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Purpose In linac-based stereotactic radiosurgery (SRS) utilizing a multileaf collimator (MLC) for brain metastases (BMs), a volumetric-modulated arc (VMA) technique is indispensable for generating a suitable dose distribution with efficient planning and delivery. However, the optimal calculation grid spacing (GS) and statistical uncertainty (SU) of the Monte Carlo algorithm for VMA optimization have yet to be determined. This planning study aimed to examine the impacts of GS and GU settings on VMA-based SRS planning and to find the optimal combination for templating. Materials and methods Thirty clinical BMs with a gross tumor volume (GTV) of 0.08-48.09 cc (median 9.81 cc) were included. The treatment platform included a 5-mm leaf-width MLC Agility ® (Elekta AB, Stockholm, Sweden) and a planning system Monaco ® (Elekta AB). The prescribed dose was uniformly assigned to the GTV D V-0.01 cc , the minimum dose of GTV minus 0.01 cc, i.e.,  D >95% for GTV >0.20 cc or to the GTV D 95% for GTV ≤0.20 cc, to minimize the uncovered GTV to the equivalent of a 3 mm diameter lesion. Five combinations of GS and SU per plan were examined for 12 selected GTVs (median 17.41 cc): GS of 2 mm and SU of 3% (G2U3), 2 mm and 2% (G2U2), 2 mm and 1% (G2U1), 1 mm and 2% (G1U2), and 1 mm and 1% (G1U1). Otherwise, the same arc arrangement and optimization method were uniformly used to prioritize the GTV dose conformity and the steepness of the dose gradient outside the GTV without dose constraints inside the GTV boundary. Further comparisons were conducted using 30 GTVs between the two groups with the highest plan quality. Results The G2U3 and G2U2 resulted in the equivalent total calculation time (tCT) and exactly the same plan quality. The overall plan quality was significantly superior in the G1U2 and G1U1 than in the G2U1 and G2U2, although the tCT was significantly longer in the G1U1 and G1U2 than in the G2U1 and G2U2. In the comparison of the G1U2 and G1U1, the concentric lamellarity of dose gradients 2 mm outside and 2-4 mm inside the GTV boundary was significantly superior in the G1U1 than in the G1U2, while there was no significant difference in the other parameters. The tCT tended to be longer in the G1U1 than in the G1U2. Conclusions The initial settings of GS and SU have significant impacts on the plan quality and tCT. The settings with GS of 1 mm and SU of 1% per plan are recommended to create the most suitable dose distribution for single BMs, especially for irregularly shaped and/or large lesions, although the tCT is long. In addition to common evaluation metrics, the coverage values of 2 mm outside and 2-4 mm inside the GTV surface by the D eIIV , the minimum dose to cover the irradiated isodose volume equivalent to each target volume, are valuable for in-depth plan comparison., Competing Interests: Human subjects: Consent for treatment and open access publication 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 20240830-01. 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 C with the grant number JP21K07561. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. 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.)

Introduction Volumetric-modulated arcs (VMA) can produce dose distributions suitable for stereotactic radiosurgery (SRS) with a multi-leaf collimator (MLC) for brain metastases (BMs). The treatment planning and verification for VMA are more complicated than for dynamic conformal arcs. The longer the preparation time from image acquisition to the start of irradiation, the higher the risk of tumor growth and/or displacement. This planning study aimed to exploit the simple and effective cost function (CF) for establishing semi-automatic efficient VMA optimization for SRS of single BMs. Materials and methods The study population included 30 clinical BMs with a gross tumor volume (GTV) of 0.72-44.30 cc (median 9.81 cc) and a depth of 20-79 mm (median 41 mm). The treatment platform included a 5-mm leaf-width MLC Agility ® (Elekta AB, Stockholm, Sweden) and a planning system Monaco ® (Elekta AB). Among various physical and biological CFs available, three combinations consisting of just two or three physical CFs were compared. The Target Penalty CF was uniformly used for ensuring the GTV dose. Three different CF combinations were applied for reducing the surrounding tissue doses: (1) the Conformality alone with the 4-cm margin around target (MAT) that optimizes the limited voxels around the GTV ( wo QO); (2) the Conformality with the 4-cm MAT and the Quadratic Overdose ( w QO&#95;4 cm); and (3) the Conformality with the 8-cm MAT that optimizes the overall voxels around the GTV and the Quadratic Overdose ( w QO&#95;8 cm). The prescribed dose was uniformly assigned to each GTV D V-0.01 cc , the minimum dose of GTV minus 0.01 cc. Results Adding the Quadratic Overdose ( w QO&#95;4 cm and w QO&#95;8 cm) significantly improved the overall dose distribution in comparison to the wo QO, while no significant difference was observed between the w QO&#95;4 cm and w QO&#95;8 cm overall. However, for the GTVs of ≥14 cc, the GTV dose conformity and dose gradient outside the GTV boundary, including the dose attenuation margin, were significantly superior in the w QO&#95;8 cm than w QO&#95;4 cm. In addition, for the GTV depth of ≥41 mm, the GTV dose conformity and the dose concentric lamellarity at 2 mm outside the GTV were significantly superior in the w QO&#95;8 cm than w QO&#95;4 cm. Meanwhile, for the GTVs of ≥10 cc, the GTV dose was significantly more inhomogeneous in the w QO&#95;4 cm than the  w QO&#95;8 cm. In addition, for the GTVs of <10 cc and the depth of ≤40 mm, the dose concentric lamellarity at 4 mm inside the GTV surface was significantly higher in the w QO&#95;4 cm than the  w QO&#95;8 cm. Conclusions Applying at least three physical CFs to a GTV and the head surface contour is recommended as an effective and efficient optimization method using Monaco for VMA-based SRS of single BMs. In addition, optimizing the overall voxels around the GTV is suitable for reducing the surrounding tissue dose, especially for large and deeply located lesions. Templating the combination of the three CFs with the detailed settings allows for semi-automated and rapid treatment planning, facilitating the prompt start of irradiation after image acquisition., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Clinical Research Review Board of Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives issued approval 20220727-01. 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 C with the grant number JP21K07561. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. 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.)

