Results of the HypoG-01 study demonstrated that moderately hypo-fractionated loco-regional radiotherapy is non-inferior to normo-fractionated radiotherapy in terms of arm lymphedema risk in early breast cancer and did not lead to unfavourable safety or overall survival concerns.
Hypofractionated (HF) radiation therapy (RT) is the standard regimen for whole breast RT but normo-fractionated (NF) RT using 50 Gy/25 fractions is still standard in most countries for loco-regional early breast cancer (EBC). HypoG-01, a UNICANCER, open-label, multicentre, randomised phase III trial, assessed non-inferiority of HF RT with 40 Gy/15 fractions (2.67 Gy/fraction) versus NF RT 50 Gy/25 fractions (2.0 Gy/fraction).
HypoG-01 is a randomised open-label phase III study conducted in 29 French hospitals. Adult women with invasive early breast cancer (stage T1-3 N0-3 M0) who had undergone mastectomy or lumpectomy were eligible to participate if there was an indication for regional lymph node irradiation. Patients could be included regardless of the hormone receptor status of the tumour. Participants were randomised 1:1 between hypofractionation (40 Gy divided into 15 fractions in 3 weeks) or standard fractionation (50 Gy divided into 25 fractions in 5 weeks) of radiotherapy. Boost irradiation was optional.
The primary outcome was the cumulative incidence of arm lymphedema over 3 years, with a non-inferiority margin of 1.545. Lymphedema of the arm was defined as a ≥10% increase in arm circumference 15 cm proximal and/or 10 cm distal of the olecranon relative to baseline, compared to the contralateral circumference. Secondary outcome measures were breast cancer-specific survival (BCSS), overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DDFS) and the cumulative incidence of limited range of motion of the shoulder (defined as a decrease ≥25° in active abduction or flexion of the arm). The safety of the treatments was also investigated.
A total of 1,265 patients were randomised, of whom 1,221 patients belonged to the ‘per-protocol’ population: 614 in the group that received hypofractionated radiotherapy and 607 in the group that received radiotherapy according to the standard radiation schedule. The median age of participants was 58 years (range: 23-91). Of these, 45.0% had undergone mastectomy and 82.2% had undergone axillary lymph node dissection. The median follow-up time was 4.8 years.
The cumulative incidence of arm lymphedema over 5 years did not differ between treatment groups (33.3% vs. 32.8%; HR[95%CI]: 1.02[0.83-1.26], p< 0.001). The upper limit of the 90% CI was within the non-inferiority margin, meaning that hypofractionation is not inferior to standard fractionation of radiotherapy. In addition, hypofractionated radiotherapy had no adverse effect on 5-year BCSS (HR[95%CI]: 0.53[0.30-0.94]), 5-year OS (HR[95%CI]: 0.59[0.37-0.93]), 5-year LRFS (HR[95%CI]: 0.62[0.32-1.00]) and 5-year DDFS (HR[95%CI]: 0.54[0.31-0.96]). Also, no clear difference was found in the cumulative incidence of limited range of motion of the shoulder between the two groups (19.6% vs. 20.7%; HR[95%CI]: 0.90[0.81-1.00]). However, the study was not powered to demonstrate a difference in survival or range of motion of the shoulder.
The most common adverse events (AEs) were radiation skin injury (82 vs. 89%), pain (65 vs. 69%), fatigue (64 vs. 64%) and fibrosis (48 vs. 44%). Grade ≥3 AEs occurred in a similar percentage of patients in the hypofractionated radiotherapy group and the standard radiotherapy group (12.7% vs. 12.6%). A serious AE occurred in 32 patients (2.6%), of which 17 in the group that received hypofractionated radiotherapy and 15 in the group that received radiotherapy according to the standard radiation schedule. Only three of the serious AEs (radiation pneumonitis, radiodermatitis and lymphedema of the arm) were related to radiotherapy. No grade 5 AEs were reported.
This randomised phase III study (HypoG-01) shows that moderately hypofractionated, locoregional irradiation of the lymph nodes is not inferior to radiotherapy according to the standard radiation schedule with regard to the risk of lymphedema of the arm in women with early breast cancer. Hypofractionation of locoregional irradiation of the lymph nodes has no adverse effect on survival, range of motion of the shoulder and safety.
Reference
Rivera S, et al. Locoregional hypo vs normofractionated RT in early breast cancer: 5 years results of the HypoG-01 phase III UNICANCER trial. Presented at ESMO 2024; Abstract 231O.
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