TOPLINE

Hypofractionated locoregional radiotherapy using 40Gy in 15 fractions over 3 weeks does not increase the odds of patients with high-risk breast cancer having more arm lymphedema vs standard 50Gy in 25 fractions over 5 weeks. At 3 years, lymphedema rates were 8.0% with hypofractionation vs 9.4% with standard fractionation, well within the prespecified noninferiority margin, with no differences in locoregional recurrence, distant recurrence, or all-cause mortality between treatment arms.

METHODOLOGY

• For locoregional radiotherapy of high-risk patients, two trials tested 43.5Gy in 15 fractions against 50Gy in 25 fractions in patients who underwent lumpectomy and mastectomy, reporting no differences in locoregional recurrences and acute and late morbidities at 5-year follow-up. The Danish Breast Cancer Group Skagen trial 1 was initiated to test whether 40Gy in 15 fractions over 3 weeks did not cause more arm lymphedema than 50Gy in 25 fractions over 5 weeks at 3 years after radiotherapy without compromising the pattern of failure in patients with high-risk breast cancer requiring locoregional radiotherapy.
• Researchers conducted Skagen trial 1, a multicenter, phase 3, noninferiority, open-label, randomized controlled trial, across 17 centers in Denmark and six other countries. They randomly assigned 2908 patients with high-risk breast cancer 1:1 to receive either standard 50Gy in 25 fractions or experimental 40Gy in 15 fractions for locoregional radiotherapy. Most radiotherapy was delivered using 3D-conformal techniques with two tangential fields for the breast/chest wall, supplemented by anterior-posterior periclavicular fields.
• Participants included women at least 18 years of age who underwent lumpectomy or mastectomy for early breast cancer with an indication for locoregional radiotherapy, including those with operable disease at diagnosis and those with locally advanced breast cancer who became operable after neoadjuvant chemotherapy. The primary endpoint was arm lymphedema defined as ≥ 10% increased circumference measured in the ipsilateral arm 15 cm proximal and/or 10 cm distal to the olecranon compared with the contralateral arm. Noninferiority was predefined as maximum 5% excess incidence with 40Gy compared with 50Gy at 3 years.
• Morbidity evaluations and breast photographs were performed at baseline and at yearly follow-up visits from years 1-5 and at 10 years after radiotherapy, with median follow-up for morbidities of 4.1 years and median follow-up for overall survival of 5.25 years.

TAKEAWAY

• The 3-year rates of lymphedema were 9.4% with 50Gy in 25 fractions vs 8.0% with 40Gy in 15 fractions, with an odds ratio of 0.84 (P = .27), demonstrating noninferiority within the prespecified +5-percentage-point margin.
• Within 8 years, the hazard ratio (HR) was 0.96 for locoregional recurrence, 1.10 for distant recurrence, and 1.08 for all-cause mortality, with no significant differences by random assignment.
• Among patients who underwent axillary lymph node dissection, the 3-year lymphedema risk was 12.3% with 50Gy vs 10.1% with 40Gy (HR for 5 years, 0.97), whereas those with sentinel node biopsy only had a 3-year risk of 2.1% vs 2.4% (HR for 5 years, 1.08).
• The 5-year risk for breast cancer mortality was significantly higher with 40Gy at 7.2% vs 5.1% with 50Gy, with a risk difference of 2.1% (P = .26), though the HR within 8 years was 1.25 and not statistically significant.

IN PRACTICE

“The trial confirms that moderately hypofractionated locoregional radiotherapy of high-risk early [breast cancer] did not increase the risk of lymphedema, neither at 3 years nor during the initial 5-year period,” the authors of the study wrote.

SOURCE

Birgitte V. Offersen, MD, PhD, Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark, led the study. It was published online on July 23 in Journal of Clinical Oncology.

LIMITATIONS

According to the authors, the primary endpoint of lymphedema was evaluated only by measuring arm circumference, while more advanced methods were not used, which may not show the full picture of the patient burden from lymphedema and may overestimate or underestimate the problem. The subgroup analysis using breast cancer mortality as the endpoint was not preplanned but deemed relevant for a better understanding of the short-term breast cancer mortality results. The trial accrued patients from few departments with no hesitation in including patients with large breasts, smoking, chemotherapy, or a high nodal burden, which may affect the generalizability of the findings to other populations or settings.

DISCLOSURES

The study received support from grants provided by the Danish Cancer Society. Offersen disclosed having no relevant conflicts of interest related to this work. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.