A shorter course of locoregional radiotherapy did not increase the risk of arm lymphedema or compromise cancer outcomes among patients with high-risk breast cancer, according to findings from the randomized Phase III Danish Breast Cancer Group Skagen Trial 1.
The study compared hypofractionated radiotherapy delivered as 40 Gy in 15 fractions with the Danish Breast Cancer Group standard regimen of 50 Gy in 25 fractions. The results were published in the Journal of Clinical Oncology on July 23, 2026.
Why Locoregional Hypofractionation Has Raised Concern
Hypofractionated radiotherapy, which delivers a higher dose during each treatment session while reducing the total number of fractions, has been increasingly adopted in breast cancer care.
However, its use for locoregional treatment has remained less frequent than its use for breast irradiation alone. One of the principal concerns has been the possibility of increased morbidity, particularly arm lymphedema, when regional lymph nodes are included in the treatment field.
For patients with node-positive or otherwise high-risk breast cancer, locoregional radiotherapy is an important part of adjuvant treatment. Establishing whether a shorter regimen can provide comparable safety and cancer control is therefore clinically relevant.
The Skagen Trial 1 was designed to determine whether 40 Gy delivered in 15 fractions caused no more lymphedema than 50 Gy delivered in 25 fractions three years after radiotherapy, without altering patterns of disease failure.
Inside the Skagen Trial 1
Skagen Trial 1 was a randomized Phase III noninferiority trial involving patients with high-risk breast cancer who had an indication for locoregional radiotherapy.
Between 2015 and 2021, 2,963 patients consented to participate across 17 centers. The intention-to-treat population included 2,908 patients.
Of these
- 1,444 patients received 50 Gy in 25 fractions.
- 1,464 patients received 40 Gy in 15 fractions.
The median age of participants was 57 years, with an age range of 23 to 86 years.
The primary endpoint was arm lymphedema. Based on an expected three-year lymphedema rate of 10% with the standard regimen, noninferiority was defined as no more than a five-percentage-point excess incidence with the 40 Gy regimen.
A Shorter Schedule Without More Lymphedema
At a median follow-up of 4.1 years, the three-year rate of arm lymphedema was:
- 9.4% among patients receiving 50 Gy in 25 fractions.
- 8.0% among patients receiving 40 Gy in 15 fractions.
The odds ratio was 0.84, with a 95% confidence interval of 0.62 to 1.14 and a P value of .27.
The result remained within the predefined five-percentage-point noninferiority margin, demonstrating that the hypofractionated regimen did not result in more arm lymphedema than the standard schedule.
Rather than showing an increase in this clinically important complication, the observed lymphedema rate was numerically lower in the 40 Gy group, although the trial was designed to establish noninferiority rather than superiority.
Cancer Control Remained Comparable
The investigators also assessed whether reducing the number of fractions affected recurrence or survival outcomes.
The median follow-up for cancer outcomes was 5.25 years. Within eight years, there were no differences between the randomized treatment groups in locoregional recurrence, distant recurrence, breast cancer mortality, or all-cause mortality.
The hazard ratios were:
- 0.96 for locoregional recurrence.
- 1.10 for distant recurrence.
- 1.25 for breast cancer mortality.
- 1.08 for all-cause mortality.
The corresponding confidence intervals showed no differences according to treatment assignment.
These findings indicate that delivering locoregional radiotherapy as 40 Gy in 15 fractions did not compromise the pattern of cancer failure compared with the established 50 Gy in 25 fractions regimen.
A More Convenient Approa ch to Regional Treatment
The results address one of the central questions surrounding moderate hypofractionation in patients requiring locoregional breast cancer radiotherapy.
The shorter regimen reduced the number of treatment fractions from 25 to 15 while maintaining comparable rates of lymphedema, locoregional control, distant control, breast cancer mortality, and overall mortality.
For patients, fewer treatment sessions can reduce the practical burden associated with repeated hospital visits. For radiotherapy departments, a shorter course can also support more efficient use of treatment capacity. The Skagen Trial 1 provides randomized evidence that this reduction in treatment fractions can be achieved without increasing lymphedema or compromising the measured cancer outcomes.
Skagen Trial Strengthens the Case for Hypofractionation
The investigators concluded that 40 Gy in 15 fractions did not result in more lymphedema than 50 Gy in 25 fractions when used for locoregional radiotherapy in high-risk breast cancer.
No differences were identified between the treatment groups in locoregional recurrence, distant recurrence, breast cancer mortality, or all-cause mortality.
The findings support moderate hypofractionation as a safe and effective locoregional radiotherapy approach for patients with high-risk breast cancer.
Written by Nare Hovhannisyan, MD
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