What were the findings of the Amaros trial regarding its treatment regimen's efficacy and safety?

AMAROS Trial Findings

The AMAROS trial demonstrated that axillary radiotherapy (ART) provides equivalent regional control to axillary lymph node dissection (ALND) in patients with T1-2 breast cancer and positive sentinel lymph nodes, with significantly lower rates of lymphedema and arm morbidity. 1

Trial Design and Patient Population

The EORTC 10981-22023 AMAROS trial was a randomized, multicenter, open-label, phase 3 non-inferiority trial that enrolled 4,823 patients between 2001 and 2010 from 34 centers across nine European countries. 1 The study included patients with:

• T1-2 primary breast cancer 1
• No palpable lymphadenopathy at presentation 1
• Positive sentinel lymph node(s) detected on biopsy (either micrometastatic or macrometastatic disease) 2, 1
• A small fraction (approximately 17-18%) who underwent mastectomy rather than breast-conserving surgery 2

Of the 4,806 eligible patients randomized, 1,425 had positive sentinel nodes: 744 were assigned to ALND and 681 to axillary radiotherapy. 1

Primary Outcome: Axillary Recurrence

At median follow-up of 6.1 years, the trial showed excellent and comparable axillary control between both treatment arms:

• 5-year axillary recurrence rate: 0.43% (95% CI 0.00-0.92) after ALND versus 1.19% (95% CI 0.31-2.08) after ART 1
• Axillary recurrence occurred in only 4 of 744 patients in the ALND group and 7 of 681 in the ART group 1
• 10-year axillary recurrence rate: 0.93% (95% CI 0.18-1.68) after ALND versus 1.82% (95% CI 0.74-2.94) after ART, with hazard ratio 1.71 (95% CI 0.67-4.39) 2

The planned non-inferiority test was underpowered due to the remarkably low number of events in both arms, but the clinical results demonstrated non-inferior regional control. 1

Survival Outcomes

No significant differences were observed in overall survival or disease-free survival between the two treatment approaches:

• 10-year overall survival: 84.6% after ALND versus 81.4% after ART (HR 1.17,95% CI 0.89-1.52) 2
• 10-year disease-free survival: No significant difference (HR 1.19,95% CI 0.97-1.46) 2
• No differences in regional or distant recurrence rates 2

Notably, among the 744 patients who underwent ALND, 220 (33%) had additional positive non-sentinel nodes identified. 1 Despite this, the excellent outcomes in the ART arm suggest that radiotherapy effectively controlled microscopic disease in these nodes.

Morbidity and Quality of Life: The Critical Advantage

The most clinically significant finding was the substantially lower morbidity with axillary radiotherapy compared to ALND:

Lymphedema Rates

• At 1,3, and 5 years: Lymphedema was noted significantly more often after ALND than after ART 2, 1
• Specific rates: 23% after ALND versus 11% after ART in the AMAROS trial 2
• Real-world data from a large population study showed even lower rates of 5.8% with ART 3

Other Arm Morbidity

• Brachial plexopathy: 1.6% with ART 3
• Arm/shoulder stiffness: Approximately 7.4% with ART versus higher rates with ALND 3
• Quality of life surveys indicated arm/shoulder stiffness, mobility, and function issues affected about 18% in the ART arm 3

Clinical Application and Guideline Integration

Current guidelines now incorporate AMAROS findings to support axillary radiotherapy as an alternative to ALND:

For Breast-Conserving Surgery

• The 2025 ASCO guideline states that RNI is noninferior to completion ALND, with axillary recurrence of 2.0% with ALND versus 1.7% with RNI (P=1.00) 2
• The 2024 ESMO guideline lists AMAROS trial eligibility criteria as a reference point for omitting ALND in favor of axillary RT 2

For Mastectomy Patients

• Postmastectomy patients with 1-2 positive sentinel nodes: RT with regional nodal irradiation is recommended in place of completion ALND 2
• The 2016 ASCO/ASTRO/SSO guideline notes that 17-18% of AMAROS participants underwent mastectomy, with no significant differences in outcomes 2
• For patients with ≥3 positive nodes after mastectomy, ALND followed by RNI RT remains the standard 2

Important Caveats

• The 2017 NCCN guideline emphasizes that the decision to integrate ALND and PMRT should be a multidisciplinary effort considering the treatment program as a whole 2
• Some Asian experts accepted the AMAROS findings only with reservation, noting that breast tumors in less developed countries are often larger at presentation, occur at younger ages, and have higher probability of positive non-sentinel nodes 2

Critical Pitfalls to Avoid

• Do not apply AMAROS findings to patients with >2 positive sentinel nodes without completion ALND, as these patients were not adequately represented in the trial 2
• Do not subject patients to PMRT toxicities without careful consideration of whether these are justified compared to ALND toxicities; the decision should ask: "Would I recommend PMRT if ALND showed no additional nodal metastases?" 2
• Do not assume AMAROS results apply equally to all populations, particularly in settings where tumors present at more advanced stages with higher-risk features 2
• Recognize that the trial was underpowered for the planned non-inferiority analysis due to remarkably low event rates, though clinical outcomes strongly support equivalence 1