Single- and Multifraction Stereotactic Radiosurgery Dose/Volume Tolerances of the Brain

Abstract

Purpose: As part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy investigating normal tissue complication probability (NTCP) after hypofractionated radiation therapy, data from published reports (PubMed indexed 1995-2018) were pooled to identify dosimetric and clinical predictors of radiation-induced brain toxicity after single-fraction stereotactic radiosurgery (SRS) or fractionated stereotactic radiosurgery (fSRS).

Methods and materials: Eligible studies provided NTCPs for the endpoints of radionecrosis, edema, or symptoms after cranial SRS/fSRS and quantitative dose-volume metrics. Studies of patients with only glioma, meningioma, vestibular schwannoma, or brainstem targets were excluded. The data summary and analyses focused on arteriovenous malformations (AVM) and brain metastases.

Results: Data from 51 reports are summarized. There was wide variability in reported rates of radionecrosis. Available data for SRS/fSRS for brain metastases were more amenable to NTCP modeling than AVM data. In the setting of brain metastases, SRS/fSRS-associated radionecrosis can be difficult to differentiate from tumor progression. For single-fraction SRS to brain metastases, tissue volumes (including target volumes) receiving 12 Gy (V12) of 5 cm³, 10 cm³, or >15 cm³ were associated with risks of symptomatic radionecrosis of approximately 10%, 15%, and 20%, respectively. SRS for AVM was associated with modestly lower rates of symptomatic radionecrosis for equivalent V12. For brain metastases, brain plus target volume V20 (3-fractions) or V24 (5-fractions) <20 cm³ was associated with <10% risk of any necrosis or edema, and <4% risk of radionecrosis requiring resection.

Conclusions: The risk of radionecrosis after SRS and fSRS can be modeled as a function of dose and volume treated. The use of fSRS appears to reduce risks of radionecrosis for larger treatment volumes relative to SRS. More standardized dosimetric and toxicity reporting is needed to facilitate future pooled analyses that can refine predictive models of brain toxicity risks.

Figure 1.

Risk of any necrosis (symptomatic or asymptomatic) after SRS for AVM vs. tissue volume receiving ≥12 Gy in one fraction (V12). Data were extracted from studies which subgrouped (binned) ranges of V10-V12 and reported the risks of necrosis for patients/lesions within the individual bins. The figure represents a rough approximation of data, as (1) the median value of V12 for a given bin was estimated as the midpoint in the range of values in that bin, except for the bin with the greatest V12; for the largest-value bins, it was assumed that the highest values within that bin represented a relatively small proportion of patients (i.e., the extremely large V12 values were outliers); (2) for data from the Voges et al. study which reported V10, the equivalent to V12 was estimated as described in the text (Eq. 2). The error bars represent 95% binomial confidence intervals and the solid lines represent a fitted logistic model to the data. Studies included Voges, 1996 and Flickinger, 1998; both were single-fraction SRS studies.

Figure 2.

Risk of symptomatic necrosis after SRS for AVM vs. tissue volume receiving ≥12 Gy in one fraction (V12). Data were extracted from studies that reported necrosis risks and median V12 among all patients or subgrouped (binned) ranges of V12 and reported the risks of necrosis for patients/lesions within the individual bins. The figure represents a rough approximation of data, as the median value of V12 for a given bin was estimated as described in the caption from Figure 1. The error bars represent 95% binomial confidence intervals and the solid lines represent a fitted logistic model to the data. Studies included Flickinger, 1998; Flickinger, 2000; Cetin, 2012; Herbert, 2012; and Kano, 2017; all were single-fraction SRS studies. The data from Herbert et al. was obtained from the authors. Three of the 5 studies included patients from one institution (University of Pittsburgh).

Figure 3.

