Background
Phase 3 noninferiority RCT (17 centers); intention-to-treat N=2908; high-risk, predominantly node-positive breast cancer with an indication for locoregional (including regional nodal) radiotherapy; moderate hypofractionation vs standard fractionation; randomized 1464 (40 Gy) vs 1444 (50 Gy); median age 57.
Results
Interventions and follow up: Arm A: Hypofractionated locoregional radiotherapy, 40 Gy in 15 fractions (n=1464)
Arm B: Standard locoregional radiotherapy, 50 Gy in 25 fractions (n=1444)
Primary endpoint: Arm lymphedema at 3 years (noninferiority margin +5 percentage points, assuming 10% with 50 Gy)
mFollow up: 4.1 yr (lymphedema); 5.25 yr (cancer outcomes)
Results: Lymphedema (3-yr): 9.4% (50 Gy) vs 8.0% (40 Gy); OR 0.84 (95% CI 0.62–1.14); P=.27 — within the +5-point noninferiority margin
Locoregional recurrence (8-yr HR): 0.96 (95% CI 0.62–1.51)
Distant recurrence (8-yr HR): 1.10 (95% CI 0.89–1.37)
Breast cancer mortality (8-yr HR): 1.25 (95% CI 0.93–1.66)
All-cause mortality (8-yr HR): 1.08 (95% CI 0.85–1.36) — all differences non-significant
Arm B: Standard locoregional radiotherapy, 50 Gy in 25 fractions (n=1444)
Primary endpoint: Arm lymphedema at 3 years (noninferiority margin +5 percentage points, assuming 10% with 50 Gy)
mFollow up: 4.1 yr (lymphedema); 5.25 yr (cancer outcomes)
Results: Lymphedema (3-yr): 9.4% (50 Gy) vs 8.0% (40 Gy); OR 0.84 (95% CI 0.62–1.14); P=.27 — within the +5-point noninferiority margin
Locoregional recurrence (8-yr HR): 0.96 (95% CI 0.62–1.51)
Distant recurrence (8-yr HR): 1.10 (95% CI 0.89–1.37)
Breast cancer mortality (8-yr HR): 1.25 (95% CI 0.93–1.66)
All-cause mortality (8-yr HR): 1.08 (95% CI 0.85–1.36) — all differences non-significant
Adverse events
Primary toxicity endpoint (arm lymphedema, 3-yr): 8.0% (40 Gy) vs 9.4% (50 Gy) — not increased with hypofractionation
Late normal-tissue effects: no significant difference between fractionation schedules
Note: axillary lymph-node dissection (not fractionation) was the dominant driver of lymphedema risk
Late normal-tissue effects: no significant difference between fractionation schedules
Note: axillary lymph-node dissection (not fractionation) was the dominant driver of lymphedema risk
Conclusions
For locoregional (including regional nodal) radiotherapy of high-risk breast cancer, 40 Gy in 15 fractions did not cause more arm lymphedema than 50 Gy in 25 fractions, with no differences in locoregional recurrence, distant recurrence, breast cancer mortality, or all-cause mortality. The trial supports moderate hypofractionation for regional nodal irradiation, shortening treatment from 5 to 3 weeks.
Key Limitations
This is a noninferiority trial whose primary endpoint is a toxicity outcome (lymphedema) rather than an oncologic endpoint. Follow-up remains relatively short for late radiotherapy toxicity (cardiac events, second malignancies) and for breast cancer mortality; the numerically higher breast cancer mortality hazard ratio (1.25, 95% CI crossing 1) is a signal flagged at ESTRO 2025 that warrants longer follow-up. Wide confidence intervals limit definitive conclusions, and the population was predominantly Danish/Norwegian.
Clinical Context
Moderate hypofractionation (40 Gy/15 fx) is long established for whole-breast radiotherapy (START trials), but its safety for regional nodal irradiation was less certain. DBCG Skagen trial 1—together with HypoG-01 and RTOG/Alliance data—supports extending hypofractionation to locoregional and nodal radiotherapy, informing ASTRO and ESTRO adoption of hypofractionated regional nodal irradiation as a standard option.