When to Use Regional Nodal Irradiation (RNI) in Addition to Whole Breast Irradiation (WBI)?

• The addition of regional nodal irradiation (RNI) to WBI:
  • Improves DFS:
    • In women at high risk for recurrence
• The National Cancer Institute of Canada Clinical Trial Group (NCIC-CTG) MA.20 trial:
  • Randomized 1832 high-risk women to:
    • Either WBI alone or
    • WBI plus RNI:
      • Following partial mastectomy and axillary lymph node dissection
  • Regional nodal radiation (RNI) included:
    • The internal mammary, supraclavicular, and high axillary nodes
  • The trial included patients with:
    • Node-positive or
    • High-risk node-negative disease
  • Eighty-five percent of patients had 1 to 3 positive nodes, 5% had more than four positive nodes, and 10% were node negative
  • Node-negative patients with tumors greater than or equal to 2 cm who had fewer than 10 axillary nodes removed:
    • Were considered high risk if they had at least one of the following:
      • Estrogen receptor-negative
      • Lymphovascular invasion, or
      • Nuclear grade 3
  • All patients had systemic therapy
• Median follow-up of 62 months
• The addition of RNI improved:
  • Locoregional DFS from:
    • 94.5% to 96.8% (P=0.02) and
  • Distant DFS from:
    • 87% to 92.4% (P=0.002)
  • There was a non-statistically significant trend:
    • Toward improvement in OS from:
      • 90.7% to 92.3% (P=0.07)
  • The addition of RNI to WBI was associated with:
    • An increase in grade 2 or greater:
      • Pneumonitis:
        • From 0.2% to 1.3% (P=0.01) and
      • Lymphedema:
        • From 4.1% to 7.3% (P=0.004).
• European Organisation for Research and Treatment of Cancer (EORTC) 22922:
  • Randomized 4004 women:
    • Undergoing breast-conserving surgery or mastectomy and ALND for:
      • Histological stage I, II, or III breast cancer:
        • To RNI (supraclavicular and internal mammary nodal irradiation) or
        • No regional nodal irradiation
  • The primary endpoint of evaluation:
    • Was overall survival
  • Median follow-up of 10.9 years
  • The addition of regional nodal irradiation improved:
    • DFS:
      • From 69.1% to 72.1% (P=0.04)
    • Again, there was a non-significant trend toward improvement in OS:
      • From 80.7% to 82.3% (P=0.06 among the RNI group)
    • Patients undergoing regional nodal irradiation experienced:
      • Higher rates of pulmonary fibrosis (4.4% vs 1.7%, P<0.001).
• The results of NCIC-CTG MA.20:
  • Have led many to conclude:
    • That all patients with axillary nodal metastases, regardless of tumor size or extent of nodal involvement:
      • Should receive comprehensive nodal radiation therapy (RT)
• A major conundrum in current practice:
  • Is resolving the apparently contradictory findings of:
    • The American College of Surgeons Oncology Group (ACOSOG) Z0011 and After Mapping of the Axilla, Radiation or Surgery? (AMAROS) with those of MA.20:
      • The modest benefit in DFS with RNT in MA.20:
        • May reflect differences in patient populations between the studies
          • Patients with clinically positive nodes were excluded from ACOSOG Z0011 and AMAROS (and not MA.20)
  • In addition, fewer than 10 nodes were removed in one-third of patients in the MA.20 study and the median node count was 12 compared to a median of 17 in the ALND arms of Z0011 and AMAROS
  • The benefit of nodal RT therefore may be limited to:
    • Higher-risk patients:
      • With more extensive nodal disease and perhaps more limited axillary surgery

REFERENCES

1. Pepels MJ, de Boer M, Bult P, et al. Regional recurrence in breast cancer patients with sentinel node micrometastases and isolated tumor cells. Ann Surg. 2012;255:116-121.
2. Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373:317-327.
3. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-316.

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