Axillary radiotherapy, lymph node surgery for early breast cancer confer comparable outcomes
SAN ANTONIO — Axillary radiotherapy and axillary lymph node dissection appeared associated with excellent and comparable 10-year recurrence and survival outcomes for patients with early-stage breast cancer who had cancer detected in a sentinel lymph node biopsy, according to results of the randomized phase 3 AMAROS trial presented at San Antonio Breast Cancer Symposium.
“It’s striking that diagnosis of axillary lymph node recurrence after 5 years is a very rare event, and significantly less lymphedema was observed among patients who had radiotherapy of the axilla,” Emiel J. Rutgers, MD, PhD, surgical oncologist at Netherlands Cancer Institute in Amsterdam, said during a presentation. “We conclude axillary radiotherapy can be considered as a standard treatment for those patients who met AMAROS eligibility criteria.”
The sentinel node is the lymph node most likely to harbor metastasis. Tracers that mimic the route of cancer cells from the primary tumor site through the lymph vessels can remove these metastases during surgery.
Patients who have cancer detected in a sentinel lymph node biopsy traditionally underwent axillary lymph node dissection. Although this surgery is effective, it is associated with considerable side effects, including lymphedema and difficulties with arm movement.
Radiotherapy to unsuspicious axillary nodes offers excellent control of cancer in the axilla, according to study background.
Researchers with the AMAROS trial initially enrolled 4,806 patients with operable T1 or T2, clinically node-negative breast cancer.
Eligibility criteria included invasive breast cancer, tumor size of 0.5 cm to 5 cm, and clinically node-negative disease. Patients of all ages were enrolled, and breast-conservation therapy or mastectomy was allowed. Exclusion criteria included multicentric disease, receipt of neoadjuvant systemic treatment or previous axillary treatment, and prior malignancy.
Researchers randomly assigned patients to axillary lymph node dissection or axillary radiotherapy in cases when sentinel lymph node biopsy was positive. This randomization was done prior to sentinel node biopsy to allow researchers to perform frozen section evaluation from patients who were assigned to have axillary clearance and to prevent selection bias.
Slightly more than one-quarter (29.6%; n = 1,425) went on to have positive sentinel lymph node biopsy; of these, 744 had been randomly assigned to axillary lymph node dissection and 681 had been assigned axillary radiotherapy.
Axillary radiotherapy began within 12 weeks of sentinel node biopsy. The extent of radiotherapy was level I, II and III, and medial supraclavicular area. Patients received 25 fractions of 2 Gy, or an equivalent dose schedule.
Axillary lymph node dissection began less than 12 weeks after sentinel node biopsy. Level I and II were mandatory, and level III was optional. Patients who had four or more positive nodes were allowed to have postoperative radiotherapy, as well.
Results of the first primary analysis, performed in 2013 after median follow-up of 6.1 years, showed 5-year cumulative incidence rates of axillary recurrence of 0.43% (95% CI, 0-0.92) in the lymph node dissection group and 1.19% (95% CI, 0.31-1.19) in the radiotherapy group.
“This was not statistically significant. However, due to the extremely low number of events, the planned comparison was underpowered,” Rutgers said.
In San Antonio, Rutgers provided updated results based on median follow-up of 10 years, focusing on the patients with positive axillary sentinel lymph node.
The axillary lymph node dissection and axillary radiotherapy groups were balanced with regard to median age (56 years vs. 55 years), menopausal status (premenopausal, 38.1% vs. 42.5%), median tumor size (17 mm vs. 18 mm), tumor grade (grade 1 or grade 2, 71.9% vs. 78.3%), receipt of preoperative ultrasound of the axilla (59.2% vs. 61.5%), receipt of breast conservation surgery (81.9% vs. 81.8%) or mastectomy (17.1% vs. 17.8%), systemic therapy (chemotherapy, 60.9% vs. 61.3%; hormonal therapy, 78.6% vs. 77.1%; immunotherapy, 6% vs. 6.4%); none, 9% vs. 9.4%) and radiotherapy to the chest wall (84.9% vs. 87.8%).
Sentinel node biopsy results showed the median number of sentinel nodes removed in each group was equivalent (2; range, 1-3), as was size of metastases in sentinel nodes (macrometastases, 59.4% vs. 61.5%; micrometastases, 28.9% vs. 28.6%; isolated tumor cells, 11.7% vs. 9.8%).
Among patients who underwent axillary lymph node dissection, a median 15 nodes (range, 12-20) were removed. Two-thirds of patients (67.1%) had no additional positive nodes besides sentinel nodes removed, whereas 25% had one to three additional positive nodes removed, and 7.8% had four or more additional positive nodes removed.
The 10-year follow-up data continued to show no significant difference in axillary recurrence rate among patients who underwent axillary lymph node dissection (0.93%; 95% CI, 0.18-1.68) or axillary radiotherapy (1.82%; 95% CI, 0.74-2.94), translating to an HR of 1.71 (95% CI, 0.67-4.39).
Researchers also reported no significant difference in DFS (HR = 1.19%; 95% CI, 0.97-1.46) or OS (10-year OS, 84.6% vs. 81.4%; HR = 1.17; 95% CI, 0.89-1.52).
Distant metastasis-free survival rates were 81.7% in the dissection group and 78.2% in the radiotherapy group.
The percentage of patients who underwent clinical observation or treatment for lymphedema was significantly less among those who received axillary radiotherapy at 1 year (21.7% vs. 39.9%; P < .0001), 3 years (17.9% vs. 31%; P < .0001) or 5 years (14.6% vs. 29.4%; P < .0001) after sentinel node biopsy.
However, results showed no significant differences in shoulder function between treatment groups at 1 year or 5 years.
A significantly higher percentage of patients assigned axillary radiotherapy developed second primary cancers (11% vs. 7.7%). This difference was due primarily to higher incidence of contralateral breast cancer among the radiotherapy group. Because the radiation technique was performed with use of two tangential fields, a negligible amount of “extra” radiation to the contralateral breast by including an axillary or periclavicular field is negligible, according to Mila Donker, MD, PhD, radiation oncologist at Netherlands Cancer Institute.
“We have found no indication that the increased incidence of second primary cancers is induced
by the radiotherapy,” Donker said in a press release. “Therefore, we strongly believe that axillary radiotherapy is a good alternative to axillary lymph node dissection in this group of patients.”
The size of the radiation field used in this study was greater than currently considered necessary. This led to some of the morbidity that could now be avoided, researchers said.
They also acknowledged an imbalance in the number of patients who had a sentinel lymph node biopsy in the two groups, and that the lower-than-expected number of recurrences reduced the statistical power of the study.
However, researchers determined these limitations should not alter the conclusion that axillary radiotherapy is not inferior to axillary lymph node dissection for locoregional control.
“Data from another recent clinical trial suggested that there may be some patients who do not need axillary treatment even if they have a positive sentinel lymph node biopsy,” Rutgers said in the release. “Moving forward, we need to better tailor treatment for each individual patient. Some will still need axillary treatment, and our data indicate that axillary radiotherapy is a good option here.” – by Mark Leiser
Rutgers EJ, et al. Abstract GS4-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 4-8, 2018; San Antonio.
The EORTC Charitable Trust supported this study. Rutgers and Donker report no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.