Introduction In linac-based stereotactic radiosurgery (SRS) leveraging a multileaf collimator (MLC) for brain metastasis (BM), volumetric-modulated arcs (VMAs) enable the generation of a suitable dose distribution with efficient planning and delivery. However, the arc arrangement, including the number of arcs, allocation, and rotation ranges, varies substantially among devices and facilities. Some modalities allow coplanar arc(s) (CA(s)) or beam(s) alone, and some facilities only use them intentionally despite the availability of non-coplanar arcs (NCAs). The study was conducted to examine the significance of NCAs and the optimal arc rotation ranges in VMA-based SRS for a single BM. Materials and methods This was a planning study for the clinical scenario of a single BM, including 20 clinical cases with a gross tumor volume (GTV) of 0.72-44.30 cc. Three different arc arrangements were compared: 1) reciprocating double CA alone of each 360º rotation with different collimator angles of 0 and 90º, 2) one CA and two NCAs of each 120º rotation with the shortest beam path lengths to the irradiation isocenter (NCA&#95;L), and 3) one CA of 360º rotation and two NCAs of each 180º rotation (NCA&#95;F). The three arcs were allocated similarly to equally divide the cranial hemisphere with different collimator angles of 0, 45, and 90º. Three VMA-based SRS plans were generated for each GTV using a 5 mm leaf-width MLC with the identical optimization method that prioritized the steepness of dose gradient outside the GTV boundary without any constraints to the GTV internal dose. A prescribed dose was uniformly assigned to the GTV D V-0.01 cc , the minimum dose of GTV minus 0.01 cc. The GTV dose conformity, the steepness of dose gradients both outside and inside the GTV boundary, the degree of concentric lamellarity of the dose gradients, and the appropriateness of the dose attenuation margin outside the GTV boundary were evaluated using metrics appropriate for each. Results The arc arrangements including NCAs showed significantly steeper dose gradients both outside and inside the GTV boundary with smaller dose attenuation margins than the CAs alone, while NCAs showed no significant advantage on the GTV dose conformity. In the NCA-involved arc arrangements, the NCA&#95;F was significantly superior to the NCA&#95;L in terms of the GTV dose conformity, the steepness of dose gradient outside the GTV, the degree of concentric lamellarity of the dose gradients outside and inside the GTV boundary, and the appropriateness of dose attenuation margin. However, the NCA&#95;F showed no significant advantage on the steepness of dose increase inside the GTV boundary over the NCA&#95;L. The dose increase just inside the prescribed isodose surface to the GTV boundary was significantly steeper with the NCA&#95;L than the NCA&#95;F. Conclusions In VMA-based SRS for a single BM, an arc arrangement including NCAs is indispensable, and sufficient arc rotations are suitable for achieving a dose distribution that maximizes therapeutic efficacy and safety in comparison to limited ones which are appropriate for dynamic conformal arcs. Although VMA with CAs alone can provide a non-inferior GTV dose conformity to NCAs, CA(s) alone should be applied only to situations where shorter irradiation time is prioritized over efficacy and safety., 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 C with the grant number JP21K07561. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. 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.)

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.)

Introduction In stereotactic radiosurgery (SRS) for brain metastasis (BM), volumetric-modulated arcs (VMA) can provide a suitable dose distribution and efficient delivery, even with a widely available 5-mm leaf-width multileaf collimator (MLC). The planning optimization with affirmatively accepting internal high doses of a gross tumor volume (GTV) enhances the steepness of the dose gradient outside the GTV. However, an excessively steep dose falloff outside a GTV is susceptible to insufficient coverage of inherent irradiation uncertainties with the dose attenuation margin. This study was conducted to examine the appropriateness of dose attenuation margin outside a GTV in 5-mm MLC VMA-based SRS with a steep dose gradient and dose prescription with a biologically effective dose (BED) 80 Gy in various fractions to the GTV margin. Materials and methods This was a planning study for the clinical scenario of a single BM and targeted 28 GTVs, including nine sphere-shaped models with diameters of 5-45 mm and 19 clinical BMs (GTV 0.08-44.33 cc). SRS plans were generated for each GTV using 5-mm MLC VMA with an optimization that prioritized the steepness of dose falloff outside the GTV boundary without any internal dose constraints. A prescribed dose with the BED 80 Gy in 1-10 fraction(s) was assigned to the GTV D V-0.01 cc , a minimum dose of GTV minus 0.01 cc ( D >95% for GTV >0.20 cc, D 95% for GTV ≤0.20 cc). The BED was based on the linear-quadratic formula with an alpha/beta ratio of 10 (BED 10 ). Two planning systems were compared for the GTV + 2 mm structures that were generated by adding an isotropic 2-mm margin to the GTV. Results The GTV + 2 mm volumes differed significantly between the systems and further varied on the dose-volume histograms. The D V-0.05 cc , D 98% , and D 95% of the GTV + 2 mm were associated with substantial over- or under-coverages of the GTV + 2 mm, although the irradiated isodose volumes (IIVs) of the D 98% were closest to the GTV + 2 mm in general. The coverage values of the GTV + 2 mm with the minimum dose of the IIV equivalent to the GTV + 2 mm, D eIIV , were 93.3%-98.7% (≥95% in 26 cases). The GTV + 2 mm D eIIV relative to the GTV D V-0.01 cc was ≥81.9% (BED 10 ≥60 Gy in ≤5 fractions) in 13 cases, while those were <69.8% (BED 10 <48 Gy in ≤5 fractions) in four cases with the GTV of 0.33-1.77 cc. Conclusions A dose attenuation margin outside a GTV can be excessively steep for some small GTVs in 5-mm MLC VMA-based SRS with a steepest dose gradient and a BED 10 80 Gy in ≤5 fractions to the GTV D V-0.01 cc , for which an adjustment of the too precipitous dose gradient is preferred to sufficiently cover relevant uncertainties. A GTV + 2 mm D eIIV with ≥95% coverage is more suitable for evaluating the appropriateness of dose attenuation outside the GTV than other common metrics with a fixed % coverage or D V-≤0.05 cc . Given the substantial variability in margin addition functions among planning systems, dose prescription to a margin-added GTV is unsuitable for ensuring uniform dose prescription., 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: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. 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.)

