A prospective analysis from the DBCG Skagen Trial 1 has provided clinical validation of the European Society for Radiotherapy and Oncology (ESTRO) consensus guideline for target volume delineation in early-stage breast cancer.
Published in Radiotherapy and Oncology, the study evaluated patterns of loco-regional recurrence among patients treated according to ESTRO-defined clinical target volumes and found that recurrences occurred almost exclusively within the irradiated volumes.
Among 2,908 patients included in the intention-to-treat cohort, only 78 developed loco-regional recurrence after a median follow-up of 5.2 years. Of these patients, 74, or 95%, had recurrences within the ESTRO-defined clinical target volumes, with the recurrent area planned to receive the full prescribed radiation dose.
The findings provide prospective evidence supporting the adequacy of ESTRO-defined target volumes and do not indicate a need for routine expansion beyond the current recommendations.
Why Did the ESTRO Target Volumes Need Prospective Validation?
Adjuvant loco-regional radiotherapy is an established component of treatment for selected patients with early-stage breast cancer. As radiation planning has become increasingly conformal, accurate definition of the clinical target volume has become particularly important.
The ESTRO consensus guideline for elective radiotherapy target delineation in early-stage breast cancer, introduced in 2015, was developed to standardize contouring while balancing adequate treatment coverage against radiation exposure to surrounding organs.
Compared with other contemporary atlases, including the RTOG and RADCOMP approaches, the ESTRO guideline defines relatively smaller clinical target volumes.
Although recurrence patterns had previously been examined retrospectively, prospective validation of these volumes remained limited.
The DBCG Skagen Trial 1 offered an opportunity to address this question because target volumes were prospectively delineated according to the ESTRO guideline as part of the trial protocol.
Nearly 3,000 Patients Treated Across Seven Countries
The phase III DBCG Skagen Trial 1, conducted between 2015 and 2021, enrolled 2,963 patients, including 2,908 in the intention-to-treat population, across seven countries.
Eligible patients were women aged 18 years or older with histologically confirmed invasive breast cancer, ranging from T1–4, pN0–3, M0, who had undergone either breast-conserving surgery or mastectomy and had an indication for loco-regional radiotherapy.
Patients were randomized 1:1 to receive either:
50 Gy in 25 fractions, or
40 Gy in 15 fractions.
A simultaneous integrated tumor bed boost was permitted when indicated.
Regional nodal radiotherapy could include levels I, II–IV, interpectoral nodes, and internal mammary nodes. All clinical target volumes were delineated according to the ESTRO consensus guideline.
The trial primarily used conventional three-dimensional conformal radiotherapy, although intensity-modulated techniques, including VMAT and tomotherapy, were permitted when required.
Loco-Regional Recurrence Remained Uncommon
At a median follow-up of 5.2 years, loco-regional recurrence was identified in 78 patients.
The estimated 5-year cumulative risk of loco-regional recurrence was 2.7%, with a 95% confidence interval of 2.1%–3.4%.
Among the 78 patients:
41 experienced isolated loco-regional recurrence, while
37 experienced loco-regional recurrence together with distant recurrence.
Overall, 64 patients developed local recurrence, while 23 experienced regional recurrence, with some patients having both local and regional disease.
The recurrence patterns differed between the groups. Isolated loco-regional recurrence occurred predominantly within the breast target volume following breast-conserving surgery, whereas loco-regional recurrence accompanying distant disease was more frequently associated with greater nodal involvement and higher initial disease stage.
All Local Recurrences Occurred Within the Breast or Chest Wall Target
One of the clearest findings involved local recurrence.
All 64 local recurrences occurred within the ESTRO-defined CTVp, covering the breast or chest wall, and all had received the full prescribed radiation dose.
Regional recurrence was also largely confined to the planned nodal target volumes.
Among patients with regional recurrence, the most frequently involved nodal region was level I, followed by levels II and III. Recurrences were also observed in level IV, the interpectoral region, and internal mammary nodes.
Across these regions, the majority of recurrent nodal sites had received at least 90% of the prescribed radiation dose.
Only Three Marginal Misses Were Identified
Despite the relatively confined target volumes used by ESTRO, marginal recurrence was uncommon.
Only three marginal misses were identified.
