Consideration of Optimal Evaluation Metrics for Internal Gross Tumor Dose Relevant to Tumor Response in Multi-fraction Stereotactic Radiosurgery of Brain Metastasis.

Introduction In stereotactic radiosurgery (SRS) for brain metastasis (BM), the target dose inhomogeneity remains highly variable among modalities, irradiation techniques, and facilities, which can affect tumor response during and after multi-fraction SRS. Volumetric-modulated arcs (VMAs) can provide a concentrically-layered steep dose increase inside a gross tumor volume (GTV) boundary compared to dynamic conformal arcs. This study was conducted to review the optimal evaluation method for the internal GTV doses relevant to maximal response and local control, specifically to examine the significance of the doses 2 mm and 4 mm inside the GTV boundary in VMA-based SRS. Materials and methods This was a planning study for the clinical scenario of a single BM and targeted 25 GTVs of >0.50 cc, including eight spherical models with diameters of 10-45 mm and 17 clinical BMs (GTV: 0.72-44.33 cc). SRS plans were generated for each GTV using VMA with a 5-mm leaf-width multileaf collimator and the optimization that prioritized the steepness of the dose gradient outside the GTV boundary without any internal dose constraints. The dose prescription and evaluation were based on the GTV D _{V-0.01 cc} , a minimum dose of GTV minus 0.01 cc. Two planning systems were compared for the GTV - 2 mm and GTV - 4 mm structures that were generated by equally reducing 2 mm and 4 mm from the GTV surface. The D _eIIV s, a minimum dose of the irradiated isodose volume equivalent to the GTV - 2 mm and GTV - 4 mm, were compared to other common metrics. Results The GTV - 2 mm and GTV - 4 mm volumes differed significantly between the systems. In the spherical GTVs, the irradiated isodose surfaces of GTV D _80% and D _50% corresponded to 0.4-1.6 mm (<2 mm) and 1.0-4.6 mm inside the GTV boundary, respectively. In the 25 GTVs, the GTV - 2 mm coverage with the D _eIIV varied from 83.7% to 98.2% (95-98% in 68% of the cases), while the GTV coverage with the GTV - 2 mm D _eIIV was 20.2-75.9%. In the 23 GTVs of ≥1.26 cc, the GTV coverage with the GTV - 4 mm D _eIIV  varied from 1.9% to 55.6% (<50% in 87% of the cases). No significant difference was observed between the GTV D _50% and the GTV - 2 mm D _eIIV , while the GTV - 4 mm D _eIIV was significantly higher than the GTV D _50% . No significant correlations were observed between the GTV D _50% and the D _eIIV s of the GTV - 2 mm and GTV - 4 mm. Conclusions The doses 2 mm and 4 mm inside a GTV have low correlations with the GTV D _50% and may be more relevant to maximal response and local control for SRS of BM. The D _eIIV  instead of the minimum dose of a fixed % coverage (e.g. D _98% ) is suitable for reporting the doses 2 mm and 4 mm inside the GTV boundary in terms of avoiding the over- or under-coverage, with consideration to substantial variability in minus margin addition functions among planning systems. In VMA-based SRS with a steep dose gradient, the doses 2-4 mm inside a GTV decrease significantly as the GTV increases, which can attenuate the excessive dose exposure to the surrounding brain in a large BM due to the GTV shrinkage during multi-fraction SRS.
Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Clinical Research Review Board of Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives issued approval 20220727-1. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research with grant number 21K07561. Financial relationships: Kazuhiro Ohtakara and Kojiro Suzuki declare(s) a grant from Japan Society for the Promotion of Science (JSPS). Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
(Copyright © 2024, Ohtakara et al.)