Introduction In stereotactic radiosurgery (SRS) for brain metastasis (BM), the prescribed dose is generally reported as a minimum dose to cover a specific percentage (e.g. D 98% ) of the gross tumor volume (GTV) with or without a margin or an unspecified intended marginal dose to the GTV boundary. In dose prescription to a margin-added planning target volume (PTV), the GTV marginal dose is likely variable and unclear. This study aimed to reveal major flaws of dose prescription to a fixed % coverage of a target volume (TV), such as GTV D 98% or PTV D 95% , and to propose an alternative. Materials and methods Seven quasi-spherical models with volumes ranging from 1.00 to 15.00 cc were assumed as GTVs. The GTVs and the volumes generated by adding isotropic 1- and 2-mm margins to the GTV boundaries (GTV + 1 and 2 mm) were used for SRS planning, dose prescription, and evaluation. Volumetric-modulated arcs with a 5-mm leaf-width multileaf collimator were used to optimize each SRS plan to ensure the steepest dose gradient outside each TV boundary. In dose prescription to the GTV D 98% , 0.02-0.3 cc of the GTV is below the prescribed dose, and the volume increases with larger GTVs. The volume below the prescribed dose should be less than the equivalent of a 3-mm-diameter lesion, i.e. 0.01 cc. Therefore, D V-0.01 cc was defined as an alternative near-minimum dose for which the TV below a relevant dose is less than 0.01 cc. Four different dose prescriptions, including the GTV  D V-0.01 cc , were compared using specific doses in 1, 3, and 5 fractions, equivalent to 80, 60, and 50 Gy, respectively, as biologically effective doses (BEDs) to the boundaries of GTV, GTV + 1 mm, and GTV + 2 mm, respectively. Results Dose prescription to the GTV D V-0.01 cc corresponds to 95.0, 98.0, and 99.0-99.93% coverages for the GTV of 0.20, 0.50, and 1.00-15.00 cc, respectively. The GTV D V-0.01 cc varied substantially and decreased significantly as the GTV increased in dose prescriptions to the GTV D 98% , GTV + 1 mm D 95% , and GTV + 2 mm D 95% . The GTV + 2 mm D V-0.01 cc increased significantly as the GTV increased, except for the dose prescription to the GTV + 2 mm D 95% with a decreasing tendency. When comparing BED-based specific dose prescriptions, dose prescription to the GTV D V-0.01 cc was optimal in terms of the following: 1) consistency of the near-minimum dose of GTV; 2) the highest BED at 2 mm outside the GTV, except for 1.00 cc GTV, and the rational increase with increasing GTV; and 3) the highest BED at 2 mm inside the GTV. In dose prescription with the BED of 80 Gy in 1 fraction and 5 fractions to the GTV D V-0.01 cc , the GTV limits were ≤1.40 and ≤8.46 cc, respectively, in order for the irradiated isodose volume not to exceed the proposed thresholds for minimizing the risk of brain radionecrosis. Conclusions Dose prescription to a fixed % coverage of a GTV with or without a margin leads to the substantially varied near-minimum dose at the GTV boundary, which significantly decreases with increasing GTV. Alternatively, GTV D V-0.01 cc with a variable coverage ( D >95% ) for >0.20 cc GTV and fixed  D 95% for ≤0.20 cc GTV is recommended as the basis for dose prescription and evaluation, along with supplemental evaluation of the marginal dose of the GTV plus a margin (e.g. GTV + 2 mm) to demonstrate the appropriateness of dose attenuation outside the GTV boundary., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Ohtakara et al.)

General radiotherapeutic management for >10 brain metastases (BMs) totaling >100 cm 3 , including multiple large lesions (>10-30 cm 3 ) in close proximity, demonstrated limited efficacy and/or safety. We describe a case of 12 BMs, summating 122.2 cm 3 , including a 39.6 cm 3 maximum lesion and adjacent ones. The patient had an 8.1-year treatment history for recurrent/metastatic breast cancer refractory to endocrine and chemotherapy. BMs were treated with conventional whole-brain radiotherapy (WBRT) with 30 Gy/10 fractions (fr), followed by an immediate stereotactic radiosurgery (SRS) boost with 27 Gy/5 fr (52-64% isodoses) which covers the gross tumor boundaries of selected eight lesions (total 118.4 cm 3 ). The SRS dose was defined to ensure the cumulative biologically effective dose (BED 10 ) of just ≥80 Gy while minimizing the risk of radiation injury. The SRS was performed using a CyberKnife (CK) robotic system (Accuray Incorporated, Sunnyvale, California, United States) with a variable-sized collimator (10-40 mm), for which en bloc consecutive irradiation, using 215 beams based on a comprehensively optimized single plan (path), was adopted. The treatment time per fraction was ≤45 min (mean 5.6 min per lesion). Afterward, BMs demonstrated remarkable regression over six months, causing the total residual visible lesions of 12.6 cm 3 (10.3%) at 11.4 months, despite the absence of obvious lesion shrinkage during the radiotherapy. WBRT, followed by an immediate 5-fr SRS boost with a total BED 10  of 80 Gy to large and/or culprit lesions, can be an efficacious and safe treatment option for multiple BMs, totaling >120 cm 3 . En bloc consecutive irradiation with a single path provides overwhelmingly more efficient delivery for treating multiple lesions using CK in terms of irradiation time and comprehensive reduction of normal brain dose compared to individual planning. Volumetric-modulated arc-based >10-fr SRS with simultaneously integrated reduced-dose WBRT may be an alternative to further enhance efficacy and safety., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

A deep-seated, locally infiltrative 5.8-cm brain metastasis (BM) involving the ventricular wall and optic radiation is deemed unamenable for a safe total resection, while preventing tumor seeding. Meanwhile, radiotherapeutic management alone for such a BM close to the brainstem is also challenging. We describe such a BM (gross tumor volume [GTV] 40.3 cm 3 ) from lung adenocarcinoma (LAC), located in the left temporo-occipital lobes, with extensive invasion to the tentorium cerebelli and a high potential for dissemination. The BM was treated with 15-fraction(s) (fr) stereotactic radiosurgery (SRS) followed by whole-brain irradiation (WBI) at 27 Gy/15 fr with a 19-day interval. During the SRS, the solid component away from the tentorium showed obvious shrinkage. The cumulative biologically effective doses (BEDs) of the minimum and D 99% of the GTV were ≥92.3 Gy and ≥102.6 Gy, respectively, where the BED was based on the linear-quadratic formula at an alpha/beta ratio of 10 (BED 10 ). Despite a maximum response with nearly complete regression at 7.5 months, local tumor regrowth near the tentorial incisura became gradually apparent from 11.2 to 19.3 months. Salvage re-SRS with 53 Gy/10 fr specific to these lesions resulted in obvious regression at 5.8 months. However, radiation injury concomitant with triventriculomegaly progressed from 7.9 to 13.9 months, eventually leading to meningeal dissemination and patient mortality at 34.6 months. This case demonstrates that a BED 10 ≥90-100 Gy in 30 fr to the GTV boundary with a more than two-week interval without combined systemic therapy is insufficient for achieving complete local tumor eradication of a 40-cc LAC-BM. Shorter treatment duration with a steeper dose gradient outside and inside the GTV in the SRS or a volumetric modulated arc-based SRS combined with simultaneously integrated WBI may improve efficacy and safety., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