Risk of any necrosis (symptomatic or asymptomatic) after SRS for brain metastases vs. tissue (target plus non-target) or brain (excluding the target volume and non-brain normal tissue) volume receiving ≥12 Gy equivalent in one fraction (V12). Panel A shows data from single-fraction SRS studies; solid data points represent tissue V12 (target plus non-target) and hollow data points represent brain V12 (excluding the target volume and non-brain normal tissue). Panel B shows data from multi-fraction SRS studies (all reporting brain Vx; i.e. again excluding the target volume and non-brain normal tissue). Data were extracted from studies that reported necrosis risks and median Vx among all patients/lesions or subgrouped (binned) ranges of Vx and reported the risks of necrosis for patients/lesions within the individual bins. One study (Minniti, 2016) in Figure 3A calculated Vx per patient while the others calculated Vx per lesion (see text); all of the studies in Figure 3B calculated Vx per patient. These figures represent a rough approximation of data, as (1) the median value of V12 for a given bin was estimated as described in the caption from Figure 1; (2) for multi-fraction SRS studies, the linear-quadratic model with alpha-beta ratio of 2 was used to convert dose to single-fraction equivalent dose. The error bars represent 95% binomial confidence intervals and the solid lines represent a fitted logistic model to the data. When analyzed separately, there was no significant difference between the tissue V12 and brain V12 logistic models; they are therefore combined together in Panel A, recognizing that tissue V12 would have a larger value than brain V12, and that the figure is meant to be descriptive. Studies included in Figure 3A were Korytko, 2006; Blonigen, 2010; Minniti, 2011; Ohtakara, 2012; Sneed, 2015; Minniti, 2016. Studies included in Figure 3B were Ernst-Stecken, 2006; Minniti, 2013 (with 1 resected brain metastasis per patient); Minniti, 2014; Minniti, 2016; and Dore, 2017 (with ~1 resected brain metastasis per patient).

Figure 3.

Risk of any necrosis (symptomatic or asymptomatic) after SRS for brain metastases vs. tissue (target plus non-target) or brain (excluding the target volume and non-brain normal tissue) volume receiving ≥12 Gy equivalent in one fraction (V12). Panel A shows data from single-fraction SRS studies; solid data points represent tissue V12 (target plus non-target) and hollow data points represent brain V12 (excluding the target volume and non-brain normal tissue). Panel B shows data from multi-fraction SRS studies (all reporting brain Vx; i.e. again excluding the target volume and non-brain normal tissue). Data were extracted from studies that reported necrosis risks and median Vx among all patients/lesions or subgrouped (binned) ranges of Vx and reported the risks of necrosis for patients/lesions within the individual bins. One study (Minniti, 2016) in Figure 3A calculated Vx per patient while the others calculated Vx per lesion (see text); all of the studies in Figure 3B calculated Vx per patient. These figures represent a rough approximation of data, as (1) the median value of V12 for a given bin was estimated as described in the caption from Figure 1; (2) for multi-fraction SRS studies, the linear-quadratic model with alpha-beta ratio of 2 was used to convert dose to single-fraction equivalent dose. The error bars represent 95% binomial confidence intervals and the solid lines represent a fitted logistic model to the data. When analyzed separately, there was no significant difference between the tissue V12 and brain V12 logistic models; they are therefore combined together in Panel A, recognizing that tissue V12 would have a larger value than brain V12, and that the figure is meant to be descriptive. Studies included in Figure 3A were Korytko, 2006; Blonigen, 2010; Minniti, 2011; Ohtakara, 2012; Sneed, 2015; Minniti, 2016. Studies included in Figure 3B were Ernst-Stecken, 2006; Minniti, 2013 (with 1 resected brain metastasis per patient); Minniti, 2014; Minniti, 2016; and Dore, 2017 (with ~1 resected brain metastasis per patient).

Figure 4.

Risk of symptomatic necrosis after SRS for brain metastases vs. volume of tissue (target plus non-target; solid symbols) or brain (excluding the target volume and non-brain normal tissue; open symbols) receiving ≥12 Gy equivalent in one fraction (V12). All of the studies reported Vx per lesion (see text). Data were extracted from studies that reported necrosis risks and median Vx among all patients/lesions or subgrouped (binned) ranges of Vx and reported the risks of necrosis for patients/lesions within the individual bins. All of the multi-fraction fSRS studies used the endpoint of symptomatic necrosis requiring resection, whereas all of the single-fraction SRS studies used the endpoint of any symptomatic necrosis. The figure represent a rough approximation of data, as (1) the median value of V12 for a given bin was estimated as described in the caption from Figure 1; (2) for multi-fraction SRS studies, the linear-quadratic model with alpha-beta ratio of 2 was used to convert dose to single-fraction equivalent dose; (3) in those studies which reported V10 or V14, the equivalent to V12 was estimated as described in the text (Eq. 2). The error bars represent 95% binomial confidence intervals, and the solid and dashed lines represent fitted logistic models to the single-fraction tissue V12 and multi-fraction brain V12 (in single-fraction equivalent) data, respectively. Single-fraction SRS studies included Korytko, 2006; Blonigen, 2010; Minniti, 2011; Ohtakara, 2012; and Sneed, 2015. Multi-fraction fSRS studies included Inoue, 2013 and 2014, and Dore, 2017 (with ~1 resected brain metastasis per patient); all 3 used brain Vx.

