26 Gy in 5 fractions non-inferior to 40 Gy in 15 fractions for breast cancer recurrence at 10 years

This phase 3 randomised controlled trial, conducted across 97 hospitals in the UK, evaluated two hypofractionated radiotherapy schedules against a standard regimen in patients with early breast cancer. A total of 4110 participants were enrolled, with 4087 included in the intention-to-treat population for the 10-year analysis. Eligible patients were aged 18 years or older with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy. The interventions were 26 Gy in five fractions over 1 week and 27 Gy in five fractions over 1 week, compared with the standard 40 Gy in 15 fractions over 3 weeks. Median follow-up was 10.1 years (IQR 10.0-10.2) for the main trial and 7.0 years (IQR 6.2-7.1) for a nodal substudy that included 466 patients.

The primary outcome was non-inferiority of ipsilateral breast recurrence at 5 years, but the main results reported here focus on 10-year outcomes. For 10-year ipsilateral breast recurrence, the rates were 3.6% (95% CI 2.7-4.9) for 40 Gy, 2.9% (95% CI 2.1-4.0) for 27 Gy, and 2.1% (95% CI 1.5-3.1) for 26 Gy. Absolute events were 45 in the 40 Gy group, 41 in the 27 Gy group, and 30 in the 26 Gy group. These results indicate that both hypofractionated schedules are at least as effective as the standard regimen in controlling local recurrence.

Key secondary outcomes included 10-year clinician-reported moderate or marked breast or chest wall effects. Rates were 13.1% for 40 Gy (100 events in 765 participants), 19.3% for 27 Gy (157 events in 814 participants), and 14.4% for 26 Gy (111 events in 770 participants). Notably, the 27 Gy schedule showed a higher rate of these effects compared with 40 Gy, while 26 Gy had a rate similar to the standard. Another secondary outcome was 5-year efficacy in patients requiring axillary treatment, with 32 locoregional recurrences reported overall. The authors note that efficacy data for the axillary nodal radiotherapy setting are reassuring, but the sample size limits precision of estimation for this subgroup on its own.

Safety and tolerability were assessed primarily through clinician-reported moderate or marked breast or chest wall effects, as described above. No serious adverse events were reported in the provided data. Discontinuations included 23 patients who withdrew consent for data use and were excluded from analyses. The authors conclude that 26 Gy in five fractions over 1 week is safe and efficacious for adjuvant radiotherapy to the breast or chest wall, supporting its use as a standard of care.

Compared with prior landmark studies, this trial provides long-term follow-up data confirming the non-inferiority of ultra-hypofractionated schedules. Previous trials, such as the UK START trials, established hypofractionation (e.g., 40 Gy in 15 fractions) as standard. This study extends that evidence to a 5-fraction regimen, offering a more convenient option for patients.

Key methodological limitations include the sample size limiting precision for the axillary nodal radiotherapy subgroup. Additionally, the open-label design and potential for observer bias in clinician-reported outcomes are inherent limitations, though not explicitly stated in the provided data. The study was funded by the UK National Institute for Health and Care Research.

Clinical implications: For patients with early breast cancer requiring adjuvant radiotherapy, the 26 Gy in 5 fractions schedule is a safe and effective alternative to the standard 40 Gy in 15 fractions, with comparable local control and similar rates of moderate or marked breast or chest wall effects. This shorter regimen may improve patient convenience and resource utilization. However, questions remain regarding its efficacy in patients requiring axillary nodal irradiation, as the data for that subgroup are less precise. Further research with larger samples in that setting is warranted.