An isolated single brain metastasis (BM) is an extremely rare manifestation of failure in patients with cecal adenocarcinoma (CAC). Total en bloc resection (while preserving function) of a 3-cm BM involving both the primary motor and sensory cortexes presents a conundrum: achieving long-term local control and safety of such a BM is also challenging for stereotactic radiosurgery (SRS). We describe the case of a 3.1-cm BM from CAC in the left parasagittal para-central sulcus region, which was treated using five-fraction SRS with a biologically effective dose (BED) of 81.6 Gy. In the SRS, the gross tumor volume (GTV, 7.14 cm 3 ) was defined based on computed tomography (CT)/T1/T2 matching (enhancing lesion 11.66 cm 3 ), and 98.7% of the GTV (CT/T2 mass) was covered with 43.6 Gy (58% isodose) using volumetric-modulated arcs. The maximum tumor response was partial (19.7% of the prior GTV) and sustained for 15.2 months, leaving minor neurological symptoms. However, the patient developed neurological worsening at six months, attributed to adverse radiation effects with a CT/T1/T2 mismatch, for which medical management, including the addition of bevacizumab (BEV), was effective for one year. Multi-fraction SRS with a high marginal and internal BED and sequential systemic therapy, including BEV, can be a minimally invasive, efficacious, and durable treatment option for a large CAC-BM involving the central sulcus. Early co-administration of BEV following SRS, dose escalation to the GTV boundary, and more than five fractions of SRS may be considered to improve the efficacy and safety further., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

Clinical management of patients with local control failure following stereotactic radiosurgery (SRS) for brain metastasis (BM) can be frequently challenging. Re-irradiation with multi-fraction (fr) SRS by using a biological effective dose of ≥80 Gy, based on the linear-quadratic formula with an alpha/beta ratio of 10 (BED 10 ), can be an efficacious option for such a scenario with the BED 10 of <80 Gy. However, its long-term safety beyond one year remains unclear. In this report, we describe the case of a patient with a single metachronous BM from lung adenocarcinoma (LAC), without major genetic alterations, in which re-SRS with 43.6 Gy/5 fr (BED 10 81.6 Gy) for local progression, following prior 3-fr SRS of the BM, resulted in sustained regression without any local adverse radiation effects (AREs) for 19 months. The BM with a gross tumor volume (GTV) of 1.12 cm 3 in the left parietal lobe was initially treated with SRS of 27 Gy/3 fr (50% isodose). Despite steroid administration for nivolumab-induced bullous pemphigoid associated with transient elevation of tumor markers, the BM showed local progression with T1/T2 matching at 38.3 and eight months after SRS and discontinuation of nivolumab, respectively. In the 5-fr re-SRS, 99% of the GTV (1.18 cm 3 ) was covered with 43.6 Gy (63% isodose). However, along with the thoracic disease progression, multiple new BMs developed 15.5 months after the re-SRS, for which volumetric-modulated arc-based whole brain radiotherapy (WBRT) was administered, with simultaneously integrated boosts to 17 lesions and moderate dose attenuation in the pre-irradiated region. However, concurrent administration of gemcitabine and WBRT might have led to persistent severe anorexia for 2.5 months. The patient died 10.8 years after the initial chemotherapy. The relatively small GTV with the superficial location may have rendered the re-irradiated region immune to AREs after the high BED 10 re-SRS. Long-term survival can be achieved by chemoimmunotherapy in patients with pan-negative LAC, with limited systemic metastases who are unfit for targeted agents. Therefore, SRS for limited BMs in such scenarios should aim for complete local tumor eradication beyond a partial response in either a first-line or re-irradiation setting., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

First-line and possibly repeated stereotactic radiosurgery (SRS) with preserving whole-brain radiotherapy (WBRT) is an attractive and promising option for synchronous or metachronous limited brain metastases (BMs) from small cell lung cancer (SCLC), for which a modest prescription dose is generally preferred, such as a biological effective dose of ≤60 Gy, based on the linear-quadratic formula with an alpha/beta ratio of 10 (BED 10 ). In addition, the optimal planning scheme for re-SRS for local progression after SRS of BMs from SCLC remains unclear. Herein, we describe a case of limited BMs developing after a partial response to standard chemoradiotherapy (CRT) for limited-stage SCLC. The BMs, including local failures following prior single-fraction (fr) SRS, were re-treated with volumetric-modulated arc-based SRS combined with simultaneous reduced-dose WBRT. The first SRS with 36.3 Gy/3 fr (BED 10 80 Gy) for a small BM resulted in a local control of 17.2 months. However, the second SRS with 20 Gy/1 fr (BED 10 60 Gy) to the 60% or 85% isodose surface (IDS) covering the gross tumor volume (GTV) of three new BMs with a paradoxical T1/T2 mismatch, that is, a visible mass on T2 larger than an enhancing area, resulted in partial symptomatic local progression of all lesions within 5.2 months, along with the development of two new lesions, despite continued amrubicin monotherapy. In contrast, the third SRS with 53 Gy/10 fr (BED 10 81 Gy) to ≤74% IDSs encompassing the GTV boundary resulted in complete responses of all the lesions during six months. However, despite a combined use of WBRT of 25 Gy in the third SRS, symptomatic spinal cerebrospinal fluid dissemination and new BMs developed, the former leading to patient mortality. A BED 10 of ≥80 Gy to the GTV margin and a steep dose increase inside the GTV boundary are suitable to ensure excellent local control in SRS for SCLC BMs. Re-SRS with the aforementioned scheme can be an efficacious option for local failures following prior SRS with a BED 10 of ≤60 Gy. Modest dose escalation with a simultaneous integrated boost to bulky lesions in the initial CRT may reduce the development of new BM through improved control of the potential source., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

Standard whole-brain radiotherapy (WBRT) alone for large brain metastases (BMs) from small cell lung cancer (SCLC) has limited efficacy and durability, and stereotactic radiosurgery (SRS) alone for symptomatic posterior fossa BMs >3 cm with satellite lesions is challenging. Herein, we describe the case of a 73-year-old female presenting with treatment-naïve SCLC and 15 symptomatic multiple BMs, including a ≥3.8-cm cerebellar mass (≥17.7 cm 3 ) and two adjacent lesions; otherwise, the SCLC was confined to the thorax. The patient was initially treated concurrently with conventional WBRT (30 Gy in 10 fractions) without boost and chemoimmunotherapy (CIT) consisting of carboplatin, etoposide, and atezolizumab. Atezolizumab was excluded during irradiation. Five months after WBRT, the large cerebellar lesion had remarkably regressed, and the smaller lesions (≤17 mm) showed complete responses (CRs) without local progression at 20 months. However, six and 16 months after WBRT, the thoracic lesions had progressed, and although amrubicin was administered, four new BMs, including pons involvement, had developed, respectively. Despite the CRs of the four BMs following SRS (49.6 Gy in eight fractions) and the sustained regression of the thoracic lesions, meningeal dissemination and multiple new BMs were evident 3.5 months post-SRS. The small remnant of the large BM and/or newly developed BMs abutting the cerebrospinal fluid (CSF) space could have led to CSF dissemination, the presumed cause of the patient's death. Taken together, concurrent chemo-WBRT and subsequent CIT can provide excellent and durable tumor responses for SCLC BMs, but may not be fully sufficient for BMs ≥3.8 cm. Therefore, in cases with large lesions, focal dose escalation of the large lesions, consolidative thoracic radiotherapy, and dose de-escalation in the macroscopically unaffected brain region may prevent or attenuate CSF dissemination, new BM development, and adverse effects and thus should be considered., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

