Hypofractionated Radiation Noninferior to Normofractionated Radiation in Early Breast Cancer

“It's important to note that no detrimental effect of hypofractionated radiotherapy was seen regarding the safety profile, regarding all the criteria on survival,” according to Sofia Rivera, MD, PhD.

Moderately hypofractionated, locoregional radiation therapy was noninferior to normofractionated radiation therapy regarding the risk for lymphedema in patients with early breast cancer, according to findings from the phase 3 HypoG-01 trial (NCT03127995) presented at the 2024 European Society of Medical Oncology (ESMO) Congress.

“It's important to note that no detrimental effect of hypofractionated radiotherapy was seen regarding the safety profile, regarding all the criteria on survival,” Sofia Rivera, MD, PhD, 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 3 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 (P < .001), with 275 events related to arm lymphedema occurring among the 1113 patients in the study with baseline and end of radiotherapy arm measurements. The cumulative 5-year rate of arm lymphedema was 33.3% (95% CI, 28.7%-38.4%) in the hypofractionated arm vs 32.8% (95% CI, 27.9%-38.1%) in the normofractionated arm.

“That is not negligible, because it’s around 33% of the patients who have a cumulative incidence of arm 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 HR for breast cancer-specific survival was 0.53 (95% CI, 0.30-0.94), and the HR for overall survival was 0.59 (95% CI, 0.37-0.93). Rivera noted that this finding was “interesting…even though we had no statistical power to analyze that specifically, as this is a secondary end point.”

There was also no sign of detrimental effect of hypofractionated radiotherapy on local recurrent-free survival (HR = 0.62; 95% CI, 0.32-1.00) and distant disease-free survival (HR = 0.54; 95% CI, 0.31-0.96).

Additionally, hypofractionated radiotherapy did not pose a detrimental effect on patients regarding shoulder range of motion. In the per-protocol analysis, the cumulative 5-year range of motion impairment rate was 19.6% (95% CI, 16.1%-23.7%) in the hypofractionated arm vs 20.7% (95% CI, 17.2%-24.8%) in the normofractionated arm. The HR for the cumulative range of shoulder motion impairment rate was 0.90 (95% CI, 0.81-1.00).

There were limited adverse events in both arms and no sign of detrimental effect of hypofractionated radiotherapy. In total, 12.7% (n = 80) of patients in the hypofractionated group experienced a grade 3 or higher adverse event compared with 12.6% (n = 79) in the normofractionated group. Of note, there were no grade 5 events.

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

At 5 years, cardiac disorders were limited between patients assigned hypofractionated radiotherapy and those assigned normofractionated radiotherapy (2% vs 1%, respectively). The most common adverse events, which were balanced between both arms, included fibrosis, fatigue, radiation skin injury, and pain, Rivera noted.

Background and Study Design

Rivera mentioned how 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 3 weeks,” she said.

There is limited evidence for patients who require nodal irradiation, 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, 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 T1-3, N0-3, M0 breast cancer with an indication for regional nodes radiotherapy. In particular, 1265 patients were enrolled from 29 centers across France, including cancer centers, university hospitals, and private clinics between September 2016 and March 2020.

Patients in the trial were randomized 1:1 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 investigator’s choice of boost, if necessary.

The analysis for the primary endpoint included 562 patients in the hypofractionated arm and 551 in the normofractionated arm.

The primary end point of the trial was 3-year cumulative incidence of arm lymphedema, defined as a 10% or more increase in arm circumference 15 cm proximal and/or 10 cm distal of the olecranon relative to baseline, compared with the contralateral 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 3 years, is still counted in the cumulative incidence.”

Stratification was performed by mastectomy vs lumpectomy, radiotherapy technique, center of treatment, nodes cleared (0, 1-3, 4 or more), and BMI (25 or less, or greater than 35). Rivera noted that BMI was considered for stratification since BMI is “a risk factor for arm lymphedema.”

Secondary end points included overall survival, locoregional-free survival, distant disease-free survival, breast cancer-specific survival, and shoulder range of motion, with an impairment defined as a reduction of at least 25 degrees in active abduction or flexion.

A one-sided log-rank test was used at 5% significance in the per-protocol population and a prespecified noninferiority margin with a hazard ratio of 1.545.

Baseline and Treatment Characteristics

In the per-protocol population, the mean age was 58.5 years in the hypofractionated arm and 58.2 years in the normofractionated arm. 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 arms. Rivera noted a typical distribution regarding histology of breast cancer subtypes, with most patients in both groups having ductal histology.

Regarding treatment, less than half of patients in the hypofractionated and normofractionated arms underwent mastectomy (45.0% vs 45.1%, respectively). Most patients in the respective arms had axillary clearance (82.2% in each group). Radiotherapy was either delivered by intensity-modulated radiation therapy or 3D conformal radiotherapy, and less than half of patients had a boost on the breast.

Reference

Rivera S, Ghodssighassemabadi R, Brion T, et al. Locoregional hypo vs normofractionated RT in early breast cancer: 5 years results of the HypoG-01 phase I UNICANCER trial. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 231O