- Moderate hypofractionation in locoregional radiotherapy was adopted by North American cancer centers during the COVID pandemic as a means to reduce breast cancer patients’ daily attendance.
- In a phase III trial, the 3-year rates of arm lymphedema were similar with the standard radiotherapy dose of 50 Gy in 25 fractions over 5 weeks and the hypofractionated dose of 40 Gy in 15 fractions over 3 weeks.
- There were no differences in locoregional or distant recurrences, breast cancer mortality, or all-cause mortality between the two groups.
Hypofractionated locoregional radiotherapy for high-risk breast cancer was noninferior to standard fractionated radiotherapy for the 3-year incidence of arm lymphedema, with no significant differences in cancer outcomes, a Danish phase III trial showed.
Among over 2,900 patients, the 3-year rates of lymphedema were 9.4% with the standard radiotherapy dose of 50 Gy in 25 fractions over 5 weeks versus 8% with the hypofractionated dose of 40 Gy in 15 fractions over 3 weeks (OR 0.84, 95% CI 0.62-1.14, P=0.27), meeting the +5-percentage-point noninferiority margin, reported Birgitte V. Offersen, MD, PhD, of Aarhus University Hospital in Denmark, and colleagues.
There were no differences in locoregional or distant recurrences, breast cancer mortality, or all-cause mortality between the two groups, they noted in the Journal of Clinical Oncology.
These results were comparable to the similarly designed HypoG-01 trial from France, in which a 3-week course of moderately hypofractionated locoregional radiotherapy was noninferior to 5 weeks of normofractionated radiotherapy 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 noninferiority).
These studies “support the use of moderate hypofractionation for regional node irradiation,” wrote Elysia Donovan, MD, and Timothy J. Whelan, BM, BCh, both of McMaster University in Hamilton, Ontario, in an editorial accompanying the study. “Such an approach will lessen the burden of treatment for patients, improve convenience, and reduce healthcare costs. These findings will provide confirmation for centers that have already adopted moderate hypofractionation and should lead to change in practice in centers that are still using conventional fractionation.”
Offersen and colleagues noted that while moderate hypofractionation for whole-breast irradiation has been shown to be effective, there has been reluctance to use it for regional node irradiation due to concerns over morbidity — particularly lymphedema and brachial neuropathy.
Despite these concerns, moderate hypofractionation was adopted by centers in Europe and North America during the COVID-19 pandemic as a means to reduce patients’ daily attendance at cancer centers. However, the regimen after surgery for high-risk breast cancer “has been limitedly investigated,” the authors pointed out.
The Danish Breast Cancer Group Skagen trial 1 was conducted from March 2015 to June 2021 at 17 centers and included 2,908 patients in the intention-to-treat cohort (median age 57) — 1,444 who underwent standard fractionated radiotherapy and 1,464 who underwent hypofractionated radiotherapy.
Overall, 64.7% of patients had surgery at diagnosis followed by systemic therapies, while 35.3% had neoadjuvant chemotherapy followed by surgery and radiotherapy.
The median follow-up for cancer outcomes was 5.25 years. Within 8 years, the hazard ratio was 0.96 for locoregional recurrence (95% CI 0.62-1.51), 1.10 for distant recurrence (95% CI 0.89-1.37), 1.25 for breast cancer mortality (95% CI 0.93-1.66), and 1.08 for all-cause mortality (95% CI 0.85-1.36) — “thus all with no differences by random assignment,” Offersen and team wrote.
However, they noted that the risk of breast cancer mortality was significantly higher with hypofractionated radiotherapy at 5 years, with rates of 7.2% versus 5.1% with standard fractionated radiotherapy.
“It could be a concern that the antitumor dose is lower using [40 Gy in 15 fractions versus 50 Gy in 25 fractions],” they observed. “However, our 5-year finding is not supported by several other trials.”
They also pointed out that patients were well balanced regarding patient, tumor, and treatment characteristics, making it unlikely that the higher 5-year breast cancer mortality rate was caused by these factors.
“It is expected that there were no differences in the systemic adjuvant therapies, which was also supported by no differences in distant failures,” they added. “It appears most likely that the 5-year finding is only transient and disappears with more events.”
Offersen and colleagues acknowledged that the trial had some limitations, including the fact that its primary endpoint of lymphedema was evaluated only by measuring the arm circumference, while more advanced methods were not used.
“Therefore, the trial does not show the full picture of the patient burden from lymphedema, and our findings may overestimate or underestimate the problem,” they wrote.