The criteria for indication of salvage stereotactic radiosurgery (SRS) for local progression following multi-fraction (mf) SRS of brain metastases (BMs) remain controversial, along with the optimal planning scheme. Herein, we described a case of BMs from pan-negative lung adenocarcinoma (LAC), in which the two lesions of local progression following initial eight-fraction (8-fr) SRS were re-treated with 5-fr SRS with the biologically effective dose (BED 10 ) of ≥80 Gy, based on the linear-quadratic (LQ) formula with an alpha/beta ratio of 10. The re-SRS resulted in the alleviation of symptoms and favorable tumor responses with minimal adverse effects during the 7.3-month follow-up. In the lesions of local progression, the gross tumor volume (GTV) coverage with 49.6 Gy (BED 10 80 Gy) was generally insufficient, and the GTV dose wes relatively homogeneous with ≥87% isodose covering. In contrast, the 5-fr re-SRS was performed with sufficient GTV coverage with ≤68% isodose of 43 Gy (BED 10 80 Gy). Taken together, sufficient GTV coverage with a BED 10 of ≥80 Gy and steep dose increase inside the GTV boundary, that is, extremely inhomogeneous GTV dose, are important in 8-fr SRS for ensuring excellent local control of BMs from pan-negative LAC. For local progression following mfSRS that does not fulfill both criteria, re-SRS with the above planning scheme can be an efficacious and safe treatment option for at least six months, especially in cases in which the prior SRS was performed with a dose/fractionation under adequate consideration of brain tolerance. The BED 10 seems to be the most suitable for estimating the anti-tumor efficacies of SRS doses in 3-8 fr, similar to that of a single fraction of 24 Gy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

Five-fraction (fr) stereotactic radiosurgery (SRS) is increasingly being applied to large brain metastases (BMs) >2-3 cm in diameter, for which 30-35 Gy is the commonly prescribed dose. Since 2018, to further enhance both safety and efficacy, we have limited the five-fr SRS to approximately ≤3 cm BMs and adopted our own modified dose prescription and distribution: 43 and 31 Gy cover the boundaries of the gross tumor volume (GTV) and 2 mm outside the GTV, respectively, along with a steep dose increase inside the GTV boundary, that is, an intentionally very inhomogeneous GTV dose. Herein, we describe a case of symptomatic BM treated with five-fr SRS using the above policy, which resulted in a maximum tumor response with nearly complete remission (nCR) followed by gradual tumor regrowth despite obvious tumor shrinkage during irradiation. A 71-year-old man who had previously undergone surgery for squamous cell carcinoma (SCC) of the lungs presented with right-sided hemiparesis attributed to the para-falcine BM (27 mm in maximum diameter, 5.38 cm 3 ). The BM was treated with five-fr SRS, with 99.2% of the GTV covered with 43 Gy and 59% isodose. Neurological symptoms improved during SRS, and obvious tumor shrinkage and mitigation of perilesional edema were observed upon completion of SRS. No subsequent anti-cancer pharmacotherapy was administered due to idiopathic pulmonary fibrosis (IPF). Despite a maximum response with nCR at four months, the tiny residual enhancing lesion gradually enlarged from 7.7 months to 22.7 months without neurological worsening. Although a consistent T1/T2 mismatch suggested the dominance of brain radionecrosis, 11 C-methionine positron emission tomography showed increased uptake in the enhancing lesion. Pathological examination after total lesionectomy at 24.6 months revealed viable tumor tissue. Post-SRS administration of nintedanib for IPF may have provided some anti-tumor efficacy for lung SCC and may mitigate the adverse effects of SRS. The present case suggests that even ≥43 Gy with ≤60% isodose to the GTV boundary and ≥31-35 Gy to the 2 mm outside the GTV are insufficient to achieve long-term local tumor control by five-fr SRS alone in some large BM from lung SCC., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

In stereotactic radiosurgery (SRS) planning for brain metastases (BMs), the target volume is usually defined as an enhancing lesion based on contrast-enhanced (CE) magnetic resonance images (MRI) and/or computed tomography (CT) images. However, contrast media (CM) are unsuitable for certain patients with impaired renal function. Herein, we describe two limited BM cases not amenable to CM, which were treated with five-fraction (fr) SRS, without whole brain radiotherapy (WBRT), through a target definition based on non-CE-MRI. These included synchronous and partly symptomatic four BMs from esophageal squamous cell carcinoma (Case 1) and one presymptomatic regrowing lesion after WBRT for BMs from lung adenocarcinoma (Case 2). In both cases, all BMs were visualized as well-demarcated mass lesions almost distinguishable from the affected parenchyma on non-CE-MRI, particularly on T2-weighted images (WI). The gross tumor volume (GTV) was defined mainly based on T2-WI under a comprehensive comparison of non-CE-T1/T2-WIs and CT for SRS planning under image co-registration and fusion. Stereotactic radiosurgery was implemented with volumetric modulated arcs using a 5-mm leaf width multileaf collimator, for both of which 5 fr was selected, considering the maximum tumor volume and the effects from WBRT, respectively. Dose distribution was designed to ensure a moderate dose attenuation margin outside the GTV boundary and a concentrically-laminated steep dose increase inside the GTV boundary. Specifically, the peripheries of the GTV and 2 mm outside the GTV boundary were covered by ≥43 Gy with <70% isodose relative to the maximum dose and ≥31 Gy, respectively. The not-too-steep dose spillage margin can cover potentially invisible tumor invasion outside the GTV and other inherent uncertainties regarding target definition and irradiation accuracy. Post-SRS tumor responses were excellent clinically and/or radiographically with mild adverse radiation effects in Case 2. In limited BM cases unsuitable to CM, multi-fraction SRS with non-CE-MRI-based GTV definition and sufficient GTV dose along with moderate dose spillage margin would be a valuable treatment option for selected cases, with the entire GTV boundaries being almost visible on non-CE-MRI., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

