patients of any age with invasive breast cancer tumors between 0.5 and 5 mm that were clinically node negative. All patients had breast conservation surgery or mastectomy and then underwent mapping of the axilla and sentinel node biopsy. If the sentinel node was positive (n = 1,425, 29.7%), they were further randomly assigned to axillary lymph node dissection (n = 744) or axillary radiation therapy (n = 681).
The 5-year outcomes were reported in 2013. No differences were found between surgery and radiation therapy, with few relapses in both arms. There was less lymphedema with axillary radiation therapy.
“At the time, the study was criticized for being underpowered to show a difference, because there were too few events and the follow-up was too short. The results were not universally accepted,” Dr. Rutgers told listeners. “Now we have a 10-year analysis.”
10-Year Follow-up of AMAROS Trial
- Axillary radiation therapy and axillary lymph node dissection provide excellent locoregional control and comparable rates of survival and recurrence.
- Axillary radiation therapy reduced the rate of lymphedema compared with axillary lymph node dissection.
- These results, taken together with results of the ACOSOG Z0011 trial, suggest that axillary lymph node dissection is not necessary in early breast cancer with up to two positive sentinel nodes.
- The United States has been much slower than Europe to adopt axillary radiation therapy and to de-escalate surgery for this population.
At the 2018 San Antonio Breast Cancer Symposium, Dr. Rutgers presented the 10-year results focused solely on patients with a positive sentinel node. Data on arm morbidity and quality of life were updated from the 5-year analysis.
At baseline, both study arms were comparable. The median age was about 55 years. About 40% were premenopausal, and 56% were postmenopausal. The median tumor size was 17 mm; about 23% had grade 1 disease, 46% had grade 2 disease, and 27% had grade 3 disease. Preoperative ultrasound of the axilla was performed in about 60%.
Baseline treatment characteristics were also comparable. Nearly 80% had breast-conserving surgery, and about 17.5% had mastectomy. Approximately 60% had chemotherapy, 78% had hormonal therapy, 6% had immunotherapy, and 9% had no systemic therapy. About 86% had radiotherapy: either to the breast after breast conservation, or some to the chest wall after mastectomy.
The mean number of sentinel nodes removed was two in both arms. About 60% had macrometastasis, and 30% had micrometastasis; isolated tumor cells were found in about 10%. In the surgical group, the mean number of nodes removed was 15 (range, 12–20). Two-thirds of patients had no additional positive nodes, and 33% had more positive nodes in the axilla.
The recurrence rates were similar and low at 10 years: 0.93% in the axillary lymph node dissection group vs 1.82% in the axillary radiation therapy group. “We see at 10 years nothing much happens in either group,” he noted. “The rate of lymph node metastasis was extremely low in both arms, and there was no effect of either treatment on disease-free and overall survival.”
At 5 years, there were 7 recurrences in 681 patients who were randomly assigned to axillary radiation therapy, and this number increased to 11 recurrences at 10 years. In the axillary lymph node dissection arm, the 5-year number of recurrences was 4 of 744; 10 years later, that number increased to 7. The rate of second primary cancers was higher in the axillary radiation therapy arm (12%) vs axillary lymph node dissection (8%; P =. 035).
Side effects, as determined by questionnaires and clinical measurement of lymphedema at 1, 3, and 5 years, were significantly lower in the axillary radiation therapy arm. About 60% of patients filled out questionnaires related to lymphedema, shoulder function, and quality of life at 5 years. Five years after sentinel node biopsy, lymphedema was present and/or treated in about 30% of the axillary lymph node dissection arm and about 15% in the axillary radiation therapy arm. “This is half of what happened with surgery,” he emphasized.
At a press conference, Dr. Rutgers commented: “We now have three large trials showing that we should not worry too much about performing axillary lymph node dissection. If it is early breast cancer, we don’t remove all the lymph nodes if the sentinel node is positive. However, for larger tumors and high-grade tumors plus two positive lymph nodes, we give axillary radiation. And we discuss this on a case-by-case basis with a tumor board. Axillary radiation therapy has had good uptake in Europe. As a result of this policy, over the past 20 years, the percentage of patients in our center who received axillary lymph node dissection went from 80% to 3%. For us, it is now a rare operation.”
“This de-escalation of therapy improves morbidity of our patients without compromising their outcomes,” said Virginia Kaklamani, MD, moderator of a press conference where these data were discussed. “The chance of local recurrence is very low, and we radiate appropriate patients,” she continued. Dr. Kaklamani is Professor at UT Health San Antonio and leader of the Breast Cancer
Virginia Kaklamani, MD
Program at UT Health San Antonio MD Anderson Cancer Center.
“I am not a surgeon, but using axillary radiation therapy avoids axillary dissection and decreases the risk of lymphedema; and at the same time, it does not compromise the risk of local recurrence. Patients with bulky lymph nodes were not included in this study. The majority of patients we see have small metastases to their lymph nodes. In those cases, avoiding more surgery is appropriate,” Dr. Kaklamani said.
Longer Follow-up May Lead to Less Surgery
“In the United States, we have been slow in changing our standard from axillary lymph node dissection. Longer follow-ups are helping our surgeons cut back on the amount of surgery. We have results from this and 10-year follow-up from the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, and we are still doing more axillary lymph node dissection than we should be doing,” she stated.
The ACOSOG Z0011 trial also provided convincing evidence for de-escalating surgery in patients with a positive sentinel lymph node biopsy. In that study, 446 women with a positive sentinel node were randomly assigned to axillary lymph node dissection vs no surgery, and both groups had comparable 10-year outcomes.2
“I love the AMAROS and Z0011 trials. They both show we can de-escalate surgery for axillary lymph node dissection. We now have more conclusive information that women with one to three positive nodes and clinically negative nodes do not need axillary lymph node dissection. However, women in the community are still undergoing axillary lymph node dissection,” Dr. Kaklamani continued.
“There has not been more uptake of axillary radiation therapy because clinical trials are imperfect and personal bias often plays in favor of surgery. It takes a long time for the information that axillary lymph node dissection is not needed to trickle down to doctors in the community. Another part of the problem is many women are afraid that less treatment is not as good as more treatment,” she noted.
“Oncologists and surgeons need to tailor therapy according to the individual patient. More is appropriate for some women, and less is appropriate for other women. We need to know who to give less to and who to give more to,” she concluded. ■
DISCLOSURE: Dr. Rutgers reported no conflicts of interest. Dr. Kaklamani is on the speakers bureau for Puma, Celgene, Eisai, Genentech, Genomic Health, and Novartis and has received research funding from Eisai.
1. Rutgers EJ, Donker M, Poncet C, et al: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: 10-year follow-up results of the EORTC AMAROS trial. 2018 San Antonio Breast Cancer Symposium. Abstract GS4-01. Presented December 6, 2018.
2. Giuliano AE, Ballman KV, McCall L, et al: Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA 318:918-926, 2017.