Outcomes, Lymphedema Risk May Be Similar With Hypofractionated Versus Normofractionated Radiation in Early Breast Cancer

Hypofractionated radiation therapy was similar to normofractionated radiation therapy with regards to the risk for arm lymphedema early breast cancer, according to findings from the phase 3 HypoG-01 trial presented at the 2024 ESMO Congress.

Of note, hypofractionated radiation therapy refers to when the total dose of radiation is divided into larger doses, and treatments are given less often or once a day. This results in treatment delivery over a shorter period versus standard radiation therapy. Normofractionated radiation therapy is the standard method delivered over a longer period.

“It's important to note that no detrimental effect of hypofractionated radiotherapy was seen regarding the safety profile, regarding all the criteria on survival,” Dr. Sofia Rivera, of the Department of Oncology at Institut Gustave Roussy in Villejuif, France, said during the presentation. “Because of the benefit for the patients and the shortening of the treatment, the benefit in terms of decreased burden and the benefits for healthcare in general, I think we should now privilege the three weeks regimen, even for nodal radiotherapy, in breast cancer.”

With a median follow-up of 4.8 years, hypofractionated radiotherapy was noninferior to normofractionated radiotherapy, with 275 events related to group lymphedema (swelling from a buildup of lymph fluid in the body, often occurring in the groups and legs) occurring among the 1,113 patients in the study with baseline and end of radiotherapy group measurements. The cumulative five-year rate of group lymphedema was 33.3% in the hypofractionated group versus 32.8% in the normofractionated group.

“That is not negligible, because it’s around 33% of the patients who have a cumulative incidence of group lymphedema,” Rivera said. “So that should be taken into account in future strategies and future trials.”

There was also no sign of a detrimental effect of hypofractionated radiotherapy with regard to survival. The hazard ratio for breast cancer-specific survival was 0.53 (indicating a lower risk of the event), and the hazard ratio for overall survival (the time when a patient with cancer is still alive) was 0.59 (a similar lower risk in the event).

There was also no sign of detrimental effect of hypofractionated radiotherapy on local recurrent-free survival (the time a patient lives without the cancer returning to the same original location) and distant disease-free survival (the time after treatment that a patient survives without cancer spreading to other parts of the body).

Additionally, hypofractionated radiotherapy did not pose a detrimental effect on patients regarding shoulder range of motion. The cumulative five-year range of motion impairment rate was 19.6% in the hypofractionated group versus 20.7% in the normofractionated group.

There were limited side effects in both groups and no sign of detrimental effects of hypofractionated radiotherapy. In total, 12.7% of patients in the hypofractionated group experienced a grade 3 (severe) or higher adverse event compared with 12.6% in the normofractionated group. Of note, there were no grade 5 (death-causing) events.

Rivera noted that 32 patients (2.6%) had serious side effects, which were rather balanced between the hypofractionated and normofractionated groups (17 and 15, respectively). Three of these events were related to radiotherapy, with one of each event related to pneumonitis (inflammation of the lungs), skin injury and severe arm lymphedema.

At five years, cardiac disorders were limited between patients assigned hypofractionated radiotherapy and those assigned normofractionated radiotherapy (2% versus 1%, respectively). The most common side effects, which were balanced between both groups, included fibrosis (growth of fibrous tissue), fatigue, radiation skin injury and pain, Rivera noted.

Background and Study Design

Rivera mentioned how the practice has changed over the past few years in breast cancer radiotherapy, although the changes mainly affected the irradiation of the breast alone.

“We moved from 25 fractions/50 Gy over 5 weeks for almost all patients to moderately hypofractionated radiotherapy, roughly delivering the treatment over three weeks,” she said.

There is limited evidence for patients who require nodal irradiation (radiation targeting lymph nodes), especially as it pertains to modern techniques of radiotherapy. In addition, irradiating the nodes affects more areas than the target itself.

“When irradiating the nodes, we radiate larger volumes, including more lung, more heart and, of course, all the axillary regions (underarm areas), with a potentially higher risk of toxicity as we include more normal tissue and we give higher doses per fractions,” Rivera said.

In the HypoG-01 trial, researchers enrolled women aged 18 years and older who underwent surgery for breast cancer with an indication for regional nodes radiotherapy. In particular, 1,265 patients were enrolled between September 2016 and March 2020.

Patients in the trial were randomized to receive hypofractionated radiotherapy (40 Gy/15 fractions over 3 weeks) or normofractionated radiotherapy (50 Gy/25 fractions over 5 weeks). Both groups were allowed to receive a boost, if necessary.

The analysis of this study included 562 patients in the hypofractionated group and 551 in the normofractionated group.

The main focus of this trial was to assess the three-year cumulative incidence of arm lymphedema, defined as a 10% or more increase in arm circumference.

“In previous trials, sometimes it was the rate of arm lymphedema which was reported,” Rivera said. “But when discussing with our patients in designing the trial, we actually realized that arm lymphedema rarely completely disappears over time. Even when it decreases or disappears, that's because the patients are under treatment, either with arm sleeves, compression arm sleeves, or physiotherapy, so still with some need for medical care. So that's why we choose the cumulative incidence, so that a patient that has at some point an arm lymphedema, but does not have it at three years, is still counted in the cumulative incidence.”

Other areas of interest included overall survival, locoregional-free survival, distant disease-free survival, breast cancer-specific survival and shoulder range of motion.

Of the patients in the study, the mean age was 58.5 years in the hypofractionated group and 58.2 years in the normofractionated group. Most patients had a medium or large breast size, with a mean tumor size of 26.2 mm and 26.1 mm in the respective groups.

Regarding treatment, less than half of patients in the hypofractionated and normofractionated groups underwent mastectomy (removal of part or all of the breast; 45% versus 45.1%, respectively). Most patients in the respective groups had axillary clearance (surgical removal of lymph nodes from the underarm area; 82.2% in each group).

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