Lancet Oncol. 2014-11-01
Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.
Abstract
Background
If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects.
Methods
Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612.
Findings
Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years.
Interpretation
Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity.
Funding
EORTC Charitable Trust.
Related Questions
Under what circumstances would you pursue completion ALND in a patient with multiple positive sentinel nodes after breast-conserving surgery?
For clinical/imaging node-negative disease with 1-2 positive nodes, now there are 7 plus clinical studies (ACOSOG Z0011, AMAROS, OTOASOR, SENOMAC, IBCSG 23-01, AATRM, SINODAR-ONE) which have shown no difference in axillary recurrence, DFS with dissection, but higher lymphedema as expected. The most ...
In the post-mastectomy setting, are there situations where only the regional nodes or targeted nodal basis are covered?
Thanks for asking this question. People occasionally ask this. Essentially all of the trials that show a survival advantage with PMRT used comprehensive local-regional therapy. So, doing something other than both the chest wall and nodes would not be based on the available data. Cancer is sneaky, i...
In light of the NSABP B-51 data presented at SABCS, will you defer RNI in all patients with negative nodes after chemotherapy?
Results of the NSABP B-51 trial were presented at the 2023 San Antonio Breast Cancer Symposium (Mamounas et al., abstract GS-02-07). This trial was designed to test the value of postoperative radiation therapy in patients who presented with clinical T1-3N1 tumors with biopsy-proven axillary node inv...
Do you recommend axillary dissection for women with ER+ breast cancer and low risk Oncotype or Mammaprint if single node positive with only 1-2 SLN removed, to ensure <4 nodes positive?
No, I see no need to do dissection in this setting. Unless there is clinical or imaging evidence of gross disease, radiation should adequately control microscopic residual disease in the axilla.
What is the current criteria for sentinel node biopsy over a full axillary lymph node dissection in a patient with breast cancer?
This is a rapidly evolving space.For patients that cN0 with 1-2 or 3 SLN+, ALND can be omitted without gross ECE. Also, the NCCN guidelines have allowed for a similar approach with patients with 2 or fewer nodes on imaging/biopsy. While most patients on AMAROS/Z011 had breast conservation, this appr...
For postmastectomy patients who have >2 sentinel nodes involved, would you recommend a completion axillary dissection or proceed with PMRT?
This is a question that is still debated. I am comfortable extrapolating AMAROS/Z011 to mastectomy patients despite the limited number of patients undergoing mastectomy in AMAROS.In patients with 2-3 SLN involved (that were cN0), I would be ok with PMRT and omitting ALND as long as no ECE. If > 3 LN...
Would you treat a male breast cancer patient with post-mastectomy radiotherapy for a single positive sentinel lymph node and a low Oncotype?
In the setting of a mastectomy with a positive SLN and no ALND, I tend to extrapolate from AMAROS. While Z0011 had no mastectomy and AMAROS limited mastectomy patients, I am comfortable extrapolating axillary management to mastectomy setting.In this case, I would offer PMRT to chest wall and regiona...
Do you recommend sentinel node biopsy or ALND in cT4 or cT3 cN0 breast cancer patients?
The major trials comparing SLNB versus ALND (i.e., Table 1 from Lyman et al. 2014) either required tumors to be small (<= 2-3 cm), or had few patients with larger tumors (e.g., NSABP B-32: less than 2% with tumor > 4 cm; ALMANAC: 2% with tumor > 5 cm). Similarly, the major surgical trials comparing ...
How would you manage a premenopausal woman with a poorly differentiated pT2 HR+/HER2- breast cancer and 3/3 SLNs with ITCs?
Assuming she was clinically N0 prior to surgery, I would not subject her to an ALND but would favor axillary radiation; since ITC is not considered 'node-positive' she doesn't meet criteria for the AMAROS trial but I would extrapolate the equivalence of axillary radiation to ALND from that study to ...
Would you give/omit regional nodal irradiation in low nodal burden ER- Her2+ disease s/p BCS with SLNB?
