Residency · Residency · Radiation Oncology
Regional Nodal Irradiation: Internal Mammary and Supraclavicular Fields
Overview
Regional nodal irradiation (RNI) refers to the radiation treatment targeting the supraclavicular, infraclavicular, axillary, and internal mammary nodal (IMN) basins. Three landmark clinical trials—MA.20, EORTC 22922, and the French trial—have demonstrated that adding RNI to whole breast irradiation (WBI) or postmastectomy radiation therapy (PMRT) improves disease-free survival (DFS) and reduces distant recurrence. Among the components of RNI, internal mammary nodal irradiation remains the most controversial due to its modest absolute benefit, which must be weighed against the increased cardiac radiation dose it entails. Advances in radiation techniques such as intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and deep inspiration breath hold (DIBH) have improved the therapeutic ratio for RNI, particularly for tumors on the left side where cardiac exposure is a concern.
Clinical Trial Evidence
MA.20 (Whelan et al., 2015; 2019 update)
The MA.20 trial enrolled 1,832 patients who were either node-positive or high-risk node-negative following breast-conserving surgery (BCS) and WBI. Patients were randomized to receive either WBI alone or WBI plus RNI, which included irradiation of the supraclavicular, axillary level III, and internal mammary nodes. After 10 years, disease-free survival was significantly better in the RNI group at 82% compared to 77% in the WBI-alone group, with a hazard ratio (HR) of 0.76 (p=0.01). Overall survival (OS) showed a non-significant trend favoring RNI (82.8% vs. 81.8%). Notably, distant DFS was significantly improved with RNI. Subgroup analyses revealed that the greatest benefit was observed in estrogen receptor (ER)-negative, premenopausal, and high-risk patients.
EORTC 22922/10925 (Poortmans et al., 2015; 2020 update)
This trial included 4,004 patients with stage I-III breast cancer randomized to receive WBI or PMRT with or without irradiation of the internal mammary and medial supraclavicular nodes. At 15 years, OS was 73.1% in the RNI group versus 70.7% in the no-RNI group, with a hazard ratio of 0.87 (p=0.04), indicating a statistically significant survival benefit. Disease-free survival was also improved (65.1% vs. 61.1%, HR 0.89, p=0.02), as was distant disease-free survival (72.5% vs. 69.1%, HR 0.86, p=0.02). This trial confirmed both OS and DFS benefits from RNI with long-term follow-up and included patients treated with both breast-conserving surgery and mastectomy.
French Trial (Hennequin et al., 2013)
Involving 1,334 patients with positive nodes or medially/centrally located tumors, this trial randomized patients to WBI or PMRT with or without internal mammary nodal irradiation. The 10-year OS was 62.6% in the IMN radiation group versus 59.3% in the no-IMN group, but this difference was not statistically significant (p=0.8). However, a benefit was suggested in the subgroup of patients with medially located tumors and inner or central quadrant primaries. Although underpowered for the OS endpoint, this trial contributed to the overall evidence supporting IMN irradiation.
Internal Mammary Nodal Irradiation
Anatomy
The internal mammary nodal chain runs alongside the internal mammary (also called internal thoracic) vessels, located approximately 2 to 4 centimeters lateral to the sternal edge within the intercostal spaces. The first three intercostal spaces contain the majority of IMN metastases, accounting for over 85% of cases. Techniques such as lymphoscintigraphy and single-photon emission computed tomography/computed tomography (SPECT/CT) can help identify IMN drainage patterns in individual patients.
Risk Factors for IMN Involvement
Tumors located in the inner or central quadrants of the breast have direct lymphatic drainage to the IMN chain, increasing the risk of involvement. Additionally, patients with positive axillary nodes have a 20-40% chance of IMN involvement. Other risk factors include large tumor size, younger age, and the presence of lymphovascular invasion.
Contouring Guidelines
The clinical target volume (CTV) for IMN irradiation typically involves a 5 mm expansion around the internal mammary vessels within the first three intercostal spaces. This volume can be treated either as part of wide tangent fields or with a separate IMN field. The European Society for Radiotherapy and Oncology (ESTRO) consensus guidelines recommend including the internal mammary vessels with a 5 mm margin in intercostal spaces 1 through 3, or 1 through 4 for high-risk tumors.
Cardiac Dose Considerations
Irradiation of the IMN inevitably increases the radiation dose to the heart, particularly for left-sided tumors, and to the left anterior descending (LAD) coronary artery. The mean heart dose typically increases by 2 to 4 Gy when IMN coverage is added compared to WBI alone. Although techniques such as DIBH and IMRT/VMAT reduce cardiac exposure, they cannot completely eliminate this increase. Therefore, the decision to include IMN irradiation requires a careful risk-benefit analysis, balancing the improvements in DFS and distant DFS against the potential for long-term cardiac toxicity.
Supraclavicular and Axillary Nodal Irradiation
Supraclavicular Fossa
The supraclavicular fossa contains level IV and supraclavicular lymph nodes. The clinical target volume for this region is bounded laterally by the sternocleidomastoid muscle, posteriorly by the subclavian vessels, and superiorly by the cricothyroid membrane. The typical radiation dose prescribed is 50 Gy delivered in 25 fractions or an equivalent hypofractionated regimen, such as 40 Gy in 15 fractions.
