Hypofractionated Radiotherapy Has Excellent Risk-Benefit Profile in Brain Tumor Management

In patients with brain metastases, postoperative hypofractionated stereotactic radiotherapy (HSRT) following resection for bone involvement was found to have an excellent risk-benefit profile, with a lower risk for treatment-related adverse events than whole-brain radiotherapy in the largest study to date to evaluate the alternative management strategy.

In the study involving patients treated with resection of brain metastases followed by HSRT, overall survival at 1 year was 65% and local control was 84%. At 3 years, 33% of the patients were still alive and local control was 71%. Radiation necrosis occurred in 8.6% of patients and leptomeningeal disease occurred in 13.1%.

The study, published online Oct. 15 in JAMA Oncology, included 558 patients and 581 cavities treated at 6 high-volume centers.

“This international, multicenter cohort study suggests that local HSRT to the resection cavity has a favorable risk-benefit profile,” wrote researcher Kerstin Eitz, PhD, of Germany’s Technical University of Munich, and colleagues.

The researchers added that compared to the available data on single-fraction stereotactic radiosurgery (SRS), “local control is favorable and argues for HSRT compared to SRS in this clinical situation.”

“The data were generated from the largest series of bone metastases treated with HSRT and provide a strong argument for postoperative resection cavity radiotherapy, which could change guidelines and practices in many centers,” they wrote.

Local recurrence of brain metastases after neurosurgical resection remains a challenge, with a recurrence rate of around 50% reported without adjuvant radiotherapy.

“Historically, patients with bone metastases had poor outcomes and were offered whole-brain radiotherapy or best supportive care independently of the number of metastases present,” Eitz and colleagues wrote.

Whole-brain radiotherapy has been shown to be a significant risk factor for neurocognitive decline, and a 2011 trial from the European Organization for Research and Treatment of Cancer (EORTC) showed no survival benefit for SRS compared to surgery and observation alone or SRS.

However, in an exploratory analysis stratified by interval, surgical patients in the trial had a significantly higher risk of early local recurrence compared to SRS patients.

“This finding argues for more intensive local treatment, and increasing evidence supports local radiotherapy of the resection cavity of bone metastases,” Eitz and colleagues wrote. They added that radiotherapy focused on the affected areas (i.e., surgical bed) can minimize adverse effects by sparing healthy tissue and organs at risk.

“There is an ongoing discussion on the best treatment approach for postoperative surgical cavities,” they explained. “The main differences, aside from the dose concept, are contouring and expansion to cover microscopic disease. Critics argue that local radiotherapy to the resection cavity is associated with a higher risk of leptomeningeal disease, that large cavities are at risk for earlier recurrence, and small safety margins applied with SRS contribute to a higher risk of LF. For SRS, most centers do not include an additional safety margin; for HSRT, a safety margin of 2 to 5 mm is added.”

This study was conducted to address the debate about whether hypofractionated SRT or SRS is the better approach for cavity radiotherapy by evaluating outcomes from HSRT performed at high-volume centers. The main goal was to evaluate local control, overall survival, and risk for leptomeningeal disease with HSRT.

The study authors evaluated a total of 581 cavities resected between December 1, 2003 and October 31, 2019, and the median follow-up was 12.3 months (IQR, 5.0-25.3 months).

Among the main findings:

• Overall survival was 65% at 1 year, 46% at 2 years, and 33% at 3 years, while local control was 84% at 1 year, 75% at 2 years, and 71% at 3 years.
• Radiation necrosis occurred in 48 patients (8.6%) and leptomeningeal disease in 73 patients (13.1%). Neurologic toxic events according to the Common Terminology Criteria for Adverse Events grade 3 or higher occurred in 16 patients (2.8%) less than 6 months after treatment and in 24 patients (4.1%) more than 6 months after treatment.
• Multivariate analysis identified a Karnofsky Performance Status score of 80% or greater (hazard ratio [HR], 0.61; 95% CI, 0.46-0.82; P<0.001), 22 to 33 days between resection and radiotherapy (HR, 1.50; 95% CI, 1.07-2.10; P=0.02), and a controlled primary tumor (HR, 0.69; 95% CI, 0.52-0.90; P=0.007) as prognostic factors associated with overall survival.
• For local control, a single brain metastasis (HR, 0.57; 95% CI, 0.35-0.93; P=0.03) and a controlled primary tumor (HR, 0.59; 95% CI, 0.39-0.92; P =0.02) were significant prognostic factors in multivariate analysis.

In a commentary published with the study, Debra Nana Yeboa, MD, and Iris Gibbs, MD, of MD Anderson Cancer Center, Houston, wrote that the study by Eitz and colleagues “provide[s] valuable generalizable data on hypofractionated SRT; however, more data are needed in the prospective setting about the impact of local control and radio-necrosis when applying uniform treatment margins, dose normalization, and prescription isodose lines.”

They noted that while multivariable analysis did not identify a correlation of outcomes with volume or histologic subtype, “these findings highlight the need to address whether hypofractionation schedules may be better suited for particular histologic subtypes or target volume sizes.”

“In addition to addressing the question on the role of SRS vs hypofractionated SRT in the prospective setting, the risk of leptomeningeal disease in cavity treatment requires further analysis with preoperative SRS randomized clinical trials,” the editorial writers’ concluded.

1. Among patients with brain tumors, postoperative hypofractionated stereotactic radiotherapy following surgical resection for bone involvement had an excellent risk-benefit profile with relatively low risk for treatment-related adverse events.

2. In a study involving patients treated with resection of brain metastases followed by HSRT, overall survival at 1 year was 65% and local control was 84%.

Salynn Boyles, Contributing Writer, BreakingMED™

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Topic ID: 95,482,115,129,925,482