In single-fraction (sf) stereotactic radiosurgery (SRS) for brain metastases (BM) from lung adenocarcinoma (LAC), a marginal dose of ≥22-24 Gy is generally deemed desirable for achieving long-term local tumor control, whereas symptomatic brain radionecrosis significantly increases when the surrounding brain volume receiving ≥12 Gy (V 12 Gy ) exceeds >5-10 cm 3 , especially in a deep location. Here, we describe a 75-year-old male with a single LAC-BM of 20 mm in diameter, with a deep eloquent location, which was treated with sfSRS followed by erlotinib, resulting in sustained local complete remission (CR) with minimal adverse radiation effect at nearly five years after sfSRS. The LAC harbored epidermal growth factor receptor (EGFR) mutation. The gross tumor volume (GTV) was defined based on contrast-enhanced computed tomography (CECT) alone. sfSRS was implemented 11 days after planning CECT acquisition. The original GTV had some under- and over-coverage of the enhancing lesion. The D 98% values of corrected GTV (cGTV) (3.08 cm 3 ) and 2-mm outside the cGTV were 18.0 Gy with 55% isodose and 14.8 Gy, respectively. The irradiated isodose volumes, including the GTV, receiving ≥22 Gy and ≥12 Gy were 2.18 cm 3  and 14.32 cm 3 , respectively. Erlotinib was administered 13 days after sfSRS with subsequent dose adjustments over 22 months. There was a remarkable tumor response and subsequent nearly CR of the BM were observed at 2.7 and 6.3 months, respectively, with the tumor remnant being visible as a tiny cavitary lesion located in the cortex of the post-central gyrus at 56.4 months. The present case suggests the existence of: (i) extremely radio- and tyrosine kinase inhibitor (TKI)-sensitive LAC-BM for which sfSRS of ≤18 Gy combined with EGFR-TKI is sufficient for attaining long-term CR; and (ii) long-term brain tolerance following sfSRS despite high 12 Gy volume and deep eloquent location in the late 70s The moderate marginal dose of the GTV, the main location of the BM in the cerebral cortex, and the excellent tumor responses with sufficient extrication from the mass effect may render the BM immune to late adverse radiation effect., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

Brain metastases (BMs) from renal cell carcinoma (RCC) have the tendency of slow and insufficient tumor shrinkage along with prolongation of massive peritumoral edema following stereotactic radiosurgery (SRS). Herein, we describe a case of large lobar RCC-BM, with possible intra-sulcal location, treated with 7-fraction (fr) SRS without subsequent anti-cancer medication, which resulted in gradual and remarkable tumor shrinkage with extrication from the mass effect. A 59-year-old woman was incidentally diagnosed with bilateral RCC associated with multiple lung metastases and subsequently presented with symptomatic single BM of 32 mm in the maximum diameter (9.54 cm 3 ) two months later while vacillating. A biopsy of the kidney showed clear cell carcinoma. The patient was deemed medically inoperable for BM due to unfit conditions, including severe deep venous thromboses and thrombocytopenia. Considering the tumor volume, irregular tumor configuration, non-superficial location, and mass effect, 98% of the gross tumor volume (GTV D 98% ) was covered by 48.3 Gy in 7 fr with 64% isodose. Dose distribution was optimized with volumetric modulated arcs with the affirmative allowance of very inhomogeneous GTV dose. Anti-cancer medication was limited to nivolumab plus ipilimumab followed by everolismus 12 days before and during SRS, respectively. Subsequently, the patient transitioned to palliative care due to a declining general condition. Although long-term administration of steroids was required, gradual and marked tumor shrinkage (1.25 cm 3 , 13.1% of the initial volume) and mitigation of the peritumoral edema was observed during six months after SRS. The main location of the initial BM was deemed as intra-sulcal in the intraparietal sulcus and originated in the cerebral cortex. The patient died nine months after SRS. The gradual but remarkable tumor response obtained with 7-fr SRS alone, in this case, provides a basis to further optimize fractionated SRS dosage to enhance efficacy and safety for large and/or symptomatic RCC-BMs not amenable to immediate surgical removal, in combination with anti-cancer pharmacotherapy, if feasible, including tyrosine kinase inhibitors, which may enhance efficacy against BM and mitigate adverse effects relevant to high dose SRS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

Introduction Single or multi-fraction (mf) stereotactic radiosurgery (SRS) is an indispensable treatment option for brain metastases (BMs). The integration of volumetric modulated arc therapy (VMAT) into linac-based SRS is expected to further enhance efficacy and safety and to expand the indications for the challenging type of BMs. However, the optimal treatment design and relevant optimization method for volumetric modulated arc-based radiosurgery (VMARS) remain unestablished with substantial inter-institutional differences. Therefore, this study was conducted to determine the optimal dose distribution suitable for VMARS of BMs, especially regarding dose inhomogeneity of the gross tumor volume (GTV). The GTV boundary, not margin-added planning target volume, was regarded as a basis for planning optimization and dose prescription. Materials and methods This was a planning study for the clinical scenario of a single BM. Eight sphere-shaped objects with diameters of 5-40 mm in 5-mm increments were assumed as GTVs. The treatment system included a 5-mm leaf width multileaf collimator (MLC) Agility® (Elekta AB, Stockholm, Sweden) and a dedicated planning system Monaco® (Elekta AB). The prescribed dose (PD) was uniformly assigned to just cover 98% of the GTV (D 98% ). Three VMARS plans with different dose inhomogeneities of the GTV were generated for each GTV: the % isodose surfaces (IDSs) of GTV D 98% , normalized to 100% at the maximum dose (D max ), were ≤70% (extremely inhomogeneous dose, EIH); ≈80% (inhomogeneous dose, IH); and ≈90% (rather homogeneous dose, RH). VMARS plans were optimized using simple and similar cost functions. In particular, no dose constraint to the GTV D max was assigned to the EIH plans. Results Intended VMARS plans fulfilling the prerequisites were generated without problems for all GTVs of ≥10 mm, whereas 86.4% was the lowest IDS for the D 98%  for 5-mm GTV. Therefore, additional plans for 9- and 8-mm GTVs were generated, which resulted in 68.6% and 75.1% being the lowest IDSs for the D 98%  values of 9- and 8-mm GTVs, respectively. The EIH plans were the best in terms of the following: 1) dose conformity, i.e., minimum spillage of PD outside the GTV; 2) moderate, not too excessive, dose attenuation outside the GTV, i.e., appropriate marginal dose 2-mm outside the GTV boundary as a function of GTV size; and 3) lowest dose of the surrounding normal tissue outside the GTV. In contrast, the RH plans were the worst based on all of the aforementioned measures. Conclusions On the assumption of uniform dose assignment to the GTV margin, a very inhomogeneous GTV dose is basically the most suitable for SRS of BMs in terms of 1) superior dose conformity; 2) minimizing the dose of the surrounding normal tissue outside the GTV; and 3) moderate dose spillage margin outside the GTV with a tumor volume-dependent rational increase, i.e., appropriate dose of the common PTV boundary. The concentrically laminated steep dose increase inside the GTV boundary for the EIH plan may also be advantageous for achieving superior tumor response, although early and excessive GTV shrinkage caused by the EIH plan during mfSRS can lead to surrounding brain injury., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

