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Purpose: Uveal melanoma (UM), although a rare malignancy, stands as the most prevalent intraocular malignancy in adults. Controversies persist regarding the dose dependency of local control (LC) through radiation therapy. This study sought to elucidate the significance of the prescription dose by employing time-dose-response models for patients with UM receiving photon-based stereotactic radiosurgery (SRS)., Methods and Materials: The analysis included patients with UM treated between 2005 and 2019. All patients underwent single-fraction SRS. Datapoints were separated into 3 dose groups, with Kaplan-Meier analysis performed on each group, from which time-dose-response models for LC were created at 2, 4, and 7 years after SRS using maximum-likelihood fitted logistic models., Results: Outcomes from 594 patients with 594 UMs were used to create time-dose-response models. The prescribed doses and the number of patients were as follows: 17 to 19 Gy (24 patients), 20 Gy (122 patients), 21 Gy (442 patients), and 22 Gy (6 patients). Averaged over all patients and doses, LC rates at 2, 4, and 7 years were 94.4%, 88.2%, and 69.0%, respectively. Time-dose-response models for LC demonstrated a dose-dependent effect, showing 2-year LC rates of more than 90% with 20 Gy and 95% with 22 Gy. For 4 years and a LC of 90%, a dose of approximately 21 Gy was required. After 7 years, the 21 Gy prescription dose was predicted to maintain a LC above 70%, sharply declining to less than 60% LC with 19 Gy and less than 40% with 18 Gy., Conclusions: In contrast to prior findings, the time-dose-response models for UM undergoing photon-based SRS emphasize the critical role of the prescription dose in achieving lasting LC. The dose selection must be carefully balanced against toxicity risks, considering tumor geometry and individual patient characteristics to tailor treatments accordingly., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

We sought to systematically review and summarize dosimetric factors associated with radiation-induced brachial plexopathy (RIBP) after stereotactic body radiation therapy (SBRT) or hypofractionated image guided radiation therapy (HIGRT). From published studies identified from searches of PubMed and Embase databases, data quantifying risks of RIBP after 1- to 10-fraction SBRT/HIGRT were extracted and summarized. Published studies have reported <10% risks of RIBP with maximum doses (D max ) to the inferior aspect of the brachial plexus of 32 Gy in 5 fractions and 25 Gy in 3 fractions. For 10-fraction HIGRT, risks of RIBP appear to be low with D max < 40 to 50 Gy. For a given dose value, greater risks are anticipated with point volume-based metrics (ie, D 0.03-0.035cc : minimum dose to hottest 0.03-0.035 cc) versus D max . With SBRT/HIGRT, there were insufficient published data to predict risks of RIBP relative to brachial plexus dose-volume exposure. Minimizing maximum doses and possibly volume exposure of the brachial plexus can reduce risks of RIBP after SBRT/HIGRT. Further study is needed to better understand the effect of volume exposure on the brachial plexus and whether there are location-specific susceptibilities along or within the brachial plexus structure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Ultrahypofractionationed radiation therapy for prostate cancer is increasingly studied and adopted. The American Association of Physicists in Medicine Working Group on Biological Effects of Hypofractionated Radiotherapy therefore aimed to review studies examining toxicity and quality of life after stereotactic body radiation therapy (SBRT) for prostate cancer and model its effect., Methods and Materials: We performed a systematic PubMed search of prostate SBRT studies published between 2001 and 2018. Those that analyzed factors associated with late urinary, bowel, or sexual toxicity and/or quality of life were included and reviewed. Normal tissue complication probability modelling was performed on studies that contained detailed dose/volume and outcome data., Results: We found 13 studies that examined urinary effects, 6 that examined bowel effects, and 4 that examined sexual effects. Most studies included patients with low-intermediate risk prostate cancer treated to 35-40 Gy. Most patients were treated with 5 fractions, with several centers using 4 fractions. Endpoints were heterogeneous and included both physician-scored toxicity and patient-reported quality of life. Most toxicities were mild-moderate (eg, grade 1-2) with a very low overall incidence of severe toxicity (eg, grade 3 or higher, usually <3%). Side effects were associated with both dosimetric and non-dosimetric factors., Conclusions: Prostate SBRT appears to be overall well tolerated, with determinants of toxicity that include dosimetric factors and patient factors. Suggested dose constraints include bladder V(Rx Dose)Gy <5-10 cc, urethra Dmax <38-42 Gy, and rectum Dmax <35-38 Gy, though current data do not offer firm guidance on tolerance doses. Several areas for future research are suggested., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Stereotactic body radiation therapy (SBRT) has emerged as an effective, noninvasive treatment option for primary liver cancer and metastatic disease occurring in the liver. Although SBRT can be highly effective for establishing local control in hepatic malignancies, a tradeoff exists between tumor control and normal tissue complications. The objective of the present study was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal toxicities and derive normal tissue complication probability models., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To quantitatively evaluate published experiences with hepatic stereotactic body radiation therapy (SBRT), to determine local control rates after treatment of primary and metastatic liver tumors and to examine whether outcomes are affected by SBRT dosing regimen., Methods and Materials: We identified published articles that reported local control rates after SBRT for primary or metastatic liver tumors. Biologically effective doses (BEDs) were calculated for each dosing regimen using the linear-quadratic equation. We excluded series in which a wide range of BEDs was used. Individual lesion data for local control were extracted from actuarial survival curves, and data were aggregated to form a single dataset. Actuarial local control curves were generated using the Kaplan-Meier method after grouping lesions by disease type and BED (<100 Gy 10 vs >100 Gy 10 ). Comparisons were made using log-rank testing., Results: Thirteen articles met all inclusion criteria and formed the dataset for this analysis. The 1-, 2-, and 3-year actuarial local control rates