Hypofractionated RT Noninferior for Locoregional BC

BARCELONA, Spain — Hypofractionated radiotherapy is noninferior to conventional fractionation for the locoregional treatment of early breast cancer, suggested new results of a phase 3 trial.

Sofia Rivera, MD, PhD, presented these 5-year results of HypoG-01 at the European Society for Medical Oncology (ESMO) Annual Meeting 2024.

Rivera, who is an oncologist and radiotherapist, said these findings could change clinical practice, potentially making 3-week radiotherapy regimens a new standard for patients requiring nodal irradiation.

Study Rationale

Hypofractionated radiotherapy, which delivers larger doses per fraction over a shorter overall treatment time, has become the standard practice for whole breast irradiation in many countries, said Rivera, who is the head of the Radiotherapy Department of Gustave Roussy, Villejuif, France.

However, its use in locoregional treatment, including nodal irradiation, has remained limited because of concerns regarding increased toxicity, she said.

“When patients require nodal irradiation, we had no previous randomized trial focusing on nodal irradiation with modern techniques of radiotherapy,” Rivera explained during her talk. “The standard practice today is still 50 grays in 25 fractions over 5 weeks when irradiating the nodes.”

Study Design and Patient Population

The HypoG-01 trial, conducted by UNICANCER, aimed to address the research gap that Rivera described.

This open-label, multicenter, randomized, phase 3 trial enrolled 1265 patients across 29 centers in France between September 2016 and March 2020. Eligible patients were 18 years or older with T1-3, N0-3, M0 breast cancer requiring nodal irradiation.

Patients were randomized 1:1 to receive either hypofractionated radiotherapy (40 Gy in 15 fractions over 3 weeks) or conventional fractionation (50 Gy in 25 fractions over 5 weeks). Patients in both arms could receive an additional boost if clinically indicated.

The primary endpoint was the cumulative incidence of arm lymphedema at 3 years. During her talk, Rivera emphasized the importance of this metric and elaborated on its inclusion as a primary endpoint.

“We realized that arm lymphedema rarely completely disappears over time, and even when it decreases or disappears, that’s because the patients are under treatment with arm sleeves, compression arm sleeves, or physiotherapy,” she said.

Hypofractionated Radiotherapy Is Noninferior to Conventional Fractionation

With a median follow-up of 4.8 years, the trial demonstrated the noninferiority of hypofractionated radiotherapy vs conventional fractionation. The hazard ratio for arm lymphedema was 1.02 (90% CI, 0.83-1.26; noninferiority P < .001) in the per-protocol analysis.

“We have a noninferiority in terms of arm lymphedema of the hypofractionated radiotherapy compared to the normal fractionated radiotherapy,” Rivera reported. She noted, however, that the overall cumulative incidence of arm lymphedema at 5 years was substantial in both arms, at approximately 33%. “This is not negligible and should be taken into account in future strategies and future trials,” she emphasized in her talk.

Furthermore, the trial showed no evidence of detrimental effects from hypofractionated radiotherapy across secondary endpoints. In fact, some outcomes appeared to favor the hypofractionated regimen, although the study was not powered to show a statistically significant superiority. The hazard ratios were 0.62 (95% CI, 0.38-1.00) for locoregional relapse-free survival, 0.54 (95% CI, 0.31-0.96) for distant disease-free survival, and 0.59 (95% CI, 0.37-0.93) for overall survival.

Safety of Hypofractionated Radiotherapy for Locoregional Breast Cancer

The safety profile of hypofractionated radiotherapy was similar to that of conventional fractionation. Grade 3 or higher adverse events occurred in 12.7% and 12.6% patients in the hypofractionated and conventional arms, respectively. Only three radiotherapy-related serious adverse events were reported across both groups, and no grade 5 adverse events were reported.

“Cardiac disorders at 5 years were really limited,” Rivera noted, “and the most frequent side effects were, of course, fatigue, fibrosis, pain, and radiation skin injury with something very balanced between the two arms.”

Clinical Implications and Future Work

Rivera concluded her presentation with a strong recommendation: “Because of the benefits for the patients, the shortening of the treatment, and the decreased burden, I think we should now privilege the three-week regimen even for nodal radiotherapy in breast cancer.”

Professor Charlotte E. Coles, an independent expert from the University of Cambridge, Cambridge, England, echoed the recommendation that 3-week nodal radiotherapy should be used as the new standard of care.

“Hyperfractionation is efficacious, has reduced or similar toxicity, and reduces patient burden. It is very important that people can go back and get on with their lives quicker; it reduces health system cost, and it increases equity of access globally,” Coles emphasized during the discussion session at the meeting.

She also placed the findings from the HypoG-01 trial into the broader context of evolving breast radiotherapy practices.

“We now have data from more than 5800 participants in really high-quality randomized trials. We haven’t seen any statistical differences in late normal tissue effects, including lymphedema. And other cancer endpoints are also no different.”

Both experts noted that trials investigating even shorter courses of radiotherapy are ongoing, including trials of 1-week regimens for nodal irradiation.

Rivera reported financial relationships with Graegis Pharmaceuticals (scientific advisory board); Inca, Odyssea, Pfizer, and Eisai (institutional research and pedagogical funding); and Lilly, Eisai, Roche, Novartis, Pfizer, MSD, and Seagen (speaker honoraria). Coles reported no financial relationships.