Session Item

Hypofractionated (HF) radiation therapy (RT) is the standard regimen for whole breast RT but normofractionated (NF) RT using 50 Gy/25 fr is still standard for loco-regional early breast cancer (EBC) due to possible higher risk of morbidity. HypoG-01, a UNICANCER, non-inferiority, open-label, multicenter, randomized phase III trial (NCT03127995), conducted in parallel with the DBCG Skagen trial 1, assessed if HF RT with 40 Gy/15 fr (2.67 Gy/fr) would not result in more arm lymphedema over time than NF RT 50 Gy/25 fr (2.0 Gy/fr).

Patients (pts) were ≥18 years old operated for T1-3, N0-3, M0 breast cancer. All pts received nodal and thoracic wall or breast RT. Tumor-bed boosts and nodal levels treated were decided according to local guidelines, target volumes delineated according to ESTRO consensus, RT techniques at the investigators discretion and each center validated a dummy run. The primary endpoint was time to occurrence of arm lymphedema after RT defined as ≥10% increase in arm circumference 15 cm proximal and/or 10 cm distal of the ipsilateral olecranon relative to baseline, compared to the contralateral circumference. The primary statistic test was stratified one-sided logrank test: 5% significance level in per-protocol population (PPP) with a pre-specified non-inferiority margin of 1.545. Range of shoulder motion (ROM) impairment was a reduction ≥25° in active abduction or flexion.

1265 pts were randomized to NF or HF RT from Sep 2016 to Mar 2020 with 1221 in the PPP (HF group 614 pts (50.3%); NF group 607 (49.7%)), 5 consent withdrawn and 39 major deviations. Median age was 58 years (range 23-91), surgery included mastectomy (501 pts; 45%) and axillary clearance (921 pts; 82.8%) with a mean number of 12 removed nodes. Sequential (67.8%) or integrated (32.2%) tumor-bed boost was used in 596 pts (48.8%). With a median follow-up of 3.1 years (IQR 3.1-3.2), 251 lymphedemas occurred among the 1113 pts with baseline and end of treatment lymphedema measurements. HF was non-inferior to NF RT in terms of risk of lymphedema (HR=1.07; 90% CI 0.86-1.34, non-inferiority p=0.003; Fig 1). The 3-year rate of ipsilateral arm lymphedema was 24.1% (95% CI 20.3-28.4) in HF group vs 22.6% (95% CI 18.9-26.9) in NF. The intention-to-treat (ITT) analysis led to a similar HR=1.08 (90% CI 0.86-1.35; non-inferiority p=0.004). ROM impairment occurred in 256 pts with a time to ROM impairment HR=0.91 (90% CI 0.73-1.13) in HF vs NF. In ITT, 23 pts had at least 1 SAE (HF: 13, NF: 10), maximum grade 3, mostly not treatment-related. Further secondary endpoints results will be presented at the meeting.

Moderately HF loco-regional RT is non-inferior to NF RT in terms of lymphedema risk in EBC. Together with the Skagen 1 trial, this study provides level 1A evidence supporting the use of 40 Gy/15 fr for loco-regional radiation therapy in EBC with respect to arm lymphedema risk.