Lymphedema Risk No Higher With 3-Week RT Regimen in Early Breast Cancer

A shorter radiotherapy (RT) course proved its mettle in early-stage breast cancer in terms of lymphedema risk, without negatively impacting survival outcomes, according to a phase III trial from France.

In the HypoG-01 study, a 3-week course of moderately hypofractionated locoregional RT was noninferior to 5 weeks of normofractionated RT for the primary endpoint of arm lymphedema, with 5-year rates of 33.3% and 32.8%, respectively (HR 1.02, 95% CI 0.83-1.26, P<0.001 for non-inferiority), reported Sofia Rivera, MD, PhD, of the Institut Gustave Roussy in Villejuif, France.

While there was no sign of a detrimental effect with hypofractionated RT, that cumulative lymphedema rate “is not negligible,” she said at the European Society for Medical Oncology (ESMO) annual congress in Barcelona. “That should be taken into account in future strategies and future trials.”

Rivera pointed out that the rate of shoulder range-of-motion impairment at 5 years was also not negligible, at 19.6% versus 20.7% (HR 0.90, 95% CI 0.81-1.00).

There was no sign that the hypofractionated RT protocol (40 Gy in 15 fractions over 3 weeks) had a detrimental impact on secondary survival endpoints compared with normofractionated RT (50 Gy in 25 fractions over 5 weeks):

• Breast cancer-specific survival: HR 0.53 (95% CI 0.34-0.94)
• Overall survival: HR 0.59 (95% CI 0.37-0.93)
• Local recurrence-free survival: HR 0.62 (95% CI 0.32-1.00)
• Distant disease-free survival: HR 0.54 (95% CI 0.31-0.96)

“Nodal radiotherapy for breast cancer no longer needs 5 weeks,” Rivera concluded. “Because of the benefit to the patients, the shortening of the treatment, and the benefit in terms of decreased burden, we should now privilege the 3-week regimen — even for nodal radiotherapy — in breast cancer.”

ESMO-invited discussant Charlotte Coles, PhD, of the University of Cambridge in England, explained that hypofractionated RT “is efficacious, it has reduced or similar toxicity [as standard RT], reduces patient burden, which is so important, and reduces health system costs and increases equity of access.”

“We now have data from … really high-quality randomized trials,” Coles said. “We haven’t seen any statistical differences in late normal tissue effects, including lymphedema, and other cancer endpoints have been no different. So, I completely agree with my colleague that 5 weeks of nodal radiotherapy is no longer indicated, and 3-week nodal radiotherapy is the international standard of care.”

Moreover, Coles noted that there are ongoing trials testing ultra-hypofractionation (1-week RT to the regional node).

The HypoG-01 trial from the French UNICANCER network included 1,265 patients (mean age 58) from 29 centers who had surgery for T1-3, N0-3, M0 breast cancer, and who required nodal irradiation. They were randomized to receive either the moderated hypofractionated or normofractionated RT regimens; in either case, a boost could be given at the investigator’s discretion. Analyses were performed at a median follow-up of 4.8 years.

Arm lymphedema was defined as at least a 10% increase in arm circumference 15 cm proximal and/or 10 cm distal of the olecranon relative to baseline, as compared with the contralateral circumference.

A majority (55%) underwent lumpectomy while the remaining underwent mastectomy; 82% had axillary clearance. RT was delivered either by intensity-modulated RT or 3D-conformal RT. The vast majority of patients had either preoperative or adjuvant chemotherapy, and over 89% had adjuvant endocrine therapy.

Regarding safety, the percentage of grade ≥3 adverse events (AEs) was similar in the hypofractionated RT and normofractionated RT arms (12.7% and 12.6%), with 17 and 15 patients, respectively, experiencing serious AEs. There were few cardiac disorders (a total of 2%), and the most frequent AEs were fatigue, fibrosis, pain, and radiation skin injury, with percentages similar between the two arms.

HypoG-01 has an estimated study completion date of September 2030.

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