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Original Investigation
October 25, 2021

Effect of Elective Internal Mammary Node Irradiation on Disease-Free Survival in Women With Node-Positive Breast Cancer: A Randomized Phase 3 Clinical Trial

Author Affiliations
  • 1Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
  • 2Proton Therapy Center, Research Institute and Hospital, National Cancer Center, Goyang, Korea
  • 3Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
  • 4Department of Radiation Oncology, Dong-A University Hospital, Dong-A University College of Medicine, Busan, Korea
  • 5Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 6Department of Radiation Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea
  • 7Department of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea
  • 8Department of Radiation Oncology, Gachon University Gil Medical Center, Incheon, Korea
  • 9Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
  • 10Department of Radiation Oncology, Pusan National University School of Medicine, Busan, Korea
  • 11Department of Radiation Oncology, Bundang CHA Medical Center, CHA University, Gyeonggi-do, Korea
  • 12Department of Radiation Oncology, Ewha Womans University School of Medicine, Seoul, Korea
  • 13Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
  • 14Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
JAMA Oncol. Published online October 25, 2021. doi:10.1001/jamaoncol.2021.6036
Key Points

Question  Does internal mammary node irradiation (IMNI) improve disease-free survival in patients with node-positive breast cancer?

Findings  In this randomized clinical trial of 735 women with node-positive breast cancer, 7-year disease-free survival did not significantly differ between those who were randomized to receive regional nodal irradiation with IMNI and those who were randomized to receive regional nodal irradiation without IMNI. However, in a subgroup analysis of patients with mediocentrally located tumors, the 7-year disease-free survival rate was improved by 10% in the IMNI group.

Meaning  While this randomized clinical trial found no difference in 7-year disease-free survival between the the IMNI and no IMNI groups, the findings of an unprespecified subgroup analysis suggest that including IMNI in regional nodal irradiation might be considered for patients with medially or centrally located tumors.


Importance  The benefit of internal mammary node irradiation (IMNI) for treatment outcomes in node-positive breast cancer is unknown.

Objective  To investigate whether the inclusion of IMNI in regional nodal irradiation improves disease-free survival (DFS) in women with node-positive breast cancer.

Design, Setting, and Participants  This multicenter, phase 3 randomized clinical trial was conducted from June 1, 2008, to February 29, 2020, at 13 hospitals in South Korea. Women with pathologically confirmed, node-positive breast cancer after breast-conservation surgery or mastectomy with axillary lymph node dissection were eligible and enrolled between November 19, 2008, and January 14, 2013. Patients with distant metastasis and those who had received neoadjuvant treatment were excluded. Data analyses were performed according to the intention-to-treat principle.

Interventions  All patients underwent regional nodal irradiation along with breast or chest wall irradiation. They were randomized 1:1 to receive radiotherapy either with IMNI or without IMNI.

Main Outcomes and Measures  The primary end point was the 7-year DFS. Secondary end points included the rates of overall survival, breast cancer–specific survival, and toxic effects.

Results  A total of 735 women (mean [SD] age, 49.0 [9.1] years) were included in the analyses, of whom 373 received regional nodal irradiation without IMNI and 362 received regional nodal irradiation with IMNI. Nearly all patients underwent taxane-based adjuvant systemic treatment. The median (IQR) follow-up was 100.4 (89.7-112.1) months. The 7-year DFS rates did not significantly differ between the groups treated without IMNI and with IMNI (81.9% vs 85.3%; hazard ratio [HR], 0.80; 95% CI, 0.57-1.14; log-rank P = .22). However, an ad hoc subgroup analysis showed significantly higher DFS rates with IMNI among patients with mediocentrally located tumors. In this subgroup, the 7-year DFS rates were 81.6% without IMNI vs 91.8% with IMNI (HR, 0.42; 95% CI, 0.22-0.82; log-rank P = .008), and the 7-year breast cancer mortality rates were 10.2% without IMNI vs 4.9% with IMNI (HR, 0.41; 95% CI, 0.17-0.99; log-rank P = .04). No differences were found between the 2 groups in the incidence of adverse effects, including cardiac toxic effects and radiation pneumonitis.

Conclusions and Relevance  This randomized clinical trial found that including IMNI in regional nodal irradiation did not significantly improve the DFS in patients with node-positive breast cancer. However, patients with medially or centrally located tumors may benefit from the use of IMNI.

Trial Registration  ClinicalTrials.gov Identifier: NCT04803266

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