Axillary Nodes
The axillary lymph nodes are divided into three levels based on their anatomical relation to the pectoralis minor muscle. Level I nodes lie lateral to the lateral border of the pectoralis minor, level II nodes are located between the medial and lateral borders, and level III (infraclavicular) nodes are medial to the medial border. After axillary lymph node dissection (ALND), levels I and II are generally removed surgically, while level III and the supraclavicular fossa are included in RNI. In cases where sentinel lymph node biopsy (SLNB) reveals positive nodes but no completion ALND is performed (following protocols such as Z0011 or AMAROS), radiation to axillary levels I and II may be necessary.
AMAROS Trial
The AMAROS trial randomized patients with positive sentinel lymph nodes to either completion ALND or axillary radiation therapy. The trial found no difference in axillary recurrence or overall survival between the two groups. Importantly, axillary radiation was associated with significantly less lymphedema, supporting its use as a non-inferior alternative to completion ALND in appropriate patients.
Radiation Therapy Technique
Conventional Technique (Historical)
Historically, radiation was delivered using medial and lateral tangent fields to cover the breast or chest wall, combined with a separate anterior-posterior supraclavicular field matched inferiorly to the tangent fields. The internal mammary nodes were covered either by partially wide tangent fields or a separate direct IMN field. However, the junctions between these fields often created dose inhomogeneities, resulting in hot or cold spots.
Modern IMRT/VMAT Technique
Modern radiation therapy employs a comprehensive single-isocenter VMAT plan that covers the breast or chest wall along with all regional nodal stations. This approach eliminates the field junction issues inherent in conventional three-field techniques, providing superior dose homogeneity and conformality. It also allows better sparing of cardiac structures and the ipsilateral lung. Due to the complex target geometry, robust image-guided radiation therapy (IGRT), such as cone-beam CT (CBCT), is required to ensure accurate delivery.
Dose Prescription
The typical dose prescription for whole breast irradiation or chest wall radiation ranges from 40 to 50 Gy, depending on the fractionation scheme. Nodal stations—including the supraclavicular, internal mammary, and axillary nodes—are generally treated to doses matched to the breast or chest wall dose, typically 40 to 50 Gy. A simultaneous integrated boost (SIB) technique may be used to deliver 45 to 48 Gy to the breast and 40 to 42 Gy to elective nodal regions, especially with hypofractionation. If indicated, a sequential tumor bed boost of 10 to 16 Gy may be administered.
<image>An anterior coronal view of the breast and regional nodal anatomy with color-coded target volumes. The whole breast (light pink) is shown with the supraclavicular CTV (green) above the clavicle, axillary level I-II CTV (blue) in the axilla, level III/infraclavicular CTV (purple) behind the pectoralis minor, and the internal mammary node CTV (yellow) along the sternal border in intercostal spaces 1-3. The field borders and beam arrangement for a comprehensive VMAT plan are overlaid.</image>
<image>A summary infographic of the three landmark RNI trials (MA.20, EORTC 22922, French trial). For each trial, key information is displayed: number of patients, intervention (RNI fields included), primary endpoint results (DFS, OS, DDFS) with hazard ratios and confidence intervals, and follow-up duration. A pooled estimate at the bottom shows the consistent benefit of RNI on DFS and DDFS across trials.</image>
<image>An axial CT image at the level of the second intercostal space comparing dose distributions for IMN coverage using three techniques: (A) wide tangent field (partially wide tangents angled to include IMN), (B) separate direct electron IMN field matched to tangent edge, and (C) VMAT with full optimization. Heart dose-volume histogram curves for each technique are shown in an inset, demonstrating lowest mean heart dose with the VMAT approach using DIBH.</image>
Key Clinical Pearls
Three randomized trials—MA.20, EORTC 22922, and the French trial—consistently demonstrate that regional nodal irradiation improves disease-free survival and reduces distant recurrence. Notably, the EORTC 22922 trial showed a statistically significant overall survival benefit at 15 years. When deciding whether to include internal mammary nodes in the radiation field, clinicians must balance the modest DFS benefit against the incremental cardiac dose. The use of DIBH and advanced techniques like IMRT and VMAT has made IMN coverage safer, especially for left-sided tumors. The AMAROS trial provides strong evidence that axillary radiation therapy is a non-inferior alternative to completion axillary lymph node dissection in patients with positive sentinel lymph nodes, with the added advantage of significantly less lymphedema. For practical treatment planning, single-isocenter VMAT eliminates the field junction problems associated with conventional three-field techniques and allows simultaneous optimization of target coverage and organ-at-risk sparing. When counseling patients, it is important to consider that the absolute benefit of RNI depends on baseline risk factors; patients who are younger, have multiple positive nodes, ER-negative tumors, or lymphovascular invasion derive the greatest absolute benefit.
References
- Whelan TJ et al. "Regional nodal irradiation in early-stage breast cancer." N Engl J Med. 2015;373(4):307-316.
- Poortmans PM et al. "Internal mammary and medial supraclavicular irradiation in breast cancer." N Engl J Med. 2015;373(4):317-327.
- Poortmans PM et al. "Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial." Lancet Oncol. 2020;21(12):1602-1610.
- Donker M et al. "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." Lancet Oncol. 2014;15(12):1303-1310.
- Dijkema IM et al. "Consensus on target volume delineation for elective radiation therapy of the internal mammary nodes in breast cancer." Radiother Oncol. 2019;137:45-51.
