ACOSOG Z0011 Trial

• Background and Rationale:
  • Historically, axillary lymph node dissection (ALND) was performed when sentinel lymph node (SLN) biopsy showed metastasis:
    • For better staging and regional control
  • However, ALND is associated with significant morbidity:
    • Lymphedema, shoulder dysfunction, nerve injury, etc
  • The question:
    • In patients with limited SLN metastasis (1 to 2 positive sentinel nodes):
      • Can ALND be safely omitted (i.e. SLN biopsy alone) without compromising survival or local control?
• Trial Design and Population:
  • Name / acronym:
    • ACOSOG Z0011 (American College of Surgeons Oncology Group)
  • Type:
    • Phase III randomized noninferiority trial
  • Enrollment period:
    • May 1999 – December 2004 (115 institutions) 
  • Eligibility:
    • Clinically node-negative:
      • No palpable axillary adenopathy
    • Invasive breast cancer:
      • cT1 or cT2 (≤ 5 cm)
    • Undergoing breast-conserving surgery (lumpectomy) with planned whole-breast tangential irradiation:
      • No third-field axillary radiation
    • 1 or 2 sentinel lymph nodes positive for metastasis detected on standard hematoxylin and eosin (not just by immunohistochemistry) 
  • Exclusions / constraints:
    • Patients undergoing mastectomy (no breast radiation) were not included
    • No neoadjuvant systemic therapy (all patients had primary surgery first) 
    • Third-field / nodal-field radiation of the axilla was prohibited by protocol 
  • Randomization arms:
    • SLND (sentinel lymph node dissection) alone (no further ALND)
    • SLND + completion ALND (standard of care)
    • Patients randomized:
      • 891 total:
        • 856 (96%) completed per-protocol:
          • 446 in SLND-alone
          • 445 in ALND
    • Planned therapies in both arms:
      • Breast irradiation, adjuvant systemic therapy and endocrine therapy per treating physician 
    • Primary endpoint:
      • Overall survival:
        • Noninferiority margin:
          • Hazard ratio ≤ 1.3
    • Secondary endpoints:
      • Disease-free survival, locoregional recurrence, morbidity 
    • Follow-up:
      • Median ~ 9.3 years (IQR ~6.93–10.34) 
      • Final follow-up data locked in 2015
• In the ACOSOG Z0011 trial:
  • The impact of axillary dissection on the outcomes of both pre- and postmenopausal patients:
    • With clinically T1 to T2, N0 breast cancers was studied
  • Clinically node-negative breast cancer patients:
    • Treated with breast-conserving surgery with 1 to 2 positive SLNs:
      • Were randomized to:
        • Axillary lymph node dissection (ALND) or no additional axillary surgery
  • All women were recommended:
    • For whole-breast irradiation
  • Systemic therapy:
    • Was left to the discretion of the treating physician:
      • But 96% of women in the ALND arm and 97% in the SLN arm:
        • Received some type of systemic therapy
  • Patients were randomized:
    • To receive completion ALND, or
    • No immediate additional axillary surgery
  • Patients were monitored for:
    • Local and regional recurrence, distant recurrence, contralateral breast cancers, and death
  • The study showed that in patients with cT1 to cT2 breast cancers with 1 to 2 positive SLNs:
    • There were no significant differences in:
      • DFS and OS between patients treated with:
        • SLND (DFS: 83.9%, OS: 92.5%)
        • ALND (DFS: 82.2%, OS: 91.8%)
      • 10-year overall survival:
        • SLND – alone: 86.3 %
        • ALND – 83.6 %
          • Hazard ratio (unadjusted) = 0.85 (one-sided 95% CI: 0 – 1.16) — noninferiority P = 0.02 
      • Disease-free survival at 10 years:
        • SLND – alone: 80.2 %
        • ALND – 78.2 %
          • HR = 0.85 (95% CI 0.62 – 1.17), P = 0.32 
    • As anticipated, surgical morbidity was significantly decreased in the SLN-only group, with:
      • Fewer wound infections (P=0.016), paresthesias (P<0.001), and subjective lymphedema (P<0.001)
    • Although approximately:
      • 37% of ALND patients and 45% of SLN only patients had micrometastatic disease only in the sentinel node:
