Correlation of Brain Metastasis Shrinking and Deviation During 10-Fraction Stereotactic Radiosurgery With Late Sequela: Suggesting Dose Ramification Between Tumor Eradication and Symptomatic Radionecrosis

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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 longterm 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.

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ten-Fraction Stereotactic Radiosurgery With Different Gross Tumor Doses and Inhomogeneities for Brain Metastasis of >10 cc: Treatment Responses Suggesting Suitable Biological Effective Dose Formula for Single and 10 Fractions

Ohtakara¹,

Nakabayashi²,

Suzuki³

2023

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“…LC failure and/or symptomatic irreversible radiation injury following SRS of just a single BM can inflict a devastating effect on the patient's health and life. Local definitive and radical treatment far beyond palliation is demanded by a certain proportion of BM patients, for whom scrupulous and conscientious SRS design and planning are needed [5]. 1, 2 2 In a substantial number of BM, the brain-BM interfaces are pathologically poorly demarcated, viz., the presence of microscopic brain infiltration with various depths and patterns as a function of the BM volume and histopathology [6].…”

Section: Introductionmentioning

confidence: 99%

“…Complete tumor eradication, including brain invasion, is demanded to achieve superior long-term LC. Consequently, a steep dose gradient outside the gross tumor volume (GTV) boundary can lead to insufficient dose coverage for brain invasion [5,7]. Therefore, moderate, not too precipitous or gradual, dose attenuation outside the GTV would be desirable, also given the other treatment-related uncertainties, including intra-fractional patient movement [5].…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, a steep dose gradient outside the gross tumor volume (GTV) boundary can lead to insufficient dose coverage for brain invasion [5,7]. Therefore, moderate, not too precipitous or gradual, dose attenuation outside the GTV would be desirable, also given the other treatment-related uncertainties, including intra-fractional patient movement [5]. Thus, the ideal and optimal dose distribution of SRS for BM would be considerably different from those for pathologically well-demarcated benign tumors and vascular malformation.…”

Section: Introductionmentioning

confidence: 99%

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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

Ohtakara¹,

Suzuki²

2023

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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.

An Extremely Inhomogeneous Gross Tumor Dose is Suitable for Volumetric Modulated Arc-Based Radiosurgery with a 5-mm Leaf-Width Multileaf Collimator for Single Brain Metastasis

Ohtakara¹,

Suzuki²

2023

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IntroductionSingle 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 marginadded planning target volume, was regarded as a basis for planning optimization and dose prescription. Materials and methodsThis 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. ResultsIntended 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. ConclusionsOn 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 super...