Adjuvant loco-regional radiotherapy is an important part of treatment for selected patients with early-stage breast cancer, helping reduce recurrence risk and improve survival. A new study published in Radiotherapy and Oncology provides prospective clinical validation of the ESTRO consensus guideline for target volume delineation in early-stage breast cancer. The analysis used data from the DBCG Skagen Trial 1, a large phase III randomized trial in which all clinical target volumes were delineated according to the ESTRO guideline.
The findings showed that loco-regional recurrences occurred almost exclusively within the ESTRO-defined clinical target volumes, supporting the adequacy of the guideline without suggesting a need for routine expansion of target volumes.
Why This Study Matters
Modern breast radiotherapy has moved from 2D bone-based planning to CT-based 3D planning, respiratory gating, intensity-modulated radiotherapy, and other more conformal techniques.
These advances allow more precise dose delivery, but they also make target delineation more important. If target volumes are too small, clinically relevant regions may be missed. If they are too large, patients may receive unnecessary dose to organs at risk.
The ESTRO consensus guideline, published in 2015, aimed to standardize target volume delineation for elective radiotherapy in early-stage breast cancer. Compared with some other atlases, the ESTRO guideline defines smaller and more anatomically focused clinical target volumes. This study tested whether those volumes are clinically adequate in a prospective trial setting.
Study Design
The DBCG Skagen Trial 1 enrolled 2,963 patients, with 2,908 included in the intention-to-treat cohort. Patients had invasive breast cancer and an indication for loco-regional radiotherapy.
They were randomized to receive either 50 Gy in 25 fractions or 40 Gy in 15 fractions. A simultaneous integrated tumor bed boost was optional in both groups. All radiotherapy target volumes were delineated according to the ESTRO consensus guideline, as required by the trial protocol. This created a unique opportunity to evaluate whether loco-regional recurrences occurred inside or outside the ESTRO-defined clinical target volumes.
Patient Population
Eligible patients were women aged 18 years or older with histologically confirmed invasive breast cancer. Patients could have undergone either breast-conserving surgery or mastectomy.
The trial included patients with nodal involvement or high-risk primary tumor features requiring loco-regional radiotherapy. Neoadjuvant chemotherapy and adjuvant systemic therapy were permitted. Patients with an indication for nodal boost were excluded, meaning no patients had visible macroscopic nodal disease at the time of radiotherapy.
How Recurrences Were Evaluated
The study focused on loco-regional recurrence, with or without concurrent distant recurrence. Local recurrence was defined as recurrence in the ipsilateral mammary region, including skin, surgical scar, subcutaneous tissue, breast, or chest wall. Regional recurrence was defined as nodal relapse within ipsilateral nodal regions.
Each recurrence was mapped against the ESTRO-defined clinical target volumes and categorized as:
- inside the CTV,
- marginal miss,
- distant recurrence.
Marginal misses were defined as recurrences located outside the ESTRO-defined CTV but still within the 50% isodose line.
The authors reviewed imaging and medical records to determine recurrence location and dose coverage.
Key Results
At a median follow-up of 5.2 years, 78 patients developed loco-regional recurrence. mThis included 41 patients with isolated loco-regional recurrence and 37 patients with loco-regional recurrence occurring together with distant recurrence. The 5-year cumulative risk of loco-regional recurrence was 2.7%.
Among the 78 patients with loco-regional recurrence, 74 patients, or 95%, had recurrences located within the ESTRO-defined clinical target volumes and were planned to receive the full prescribed dose.
All 64 local recurrences were located within the primary clinical target volume. Regional recurrences were also mostly located inside the nodal clinical target volumes.
Only three marginal misses were identified.
What the Recurrence Pattern Showed
The recurrence pattern strongly supported the ESTRO target volume approach.
Isolated loco-regional recurrences were mainly local recurrences within the breast clinical target volume after breast-conserving surgery. Loco-regional recurrences occurring with distant disease were more common in patients with extensive nodal involvement and higher initial stage.
The study also found that pathological complete response after neoadjuvant chemotherapy was less frequent among patients with concurrent loco-regional and distant recurrence, suggesting a less chemosensitive tumor phenotype. Importantly, no recurrences were found medial to CTVn_L4 or in cervical regions that would have been covered by larger RTOG or RADCOMP volumes but were outside the ESTRO-defined volumes.
Clinical Interpretation
The results suggest that the ESTRO consensus guideline provides adequate clinical target volume coverage for early-stage breast cancer patients treated with adjuvant loco-regional radiotherapy. Although the ESTRO volumes are smaller than some other atlases, the recurrence pattern did not suggest that routine expansion is necessary.
This is clinically important because avoiding unnecessary expansion may help reduce radiation exposure to organs at risk while maintaining oncologic safety.
The findings support the use of anatomically based, standardized target delineation in breast radiotherapy.
Important Caution
The authors emphasized that these results should be interpreted in the context of the treatment techniques used. The validation was mainly based on conventional 3D conformal radiotherapy planning. With more conformal techniques such as VMAT or proton therapy, dose gaps between adjacent clinical target volumes may occur if planning is not carefully managed.
Therefore, ongoing evaluation is needed to determine whether recurrence patterns remain similar with newer, highly conformal techniques. The study should also be considered an early validation because longer-term follow-up is still needed.
A planned 10-year follow-up will provide additional insight.
Strengths and Limitations
A key strength of the study is its prospective design within a large randomized trial. All target volumes were delineated according to the ESTRO guideline from the start, and recurrence cases were individually reviewed using available imaging and treatment planning data.
The study also included a broad high-risk breast cancer population. The main limitation is the relatively small number of loco-regional recurrences, although this reflects the low recurrence rate achieved with contemporary treatment.
Another limitation is that recurrence localization was based on available clinical imaging, which was not always performed in treatment position.
Clinical Takeaway
The DBCG Skagen Trial 1 provides prospective validation of the ESTRO target volume consensus guideline for early-stage breast cancer radiotherapy.
At 5.2 years of median follow-up, loco-regional recurrence was uncommon, and more than 95% of recurrences occurred within the ESTRO-defined clinical target volumes.
The findings support the clinical feasibility of the ESTRO guideline and suggest that routine expansion beyond these target volumes is not necessary in early-stage breast cancer patients without residual macroscopic nodal disease. For modern breast radiotherapy, the message is clear: precise, standardized target delineation can support both effective treatment and organ-sparing care.
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