        • The remaining had macrometastasic nodal disease demonstrating that the Z0011 criteria can be applied to both groups of patients
    • Locoregional / Axillary Recurrence:
      • Between year 5 and 10:
        • Only one regional recurrence in the SLND-alone arm (versus none in ALND arm) 
      • 10-year locoregional recurrence rates did not differ significantly between arms
    • Additional findings / observations:
      • The number of nodes removed was vastly different:
        • Median ~ 2 nodes (IQR 1to 4) in SLND-alone vs ~ 17 nodes (IQR 13 to 22) in ALND arm
      • Some patients in the ALND arm had additional non-sentinel nodal metastases:
        • That would not have been known without dissection (~ 27% in ALND group)  
      • Radiation protocol deviations:
        • About 19% of patients received protocol-prohibited nodal field irradiation (some unplanned nodal radiation):
          • But these deviations were balanced between arms, minimizing bias
      • Exploratory subanalyses by hormone receptor status (ER / PR) did not show statistically significant differences in survival by arm
• Finally, Chung et al:
  • Applied the ACOSOG Z0011 criteria to:
    • High-risk, node-positive breast cancer patients undergoing breast conservation including patients:
      • Younger than age 50 years who were considered by some to be ineligible for management using ACOSOG Z0011 criteria due to poor prognosis
  • Overall, 186 high-risk breast cancer patients with at least 1 positive node were identified:
    • 57 (31%) were HER2-positive
    • 55 (30%) were triple negative
    • 74 (40%) were younger than age 50 years
  • Of the eligible patients who had an ALND (n = 105):
    • 38% had involvement of non-sentinel nodes
    • The median number of positive non-sentinel nodes was only 1 (range 1 to 3)
  • These findings demonstrate that patients with high-risk tumor features:
    • Are not more likely to have a higher burden of residual axillary nodal disease compared to low-risk patients:
      • Confirming that Z0011 criteria can be applied to a heterogeneous breast cancer population with similar results
• Interpretation and Clinical Implication:
  • The Z0011 data support that, in a selected group of women with clinical T1 to T2, node-negative by palpation, who have 1 to 2 positive sentinel lymph nodes, and who receive breast-conserving surgery + whole-breast irradiation + systemic therapy:
    • Omitting completion ALND does not worsen overall survival, disease-free survival, or regional control (over ~10 years)
  • As such, ALND is no longer considered mandatory in this specific population, reducing surgical morbidity for many patients
  • The additional information gained by ALND (e.g. total number of positive nodes beyond the sentinel ones):
    • Rarely changes systemic therapy decisions in current practice, given that systemic therapy is mostly guided by tumor biology rather than exact nodal count for many patients

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REFERENCES

1. Chung A, Gangi A, Mirocha J, Giuliano A. Applicability of the ACOSOG Z0011 criteria in women with high-risk node-positive breast cancer undergoing breast conserving surgery. Ann Surg Oncol. 2015;22:1128-1132.
2. Giuliano AE, Ballman K, McCall L. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: long-term follow-up from the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial. Ann Surg. 2016;264:413-420.
3. Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases. The American College of Surgeons Oncology Group Z0011 Randomized Trial. Ann Surg. 2010;252:426-432.
4. Latosinsky S, Berrang TS, Cutter CS, et al; for the Members of the Evidence Based Reviews in Surgery Group. CAGS and ACS evidence based reviews in surgery. 40. Axillary dissection versus no axillary dissection in women with invasive breast cancer and sentinel node metastasis. Can J Surg. 2012;55:66-69.
5. Lucci A, McCall LM, Beitsch PD, et al; American College of Surgeons Oncology Group. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol. 2007;25:3657-3663.