These included one recurrence within level I in a patient for whom this region had not been included in the treatment volume, one recurrence lateral to level I, and one patient who developed several cervical recurrences, including a lesion cranial to level IV.
The two patients with marginal misses outside the ESTRO-defined target volumes had received neoadjuvant chemotherapy but had not achieved a pathological complete response. Both initially had ER-negative/HER2-negative tumors, although one tumor converted to ER-positive status at surgery, and both subsequently developed extensive distant disease.
Importantly, the nodal sites associated with these marginal misses had not been identifiable on the diagnostic imaging performed when the primary tumors were evaluated.
95% of Recurrences Were Within ESTRO-Defined Volumes
Overall, 74 of the 78 patients with loco-regional recurrence, or 95%, had recurrence within the ESTRO-defined clinical target volumes, with the involved volume planned to receive the full prescribed dose.
Only four patients among the entire 2,908-patient intention-to-treat cohort developed recurrence close to but outside the ESTRO volumes planned to receive the full dose.
The investigators also systematically assessed recurrence locations relative to other contouring approaches.
No recurrences were identified medial to level IV or within cervical regions that would have been covered by RTOG or RADCOMP volumes but excluded from the ESTRO clinical target volumes.
The findings therefore did not provide evidence that routinely using larger target volumes would have prevented the observed recurrences.
Recurrence With Distant Disease Reflected Higher-Risk Features
Patients who developed loco-regional recurrence concurrently with distant disease showed several indicators of more extensive disease.
Among patients receiving neoadjuvant chemotherapy, pathological complete response was less frequent in those with concurrent loco-regional and distant recurrence.
Extensive residual nodal disease was also more common.
At least four positive lymph nodes after neoadjuvant chemotherapy were observed in 43% of patients with concurrent loco-regional and distant recurrence, compared with 11% of those with isolated loco-regional recurrence.
Among all patients with loco-regional recurrence, the most frequent molecular subtype was ER-positive/HER2-negative disease, representing 46% of cases, followed by ER-negative/HER2-negative disease at 38%.
What Do the Findings Mean for ESTRO-Based Breast Radiotherapy?
The study provides what the investigators describe as the first prospective clinical validation of the ESTRO consensus guideline based on recurrence patterns in patients treated within a large randomized phase III trial.
The results suggest that loco-regional failure was rarely attributable to insufficient geographical coverage of the ESTRO-defined clinical target volumes.
Instead, recurrences predominantly developed inside regions that had already been included in the radiotherapy plan and had been planned to receive the prescribed dose.
This finding is particularly relevant because ESTRO target volumes are generally more anatomically confined than those defined by some other breast radiotherapy atlases.
According to the investigators, the results support the adequacy of these smaller volumes and do not provide evidence supporting their routine expansion in early-stage breast cancer without residual macroscopic nodal disease.
More Conformal Techniques Require Continued Evaluation
The investigators nevertheless emphasized several considerations when interpreting the findings.
The validation primarily reflects treatment delivered using conventional 3D conformal radiotherapy.
With increasingly conformal approaches, including VMAT and proton therapy, anatomical regions between adjacent target volumes can potentially receive lower incidental radiation doses than they would with traditional tangential and anterior-posterior fields.
The authors therefore noted that continued evaluation will be important to determine whether these dosimetric differences influence recurrence patterns when highly conformal treatment techniques are used.
The study also included patients treated during a period when diagnostic 18F-FDG PET/CT was not routinely used, meaning that the initial extent of disease could have been underestimated in some cases compared with contemporary staging.
In addition, patients requiring a nodal boost were excluded from the trial. The findings therefore apply primarily to patients considered radically operated without evident postoperative macroscopic nodal disease.
Longer Follow-Up Will Further Define the Results
The investigators highlighted the prospective design, large randomized trial population, protocol-mandated ESTRO delineation, and detailed individual review of recurrence imaging as major strengths of the analysis.
However, the relatively small number of loco-regional recurrences limits the number of events available for validation.
The authors therefore described the current analysis as an early validation.
A planned 10-year follow-up of the DBCG Skagen Trial 1 is expected to provide additional information on longer-term recurrence patterns.
For now, the findings provide prospective evidence that the ESTRO consensus target volumes adequately encompass the overwhelming majority of loco-regional breast cancer recurrences, without evidence supporting routine enlargement of those volumes in early-stage disease.
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