onc brain

Phase III noninferiority RCT, 17 centers, accrual 2015-2021. ITT cohort n=2,908 (1,444 at 50Gy, 1,464 at 40Gy). Accrual continued until 3-year lymphedema estimates were reported in 1,012 patients.

High-risk breast cancer with an indication for locoregional radiotherapy, the population where nodal coverage has kept 25 fractions standard in Denmark. Median age 57 (range 23-86).

Standard arm 50Gy/25fx, experimental arm 40Gy/15fx, both delivered to the locoregional volume rather than breast or chest wall alone. That target volume is the whole point: it is where the morbidity concern lives.

Primary: arm lymphedema at 3 years, with an assumed 10% incidence under 50Gy/25fx and noninferiority predefined as maximum 5 percentage points excess. Cancer endpoints (locoregional recurrence, distant recurrence, breast cancer mortality, all-cause mortality) were assessed within 8 years.

Lymphedema 8.0% vs 9.4%, OR 0.84 (0.62-1.14), P=.27, comfortably inside the margin. Cancer-outcome HRs are tabulated above and show no difference by random assignment.

The UK hypofractionation programme (START A/B, then FAST-Forward) established 40Gy/15fx and shorter for breast and chest wall, but node-positive patients receiving comprehensive regional coverage were a small fraction, which left the nodal question open. Skagen 1 tests exactly that gap prospectively with morbidity as the primary endpoint.

Median lymphedema follow-up of 4.1 years captures the 3-year endpoint but not the later plateau, and the abstract reports no brachial plexopathy, shoulder, cardiac, or pulmonary late toxicity. The BC mortality HR 1.25 (0.93-1.66) runs the wrong way with a CI that does not exclude harm; the trial was sized for lymphedema, not survival.

The trial removes the specific objection that blocked hypofractionated nodal RT rather than merely adding another positive fractionation result. It does not settle very-long-term arm and shoulder function, nor whether the same holds with a simultaneous integrated boost or in reconstructed chest walls.

Phase III, prespecified noninferiority margin met on the morbidity endpoint that blocked nodal hypofractionation, with 8yr recurrence and mortality HRs showing no difference.