HypoG-01: 3-week nodal radiotherapy non-inferior for arm lymphoedema in high-risk early breast cancer

Evidence before this study

Approximately one-third of breast cancer patients are diagnosed with regional-stage disease and require regional nodal irradiation as part of their treatment to reduce the risk of recurrence and improve survival. Hypofractionated radiotherapy has been shown to be non-inferior to the historical 50 Gy in 25 fractions over 5 weeks for whole breast irradiation with level 1A evidence, introducing a major shift in modern breast cancer management when no regional irradiation was needed. The UK START trials established that 40 Gy in 15 fractions is non-inferior to 50 Gy in 25 fractions for efficacy outcomes and is associated with lower rates of late normal tissue effects. We searched PubMed on Oct 2, 2025, using the search terms “breast cancer”, “regional nodal irradiation”, “hypofractionation”, and “randomised clinical trials” and combinations thereof. We searched for original research articles and reviews published in English between Jan 1, 1980, and April 22, 2020. We found the primary endpoint report of three randomised studies (one phase 2, two phase 3) testing adjuvant locoregional hypofractionated radiotherapy against 5-week regimens, ranging in sample size from 50 to 820 patients. All offered consistent support for hypofractionation but only the smallest one included irradiation of the internal mammary chain and a small proportion of patients were irradiated on the lower axilla.

Previously, the Early Breast Cancer Trialists' Collaborative Group meta-analysis has shown that regional irradiation improves survival in women receiving effective local and systemic therapies. As none of the included trials used hypofractionation, the morbidity and risk/benefit of hypofractionated regional irradiation remained to be evaluated.

Added value of this study

The UNICANCER HypoG-01 trial, alongside the Danish Breast Cancer Group Skagen trial 1, are the first phase III randomised controlled trials to publish 5-year outcome data specifically comparing locoregional radiotherapy over 3 weeks with 40 Gy in 15 fractions versus 5 weeks with 50 Gy in 25 fractions. HypoG-01 shows non-inferiority of the shorter regimen in terms of ipsilateral arm lymphoedema with a reassuring safety profile. Additionally, HypoG-01 trial provides contemporary evidence confirming the safety of moderately hypofractionated radiotherapy for comprehensive regional nodal volumes, including the internal mammary nodes (IMN) on survival endpoints: locoregional relapse-free survival, distant disease-free survival, breast cancer specific-survival, and overall survival. While 40 Gy in 15 fractions has been the standard of care for nodal irradiation in the UK since NICE guidance in 2009, based on the 5-year results of the START B trial, IMN irradiation was not carried out in the trial. Hypofractionation adoption for IMN irradiation became widespread in the UK following the 2016 consensus of the UK Royal College of Radiologists. HypoG-01 provides robust, prospective data from a phase 3 trial specifically designed to assess the lymphoedema risk of this modern treatment approach, confirming its safety and supporting its use as a global standard of care.

Implications of all the available evidence

HypoG-01 provides evidence that moderately hypofractionated, 3-week, locoregional radiotherapy is a safe alternative to historical 5-week radiotherapy for patients with high-risk early breast cancer requiring nodal irradiation. Survival outcomes in HypoG-01 are encouraging and should be integrated with evidence from efficacy-focused trials. Our findings contribute to a growing body of evidence supporting a shift in clinical practice towards a 3-week radiotherapy standard of care, offering substantial benefits to both patients and health-care systems, increasing treatment sustainability without compromising oncological outcomes.

Source: The Lancet