Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer (CHN HYPOPMRT): 10-year outcomes from a randomised, non-inferiority, open-label, phase 3 trial.
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BACKGROUND: Hypofractionated radiotherapy is an established alternative to conventional fractionation for breast cancer, but long-term evidence after mastectomy with regional nodal irradiation is scarce. We aimed to assess the long-term efficacy and adverse event profile of hypofractionated versus conventional fractionated postmastectomy radiotherapy in high-risk breast cancer. METHODS: This randomised, non-inferiority, open-label, phase 3 trial was done at a national cancer centre in China. Eligible patients were women aged 18-75 years with high-risk breast cancer who had undergone modified radical mastectomy and axillary dissection with a Karnofsky performance score 60% or higher. Participants were randomly assigned (1:1) to conventional fractionated radiotherapy (50 Gy in 25 fractions over 5 weeks) or hypofractionated radiotherapy (43·5 Gy in 15 fractions over 3 weeks) to the chest wall and supraclavicular region, using a computer-generated sequence with concealed allocation and no masking. The primary endpoint was 5-year cumulative incidence of locoregional recurrence, analysed in the modified intention-to-treat population (including all eligible patients who underwent randomisation, but excluding those who were considered ineligible or withdrew consent after randomisation) and a 5% margin was used to establish non-inferiority. In this prespecified long-term analysis, outcomes at 10 years were analysed without additional confirmatory non-inferiority testing. Safety was analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00793962, and is closed to enrolment. FINDINGS: Between June 12, 2008, and June 16, 2016, 2157 patients were assessed for eligibility. 1337 were excluded and 820 patients were enrolled and randomly assigned (414 to conventional fractionated radiotherapy and 406 to hypofractionated radiotherapy). Five patients were excluded in each group and 810 were included in the analyses (409 to conventional fractionated radiotherapy and 401 to hypofractionated radiotherapy). Median follow-up was 11·5 years (IQR 9·6-13·8). Median patient age was 49 years (range 24-74), and 761 (94%) patients had stage III disease. All patients were female, and data on race and ethnicity were not collected. At 10 years, cumulative locoregional recurrence was 10·3% (95% CI 7·3-13·3) with conventional fractionated radiotherapy and 12·0% (8·8-15·2) with hypofractionated radiotherapy (hazard ratio 1·19, 95% CI 0·79-1·82). The most common grade 3 adverse events at 10 years were ischaemic heart disease (five [1%] of 409 patients in the conventional fractionated radiotherapy group vs five [1%] of 401 patients in the hypofractionated radiotherapy group), lymphoedema (four [1%] vs three [<1%]), shoulder dysfunction (two [<1%] vs one [<1%]), and skin adverse events (none vs one [<1%]). No grade 4-5 events, brachial plexopathy, serious adverse events, or treatment-related deaths occurred. INTERPRETATION: Hypofractionated postmastectomy radiotherapy provided durable locoregional control with no increase in severe late adverse events compared with conventional fractionation, supporting its use as a more time-efficient option than conventional fractionated radiotherapy. FUNDING: Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China, National High Level Hospital Clinical Research Funding, Cooperation Fund of CHCAMS, and CAMS Innovation Fund for Medical Sciences.