When I evaluate patients in this situation, BCS + SLN with positive node, I tend to think about the decision as to the whole breast RT+/- RNI and use AMAROS/Z011 to frame my decision making.In an ER-negative patient, I would favor RNI, extrapolating from MA20 (where patients had an ALND, and 85% 1-3...
In a very young woman who is s/p mastectomy for a small, high grade, Her2 positive breast cancer, with a micromet in a sentinel node, would you favor completion axillary dissection or PMRT or close surveillance?
These are relatively common cases. The IBCSG 23-01 study does not support ALND in patients with micrometastases (Galimberti et al., PMID 30196031) though <10% underwent mastectomy so the majority of patients likely received RT to part of the axilla with whole-breast irradiation.In patients presentin...
How would you manage the axilla in a patient with Merkel cell carcinoma of the left forearm with clinically negative, axillary sentinel node positive disease?
I would irradiate the axilla with 50 Gy in 25 fractions. I would not recommend completion lymphadenectomy, regardless of number of sentinel lymph nodes involved with carcinoma, or extranodal extension of carcinoma. A randomized controlled trial has demonstrated that 50 Gy in 25 fractions targeting c...
Would you go back and do an axillary lymph node dissection if a sentinel lymph node biopsy showed a single lymph node with extracapsular extension?
For microscopic ECE, would manage with comprehensive RNI but if gross ECE, would favor dissection and then RT.
How do you approach an early stage breast cancer patient s/p BCS in which ECE is found on a positive sentinel node?
These are cases that we are facing more commonly and my thought is the answer shouldn't change whether this is BCS or mastectomy (though less data in this setting).I will discuss with the patient the limitations of Z011 and AMAROS with respect to ENE. With focal microscopic ECE, I will often proceed...
Would you consider nodal irradiation alone (not irradiating chest wall) in an otherwise early stage breast cancer, cN0 patient but has a positive node from a SLN bx who is status post mastectomy?
Though the presence of nodal disease is used to help identify women that benefit from adjuvant radiation treatment, patterns of failure data support that the majority of recurrences occur on the chest wall. Therefore if there are indications for nodal treatment (such as those noted above), I would p...
What treatment fields do you use for N1mi breast cancer after lumpectomy/SLNB?
We treat with modified tangents including level 1 and 2 nodes in tangential beam for micrometastases. ER, PR, and her2 neu or oncotype does influence the decision for micrometastases after lumpectomy.
For patients demonstrating ypN1 disease on SLNB following neoadjuvant chemotherapy, is it reasonable to proceed with regional RT in lieu of AxLND outside of the ALLIANCE A011202 trial?
Ideally these patients should go on the Alliance A011202 trial or have a full dissection as the current standard. AMAROS and other studies clearly have shown that radiation to the axilla is highly effective compared to axillary dissection for patients with a positive sentinel node at initial diagnos...
Should axillary imaging be routinely performed in all patients with a new diagnosis of breast cancer?
This issue has been debated but I would argue that patients with a new diagnosis of breast cancer should not undergo routine screening US of the axilla to look for clinically occult disease. The axillary US should be limited to diagnostic imaging for clinically suspicious nodes on clinical exam or b...
Do you routinely perform an axillary ultrasound in women with newly diagnosed breast cancer without palpable axillary nodes?
The practice has changed a bit with Z11 and AMAROS. For all invasive cancer we do perform sonogram but ifthe nodes are not palpable but only suspicious on ultrasound we don't routinely perform a percutaneus bx. The idea is these patients are still suitable for SLNB and were included in Z11. SLNB wou...
In patients with 3 or more positive sentinel lymph nodes who get a SLNB only, do you advocate for an ALND even if you are planning to treat their regional nodes regardless?
Although they were underrepresented in AMAROS study, in reality a scenerio like this is so uncommon that it would be hard to have any prospective study. We do not push for dissection if pre surgery imaging and clinical exam was consistent with NO disease and plan these patients with comprehensive no...