Internal dose escalation associated with increased local control for melanoma brain metastases treated with stereotactic radiosurgery

Abstract

OBJECTIVE The internal high-dose volume varies widely for a given prescribed dose during stereotactic radiosurgery (SRS) to treat brain metastases (BMs). This may be altered during treatment planning, and the authors have previously shown that this improves local control (LC) for non–small cell lung cancer BMs without increasing toxicity. Here, they seek to identify potentially actionable dosimetric predictors of LC after SRS for melanoma BM. METHODS The records of patients with unresected melanoma BM treated with single-fraction Gamma Knife RS between 2006 and 2017 were reviewed. LC was assessed on a per-lesion basis, defined as stability or a decrease in lesion size. Outcome-oriented approaches were utilized to determine optimal dichotomization for dosimetric variables relative to LC. Univariable and multivariable Cox regression analysis was implemented to evaluate the impact of collected parameters on LC. RESULTS Two hundred eighty-seven melanoma BMs in 79 patients were identified. The median age was 56 years (range 31–86 years). The median follow-up was 7.6 months (range 0.5–81.6 months), and the median survival was 9.3 months (range 1.3–81.6 months). Lesions were optimally stratified by volume receiving at least 30 Gy (V30) greater than or equal to versus less than 25%. V30 was ≥ and < 25% in 147 and 140 lesions, respectively. For all patients, 1-year LC was 83% versus 66% for V30 ≥ and < 25%, respectively (p = 0.001). Stratifying by volume, lesions 2 cm or less (n = 215) had 1-year LC of 82% versus 70% (p = 0.013) for V30 ≥ and < 25%, respectively. Lesions > 2 to 3 cm (n = 32) had 1-year LC of 100% versus 43% (p = 0.214) for V30 ≥ and < 25%, respectively. V30 was still predictive of LC even after controlling for the use of immunotherapy and targeted therapy. Radionecrosis occurred in 2.8% of lesions and was not significantly associated with V30. CONCLUSIONS For a given prescription dose, an increased internal high-dose volume, as indicated by measures such as V30 ≥ 25%, is associated with improved LC but not increased toxicity in single-fraction SRS for melanoma BM. Internal dose escalation is an independent predictor of improved LC even in patients receiving immunotherapy and/or targeted therapy. This represents a dosimetric parameter that is actionable at the time of treatment planning and warrants further evaluation.

Volumetric reduction of brain metastases after stereotactic radiotherapy: Prognostic factors and effect on local control

“…When the prescribed dose is 30 Gy/3 fractions (the median dose in this study) in an 80% isodose, achieving GTV D80 > BED20 58 is difficult; an inhomogeneous dose distribution is required. In previous studies, inhomogeneous dose distribution correlated with good local control after Gamma Knife radiotherapy 20 , 21 and resulted in better local control than did homogeneous distribution after Linac‐based SRT. 22 BED20 58 is approximately 41.5 Gy/5 fractions and is similar to BED10 80.…”

Modified Dynamic Conformal Arcs With Forward Planning for Radiosurgery of Small Brain Metastasis: Each Double Arc and Different To-and-Fro Leaf Margins to Optimize Dose Gradient Inside and Outside the Gross Tumor Boundary

“…Although generally unregarded dose attenuation margin outside the prescription IDS can cover these uncertainties to some degree, an approximately 1-mm setup error likely leads to marginal tumor residues, given the generally steep dose gradient for LGK [5]. Meanwhile, recent studies also suggest that the higher proportion of GTV receiving ≥30-32 Gy in the single fraction, i.e., internal dose escalation, is likely associated with superior tumor shrinkage and LC [8,9,19]. In LGK, 50% IDS is generally used for target coverage and dose prescription in multi-shot planning, i.e., a combination of multi-isocenter, which can lead to superior tumor response, particularly if concentrically laminated steep dose increase inside the GTV boundary is achieved [5,11].…”

“…Meanwhile, a steep dose increase inside the GTV boundary, i.e., an extremely inhomogeneous GTV dose can also be beneficial to enhance anti-BM efficacy by conquering the potential internal radioresistant portion and is also deemed as another essential integrant for suitable dose distribution [5,7]. Several studies suggest the advantage of so-called internal dose escalation for effecting superior tumor shrinkage and LC [8,9]. Thus, in addition to the prescribed marginal dose, the appropriateness of the dose gradient both outside and inside the GTV boundary is an indispensable requisite for SRS planning for BM [5].…”

Improving on whole-brain radiotherapy in patients with large brain metastases: A planning study to support the AROMA clinical trial

“…Vogelbaum et al reported an increased risk of local failure for brain metastases treated with 15 Gy and 18 Gy compared to 24 Gy, with a one-year LC of 45%, 49% and 85%, while higher prescription dose exhibited significantly longer time to local failure (p = 0.0005) [21]. Furthermore, other studies also noticed that doses in excess of prescription dose were predictive of LC [22,23].…”