Figure 5.

Aggregate model of edema or necrosis as a function of V12Gy, including GTV, for patients treated with cranial SRS/fSRS, using individual patient data from Chin (2001), Korykto (2006), Inoue (2013), Inoue (2014) and Peng (2018), including 34, 129, 145, 78 and 57 patients (34, 198, 159, 85 and 294 lesions), respectively. Eq. (1) (shown in the text) was used to approximate V12Gy for the aggregated data points from studies by Chin et al., Inoue et al. and Peng et al. The vertical error bars are binomial 68% confidence intervals calculated using the score method and the horizontal error bars are the standard deviations for V12 for a particular bin. Since there were relatively few targets associated with V12Gy >50 cc, the bins in that range tended to quantize towards 0% or 100%. The model parameters for the pooled data are: Vx,50=63.2 (95% CI: 49.2–97.0) and γ50=0.87 (95% CI: 0.74–1.03) with p <0.001 (calculated using chi-squared, based on likelihood ratio by comparing best fit against a horizontal line through incidence averaged over all patients). Because the reported risks from Korytko et al. were substantially greater than in other studies, the unmodified logistic model from their report (dashed line) is shown separately from the others (solid line), and only the other studies are included in the observed data (dots with error bars). The Korytko et al. data points were published in terms of V12Gy. GTV= gross tumor volume, 1fx= single-fraction equivalent dose using linear quadratic with α/β=2 Gy, V12Gy= the volume of total brain exceeding an equivalent dose of 12 Gy in one fraction. CI= confidence interval.

Figure 6.

Volume response normal tissue complication probability models for brain necrosis in patients treated with SRS/fSRS for brain metastases: (A) for grade 1–3 edema or necrosis, and (B) for grade 3 surgically removed and pathologically confirmed necrosis. Data are pooled from 3 studies: Inoue (2013), Inoue (2014) and Peng (2018), including 145, 78 and 57 patients (159, 85 and 294 lesions), respectively. The vertical error bars are binomial 68% confidence intervals calculated using the score method and the horizontal error bars are the standard deviations for V14 for a particular bin. The model parameters for the pooled data are: for Figure 6A, Vx,50=45.8 (95% CI: 33.0–106.2) and γ50=0.88 (95% CI: 0.68–1.11) with p=0.003; for Figure 6B, Vx,50=42.6 (95% CI: 33.8–75.5) and γ50=1.58 (95% CI: 1.17–2.09) with p<0.001. p values were calculated using chi-squared, based on likelihood ratio by comparing best fit against a horizontal line through incidence averaged over all patients. GTV= gross tumor volume, 1fx= single-fraction equivalent dose using linear quadratic with α/β=2 Gy, V14Gy= the volume of total brain exceeding an equivalent dose of 14 Gy in one fraction. CI=confidence interval

Figure 6.

Volume response normal tissue complication probability models for brain necrosis in patients treated with SRS/fSRS for brain metastases: (A) for grade 1–3 edema or necrosis, and (B) for grade 3 surgically removed and pathologically confirmed necrosis. Data are pooled from 3 studies: Inoue (2013), Inoue (2014) and Peng (2018), including 145, 78 and 57 patients (159, 85 and 294 lesions), respectively. The vertical error bars are binomial 68% confidence intervals calculated using the score method and the horizontal error bars are the standard deviations for V14 for a particular bin. The model parameters for the pooled data are: for Figure 6A, Vx,50=45.8 (95% CI: 33.0–106.2) and γ50=0.88 (95% CI: 0.68–1.11) with p=0.003; for Figure 6B, Vx,50=42.6 (95% CI: 33.8–75.5) and γ50=1.58 (95% CI: 1.17–2.09) with p<0.001. p values were calculated using chi-squared, based on likelihood ratio by comparing best fit against a horizontal line through incidence averaged over all patients. GTV= gross tumor volume, 1fx= single-fraction equivalent dose using linear quadratic with α/β=2 Gy, V14Gy= the volume of total brain exceeding an equivalent dose of 14 Gy in one fraction. CI=confidence interval