Volumetric Regression in Brain Metastases After Stereotactic Radiotherapy: Time Course, Predictors, and Significance

Abstract

Background: There is insufficient understanding of the natural course of volumetric regression in brain metastases after stereotactic radiotherapy (SRT) and optimal volumetric criteria for the assessment of response and progression in radiotherapy clinical trials for brain metastases are currently unknown.

Methods: Volumetric analysis via whole-tumor segmentation in contrast-enhanced 1 mm³-isotropic T1-Mprage sequences before SRT and during follow-up. A total of 3,145 MRI studies of 419 brain metastases from 189 patients were segmented. Progression was defined using a volumetric extension of the RANO-BM criteria. A subset of 205 metastases without progression/radionecrosis during their entire follow-up of at least 3 months was used to study the natural course of volumetric regression after SRT. Predictors for volumetric regression were investigated. A second subset of 179 metastases was used to investigate the prognostic significance of volumetric response at 3 months (defined as ≥20% and ≥65% volume reduction, respectively) for subsequent local control.

Results: Median relative metastasis volume post-SRT was 66.9% at 6 weeks, 38.6% at 3 months, 17.7% at 6 months, 2.7% at 12 months and 0.0% at 24 months. Radioresistant histology and FSRT vs. SRS were associated with reduced tumor regression for all time points. In multivariate linear regression, radiosensitive histology (p=0.006) was the only significant predictor for metastasis regression at 3 months. Volumetric regression ≥20% at 3 months post-SRT was the only significant prognostic factor for subsequent control in multivariate analysis (HR 0.63, p=0.023), whereas regression ≥65% was no significant predictor.

Conclusions: Volumetric regression post-SRT does not occur at a constant rate but is most pronounced in the first 6 weeks to 3 months. Despite decreasing over time, volumetric regression continues beyond 6 months post-radiotherapy and may lead to complete resolution of controlled lesions by 24 months. Radioresistant histology is associated with slower regression. We found that a cutoff of ≥20% regression for the volumetric definition of response at 3 months post-SRT was predictive for subsequent control whereas the currently proposed definition of ≥65% was not. These results have implications for standardized volumetric criteria in future radiotherapy trials for brain metastases.

Keywords: MRI; brain metastases; longitudinal analysis; stereotactic radiosurgery; stereotactic radiotherapy; volumetric analysis; volumetric regression.

Figure 1

Median metastasis volume over time following stereotactic radiotherapy in the entire cohort of metastases (N = 419). Tumor volumes are expressed relative to baseline volume. (A) Median metastasis volume over time for the total cohort (N = 419, blue), for lesions experiencing progression (N = 78, red) or pseudoprogression during follow-up (N = 16, orange) and for the subset of controlled metastases used for further analyses (N = 205, see methods section for definition, green). Dotted lines represent the 95% confidence interval. (B) Median metastasis volume over time in the entire cohort stratified by baseline metastasis diameter.

Figure 2

Median metastasis volume over time following stereotactic radiotherapy in controlled brain metastases (N = 205). Tumor volumes are expressed relative to baseline volume. Error bars show the 95% confidence interval. Note: Volumetric regression is most pronounced in the first 3 months but continues thereafter. Upper right inset: Example of longitudinal volumetry in a larger brain metastasis treated with fractionated stereotactic radiotherapy (FSRT). Left ordinate shows relative tumor volume and right ordinate shows absolute metastasis volume (cm³). Segmentation is shown for different measurement time points.

Figure 3

Median metastasis volume over time following stereotactic radiotherapy in controlled brain metastases stratified by baseline metastasis diameter.

Figure 4

Median metastasis volume over time for (A) radiosensitive vs. radioresistant histology (i.e., melanoma, renal cell carcinoma or sarcoma), (B) Nonmelanoma vs. melanoma histology, (C) single-session radiosurgery (SRS) vs. fractionated stereotactic radiotherapy (FSRT), and (D) Upfront whole-brain radiotherapy (WBRT) vs. no upfront WBRT. Asterisks indicate significant intergroup differences for the respective timepoint.

Figure 5

Prognostic significance of volumetric response at 3 months post-stereotactic radiotherapy (SRT) for subsequent local control in a second subset without prior progression and subsequent imaging follow-up. Kaplan-Meier plots for two different thresholds for the definition of volumetric response are shown: (A) ≥ 65% as per the current RANO-BM recommendation and (B) ≥ 20%, which is commonly considered the lowest volumetric threshold that can be reliably detected. Vertical bars represent censored cases.