Dynamic conformal arcs (DCA) are a widely used technique for stereotactic radiosurgery (SRS) of brain metastases (BM) using a micro-multileaf collimator (mMLC), while the planning design and method considerably vary among institutions. In the usual forward planning of DCA, the steepness of the dose gradient outside and inside the gross tumor volume (GTV) boundary is simply defined by the leaf margin (LM) setting to the target volume edge. The dose fall-off outside the small GTV tends to be excessively precipitous, especially with an MLC of 2.5-mm leaf width, which is predisposed to the insufficient coverage of microscopic brain invasion and other inherent inaccuracies. Meanwhile, insufficient dose increase inside the GTV boundary, i.e., less inhomogeneous GTV dose, likely leads to inferior and less sustainable tumor response. The more inhomogeneous GTV dose is prone to the steeper dose gradient outside the GTV and vice versa. Herein, we describe an alternative simply modified DCA (mDCA) planning that was uniquely devised to optimize the dose gradient outside and inside the GTV boundary for further enhancing and consolidating local control of small BM. For a succinct exemplification, a 10-mm spherical target was assumed as a GTV for DCA planning using a 2.5-mm mMLC. The benchmark plan was generated by adding a 0-mm LM to the GTV edge by assigning a single fraction of 30 Gy to the isocenter, in which the GTV coverage by 24 Gy with 80% isodose surface (IDS) was 96%, i.e., D 96% , while the coverage of GTV + isotropic 2 mm volume by 18 Gy with 60% IDS was 70%, with the D 98% being 12 Gy with 40% IDS, viz., too steep dose fall-off outside the GTV boundary. Alternatively, the increase of LM with or without decreasing the isocenter dose enables the increase of the GTV + 2 mm coverage by 18 Gy while resulting in an inadequate GTV dose with either a less inhomogeneous dose or an excessive marginal dose. Meanwhile, in the newly devised mDCA planning, every single arc was converted to a double to-and-fro arc with different LM settings under the same spatial arrangement, which enabled GTV + 2 mm volume coverage with 18 Gy while preserving the GTV marginal dose and inhomogeneity similar to those for the benchmark plan. Additionally, the different collimator angle (CA) setting for the to-and-fro arcs led to further trimming of the dose conformity. The limitations of general forward planning with only adjusting the LM for every single arc were demonstrated, which can be a contributing factor for local tumor progression of small BM. Alternatively, the mDCA with each double to-and-fro arc and different LM and CA settings enables optimization of the dose gradient both outside and inside the GTV boundary according to the planners' intent, e.g., moderate dose spillage margin outside the GTV and steep dose increase inside the GTV boundary., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

Stereotactic radiosurgery (SRS) with >5 fractions (fr) has been increasingly adopted to improve local control and safety for brain metastases (BM) of >10 cm 3 , given the limited brain tolerance of SRS with ≤5 fr. However, the optimal indication and treatment design, including the prescribed dose and distribution for 10 fr SRS, remains uncertain. A single fr of 24 Gy provides approximately 95% of the one-year local tumor control probability. The potential SRS doses in 10 fr that is clinically equivalent to a single fr of 24 Gy regarding anti-tumor effect range from 48.4 to 81.6 Gy as biological effective doses (BED) as a function of the BED model formulas along with the alpha/beta ratios. The most appropriate BED formula in conjunction with an alpha/beta ratio to estimate similar anti-BM effects for single and 10 fr remains controversial. Herein, we describe four cases of symptomatic radiation-naïve BM >10 cm 3 (range, 11 to 26 cm 3 ), treated with 10 fr SRS with a standard prescribed dose of 42 Gy, for which modified dynamic conformal arcs were used with forward planning to improve dose conformity. In the first two cases with gross tumor volumes (GTV) of 15.3 and 10.9 cm 3 , 42 Gy was prescribed to 70%-80% isodose, normalized to 100% at the isocenter, which encompasses the boundary of the planning target volume: GTV + isotropic 1 mm margin. The tumor responses were initially marked regression followed by regrowth within three months in case 1 and no shrinkage with subsequent progression within three months in case 2. In the remaining two cases with larger GTVs of 19.1 and 26.2 cm 3 , the GTV boundary and 2-3 mm margin-added object volume was covered by 80% and 56% isodoses with 53 Gy and 37 Gy, respectively, to further increase the marginal and internal doses of GTV and to ensure moderate dose spillage outside the GTV, while >1-1.5 mm outside the GTV was covered by 42 Gy with 63% isodose. According to the BED based on the linear-quadratic (LQ) model with an alpha/beta ratio of 10 (BED 10 ), 53 Gy corresponds to approximately 81 Gy in BED 10 and 24 Gy in a single fr. Excellent initial maximum tumor response and subsequently sustained tumor regression (STR) were achieved in both cases. Subsequently, enlarging nodules that could not exclude the possibility of tumor regrowth were disclosed within two years, while late adverse radiation effects remained moderate. These dose-effect relationships suggest that a GTV marginal dose of ≥53 Gy with ≤80% isodose would be preferred to effect ≥1-year STR and that further dose escalation of both marginal and internal GTV may be necessary to achieve ≥2-year STR, while GTV of >25 cm 3 may be unsuitable for 10 fr SRS in terms of long-term brain tolerance. Among LQ, LQ-cubic, and LQ-linear model formulas and alpha/beta ratios of 10-20, BED 10 may be clinically most suitable to estimate a 10 fr SRS dose that provides anti-BM efficacy similar to that for a single fr., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

Stereotactic radiosurgery (SRS) with >5 fraction (fr) has been increasingly adopted for brain metastases (BMs), given the current awareness of limited brain tolerance for ≤5 fr. The target volume/configuration change and/or deviation within the cranium during fractionated SRS can be unpredictable and critical uncertainties affecting treatment accuracy, plus the effect of these events on the long-term outcome remains uncertain. Herein, we describe a case of two challenging BMs treated by 10 fr SRS with a unique dose-gradient optimization strategy, in which the large cystic tumor revealed an intriguing correlation of such inter-fractional change with late radiographic sequela, suggesting a dose threshold for attaining long-term local tumor control and being immune to symptomatic brain necrosis. A 63-year-old man presented with two cystic lesions located in the left parietal lobe (19.9 cm 3 ) and pons (1.1 cm 3 ) one month after surgery for esophageal squamous cell carcinoma. The principles for 10 fr SRS were as follows: (1) very inhomogeneous gross tumor volume (GTV) dose covered by 53 Gy, biologically effective dose with an alpha/beta ratio of 10 (BED 10 ) of ≥80 Gy; (2) moderate dose spillage margin outside the GTV boundary: 2-2.5 mm outside the GTV margin was covered by 37 Gy, BED 10  of ≈50 Gy; (3) concentrically-laminated, steep dose increase inside the GTV boundary: 2 mm inside the GTV margin was covered by ≥62 Gy, BED 10  of ≥100 Gy. At the completion of SRS, the parietal lesion showed significant shrinking and dorsomedial shifting with slight evisceration of the GTV, followed by marked regression of the parietal lesion within four months. At 13.5 months, a cystic change was noted at the dorsal part of the remnant. At 16.7 months, ventral enhancement gradually expanded without enlargement of the dorsal cystic component. On the T2-weighted images, the dorsal low-intensity remnant and ventral iso-intensity blurry-demarcated component were contrasting. Pathological examinations during and after lesionectomy at 17.4 months revealed necrosis only. At 30.5 months, the patient had a left visual field defect without recurrence. In contrast, the pons lesion showed no notable change during 10 fr SRS and nearly complete remission over six months with its sustainment without radiation injury at 30.5 months. Taken together, 10 fr SRS with a sufficient BED 10  can provide superior tumor response and safety for BM that is not amenable to ≤5 fr SRS. Although a very inhomogeneous GTV dose can contribute to early and adequate tumor shrinkage and subsequent local tumor eradication, significant tumor shrinkage during fractionated SRS (fSRS) inevitably results in unnecessary higher dose exposure to the surrounding brain, which could lead to late radiation injury requiring intervention. The optimum dose should be determined through further investigation, in consideration of the dynamic and unpredictable nature of the actual absorbed doses to both the tumor and the surrounding brain., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ohtakara et al.)

