More Evidence Favors a Shorter Course of Post-Mastectomy RT

Hypofractionated post-mastectomy radiation therapy (RT) with breast reconstruction proved noninferior to standard RT when it came to reconstruction complications, high-grade toxicity, and local control, according to results from a phase III trial.

In the RT CHARM study, the reconstruction complication rate at 2 years was statistically no different, at 14% with the hypofractionated regimen versus 12% with conventional RT (P=0.0004 for noninferiority), reported Matthew Poppe, MD, of the University of Utah Huntsman Cancer Institute in Salt Lake City.

Additionally, he detailed at the American Society for Radiation Oncology (ASTRO) annual meeting in Washington, D.C., secondary endpoints showed no differences between groups for grade ≥3 acute or late complications of RT:

• Acute: 5% vs 7.7%, respectively
• Late: 6.1% vs 5.5%

As for the rate of local and locoregional recurrence, again there was no difference, Poppe observed, “with an overall low rate of recurrence in this population that is relatively higher risk because of their nodal positivity.” At 3 years, the short-course radiation arm had a recurrence rate of 1.5% compared with 1.9% in the conventional fractionation arm.

ASTRO-discussant Kathleen Horst, MD, of Stanford University in California, said that with the results from three randomized trials — RT CHARM along with FABREC and a trial from China — “we can now say that moderate, hypofractionated post-mastectomy radiation is safe compared to standard fractionation, with similar local regional recurrences, toxicity profiles, and reconstruction complications.”

Together, the trials enrolled over 2,000 patients, “with 50-60% being under 50 or premenopausal, and the majority receiving chemotherapy and regional nodal irradiation,” she said. “We now have data for implant-based reconstruction as well as autologous reconstruction.”

From 2018 to 2021, the RT CHARM study enrolled 898 patients (825 evaluable) with unilateral invasive breast cancer of any histology with positive lymph nodes or T3N0 disease at 209 centers in the U.S. and Canada. Patients with locally advanced disease were excluded.

Radiation had to start within 84 days of mastectomy or adjuvant chemotherapy, whichever was later. Patients were randomized 1:1 to either the hypofractionated RT regimen (42.56 Gy/16 fractions) or conventional RT (50 Gy/25 fractions). Minimum follow-up was 2 years.

Patients had a median age of 49 years, 9% were Black, 6% Hispanic, and 4% Asian. About 14% had a known genetic predisposition gene, 6% had diabetes, and two-thirds had a body mass index >25.

About 25% of patients underwent immediate reconstruction, two-thirds had implant-only reconstruction, and the remainder autologous reconstruction.

Regarding the primary endpoint of reconstruction complications (any reoperation or hospitalization considered nonroutine, and any Baker 3 or 4 contracture), Poppe noted that regardless of whether patients had immediate, delayed, autologous, or implant-based reconstruction, there was no difference between the hypofractionated and standard RT arms.

However, in subset analyses, researchers found a suggestion of an increased risk of complications with two-stage reconstruction and implant-only procedures, regardless of fractionation assignment.

For example, among patients who underwent conventional RT, the 2-year complication rates were 8.9% with autologous reconstruction versus 13.8% with implant-only reconstruction. Among patients who underwent hypofractionated therapy the rates were 8.5% and 17.1%, respectively. Multivariate analysis found that implant-only reconstruction was associated with a twofold increase in reconstruction complications versus autologous reconstruction (OR 0.49, 95% CI 0.30-0.80, P=0.0043).

Moreover, Poppe pointed out that among the various types of reconstruction techniques, the one with the highest risk of complications was the two-stage procedure involving the immediate insertion of a tissue expander, followed by a delayed implant.

“This may not be too surprising given that two-stage procedures give a double opportunity to have infection or wound healing problems, and using vascularized tissue with one’s own body decreases the risk of a complication over using foreign material,” Poppe said. “Cautious interpretation of these secondary results, however, is warranted, as patients were not randomized for the type and timing of reconstruction.”

In her discussion, Horst noted that analyses have shown a very slow uptake of hypofractionation over time. “Moreover, there is a slower uptake in younger patients, and Black and Hispanic patients compared to white and Asian patients,” she pointed out. “So, in thinking about the adoption of moderate hypofractionation after mastectomy, we need to make sure patients don’t get left behind.”

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