Purpose: Given its high spatial resolution and vasculature selectivity, the cone-beam computed tomography (CT) angiography (CBCTA) image acquired by selective 3D rotational angiography (3DRA) is the most suitable 3D image for the target definition of stereotactic radiosurgery (SRS) for intracranial arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Furthermore, the relatively low temporal resolution of 3DRA-based CBCTA can be complemented by the stereotactic co-registration of orthogonally paired 2D dynamic digital subtraction angiography (2D-DSA). The integration of 2D-DSA, which is usually limited to one or a few frames for each projection, into CBCTA and/or planning CT can be achieved only by catheter-directed angiography on the day of SRS via a dedicated image localizer under rigid frame fixation to the skull, which imposes substantial burdens on patients. This study aimed to demonstrate a novel, convenient, and significantly less invasive method for the frameless co-registration of biplane 2D-DSA whole frames and CBCTA on commercially available dedicated software, namely, Brainlab ® Elements (Brainlab AG, Munich, Germany), and present its prerequisite for successful image fusion. Technical Report: Elements have afforded the following functionality: A 3D vasculature image is automatically extracted as a floating image from any 3D image series containing vascular details and then subsequently co-registered manually and automatically to a selected frame pair of 2D-DSA with a six-degree-of-freedom rigid registration. As a preclinical feasibility study, two anonymous image datasets from patients harboring cerebral AVM and transverse-sigmoid (TS) DAVF were used to verify the accuracy and practicality of Elements for the frameless co-registration of 2D/3D vascular images, particularly on the assumption of clinical workflow for the target delineation of SRS planning. The use of ordinary unsubtracted CBCTA resulted in the insufficient extraction of abutting vessels or vessels that are in close proximity to bony structures, particularly in the case of TS-DAVF, where the fistulous pouch and the affected venous sinuses were adjacent to the cranial bone. By contrast, the amount and selectivity of vasculatures and the accuracy of subsequent image fusion were significantly improved from the subtracted CBCTA. The integration of CBCTA into dynamic 2D-DSA allowed the simultaneous review of both image information by sharing any concerning point and 2D or 3D structures under a common 3D coordinate., Conclusions: Elements enable the clinically useful frameless co-registration of biplane 2D-DSA whole frames into CBCTA, for which the routine acquisition of both subtracted and unsubtracted CBCTA axial images for ordinary diagnostic purposes is an indispensable prerequisite for successful image fusion and further widespread application. This frameless integration of the 2D/3D angiogram would dramatically enhance both the frame-based and frameless SRS workflow and circumstances by allowing users to forward SRS planning well in advance before SRS, along with the omission of invasive angiography on the day of SRS, and would broaden the implementation of frameless SRS. Furthermore, the comprehensive alternating interactive review of the 2D/3D integrated angiogram leads to a more in-depth quasi-4D understanding of the affected angioarchitectures compared with the separate viewing of each image., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Ohtakara et al.)

Purpose: Several factors, including the surrounding brain volume receiving specific doses, have hitherto been reported to correlate with brain radionecrosis (BR) after single or fractionated stereotactic radiosurgery (sSRS or fSRS) for brain metastases (BMs); however, those, especially for fSRS, have not yet been fully elucidated. Furthermore, the clinical outcome data of patients with BM treated with SRS using Vero4DRT are extremely limited. Therefore, this study aimed to demonstrate the incidence of BR requiring intervention (BRRI) and its highly correlated factors., Materials and Methods: Patients with BMs treated with sSRS or fSRS using Vero4DRT at Toyohashi Municipal Hospital between July 2017 and June 2021 were retrospectively reviewed, of whom patients were available for at least 20 weeks of magnetic resonance imaging follow-up from SRS were included, and analyzed. The prescribed dose fractionation schemes to the planning target volume (PTV) boundary included 24 Gy (sSRS), 35 Gy (5 fractions [fr]), 42 Gy (10 fr), and 30 Gy (3 fr), according to the tumor volume and location. The volume of the surrounding normal brain receiving 84 Gy (V84 Gy, biologically effective dose [BED 2 ] based on a linear-quadratic model with an alpha/beta ratio of 2, single-dose equivalent [SDE] to 12 Gy), V112 Gy (BED 2 , SDE to 14 Gy) for all lesions, and all irradiated volume, including gross tumor volume (GTV) receiving 81.6 Gy (81.6 Gy vol., BED 2 ) for fSRS were calculated, for which cerebrospinal fluid and bone volumes were cautiously excluded. The diagnosis of tumor progression or BR dominance was based on serial T1/T2 matching., Results: Sixty patients with 120 lesions (65 treated with sSRS and 55 treated with fSRS) were included in the final analysis, with a median follow-up period of 65 weeks. The local control rate at one year was 87.5%. The cumulative incidence of BRRI within two years was 11.5%. The risk of symptomatic BR was significantly higher for V84 Gy >10 cc ( p <0.001) and V112 Gy >5 cc ( p = 0.021). In the fSRS group, the cumulative incidence of Grade 3 BR and those requiring resection was significantly higher for 81.6 Gy vol. >14 cc ( p = 0.003 and p = 0.004, respectively). The coexistence of viable tumor tissue and BR could not be ruled out for enlarging lesions after the nadir response, especially for fSRS, due to a lower BED 10 to GTV margin (<80 Gy, BED 10 )., Conclusions: Stereotactic irradiation with Vero4DRT provided efficacy and safety comparable to previous linear accelerator series, and most of the dose-volume thresholds for BRRI presented in this study were notably lower than those reported in previous studies. This study suggests that the indication of single and up to 5 frSRS should be limited to far smaller tumors than previously acknowledged to ensure long-term safety and efficacy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Yamada et al.)