after SBRT for primary liver tumors (n = 431) were 93%, 89%, and 86%, respectively. Lower 1- (90%), 2- (79%), and 3-year (76%) actuarial local control rates were observed for liver metastases (n = 290, log-rank P = .011). Among patients treated with SBRT for primary liver tumors, there was no evidence that local control is influenced by BED within the range of schedules used. For liver metastases, on the other hand, outcomes were significantly better for lesions treated with BEDs exceeding 100 Gy 10 (3-year local control 93%) than for those treated with BEDs of ≤100 Gy 10 (3-year local control 65%, P < .001)., Conclusions: Stereotactic body radiation therapy for primary liver tumors provides high rates of durable local control, with no clear evidence for a dose-response relationship among commonly utilized schedules. Excellent local control rates are also seen after SBRT for liver metastases when BEDs of >100 Gy 10 are utilized., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1 to 5 fractions, the following spinal cord point maximum doses (D max ) are estimated to be associated with a 1% to 5% risk of radiation myelopathy (RM): 12.4 to 14.0 Gy in 1 fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. For reirradiation SBRT delivered in 1 to 5 fractions, reported factors associated with a lower risk of RM include cumulative thecal sac equivalent dose in 2 Gy fractions with an alpha/beta of 2 (EQD2 2 ) D max ≤70 Gy; SBRT thecal sac EQD2 2 D max ≤25 Gy, thecal sac SBRT EQD2 2 D max to cumulative EQD2 2 D max ratio ≤0.5, and a minimum time interval to reirradiation of ≥5 months. Larger studies containing complete institutional cohorts with dosimetric data of patients treated with spine SBRT, with and without RM, are required to refine RM risk estimates., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Dose-volume data for injury to carotid artery and other major vessels in stereotactic body radiation therapy (SBRT)/SABR head and neck reirradiation were reviewed, modeled, and summarized., Methods and Materials: A PubMed search of the English-language literature (stereotactic and carotid and radiation) in April 2018 found 238 major vessel maximum point doses in 6 articles that were pooled for logistic modeling. Two subsequent studies with dose-volume major vessel data were modeled separately for comparison. Attempts were made to separate carotid blowout syndrome from other bleeding events (BE) in the analysis, but we acknowledge that all except 1 data set has some element of BE interspersed., Results: Prior radiation therapy (RT) dose was not uniformly reported per patient in the studies included, but a course on the order of conventionally fractionated 70 Gy was considered for the purposes of the analysis (with an approximately ≥6-month estimated interval between prior and subsequent treatment in most cases). Factors likely associated with reduced risk of BE include nonconsecutive daily treatment, lower extent of circumferential tumor involvement around the vessel, and no surgical manipulation before or after SBRT., Conclusions: Initial data pooling for reirradiation involving the carotid artery resulted in 3 preliminary models compared in this Hypofractionated Treatment Effects in the Clinic (HyTEC) report. More recent experiences with alternating fractionation schedules and additional risk-reduction strategies are also presented. Complications data for the most critical structures such as spinal cord and carotid artery are so limited that they cannot be viewed as strong conclusions of probability of risk, but rather, as a general guideline for consideration. There is a great need for better reporting standards as noted in the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic introductory paper., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Stereotactic body radiation therapy (SBRT) has emerged as a viable reirradiation strategy for locally recurrent previously-irradiated head and neck cancer. Doses in the literature have varied, which challenges clinical application of SBRT as well as clinical trial design., Material & Methods: A working group was formed through the American Association of Physicists in Medicine to study tumor control probabilities for SBRT in head and neck cancer. We herein present a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally recurrent previously-irradiated head and neck cancer. Dose-response models are generated that present tumor control probability as a function of dose., Results: Data from more than 300 cases in 8 publications suggest that there is a dose-response relationship, with superior local control and possibly improved overall survival for doses of 35 to 45 Gy (in 5 fractions) compared with <30 Gy., Conclusion: Stereotactic body radiation therapy doses equivalent to 5-fraction doses of 40 to 50 Gy are suggested for retreatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

An overview of common approaches used to assess a dose response for radiation therapy-associated endpoints is presented, using lung toxicity data sets analyzed as a part of the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic effort as an example. Each component presented (eg, data-driven analysis, dose-response analysis, and calculating uncertainties on model prediction) is addressed using established approaches. Specifically, the maximum likelihood method was used to calculate best parameter values of the commonly used logistic model, the profile-likelihood to calculate confidence intervals on model parameters, and the likelihood ratio to determine whether the observed data fit is statistically significant. The bootstrap method was used to calculate confidence intervals for model predictions. Correlated behavior of model parameters and implication for interpreting dose response are discussed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We sought to investigate the tumor control probability (TCP) of spinal metastases treated with stereotactic body radiation therapy (SBRT) in 1 to 5 fractions., Methods and Materials: PubMed-indexed articles from 1995 to 2018 were eligible for data extraction if they contained SBRT dosimetric details correlated with actuarial 2-year local tumor control rates. Logistic dose-response models of collected data were compared in terms of physical dose and 3-fraction equivalent dose., Results: Data were extracted from 24 articles with 2619 spinal metastases. Physical dose TCP modeling of 2-year local tumor control from the single-fraction data were compared with data from 2 to 5 fractions, resulting in an estimated α/β = 6 Gy, and this was used to pool data. Acknowledging the uncertainty intrinsic to the data extraction and modeling process, the 90% TCP corresponded to 20 Gy in 1 fraction, 28 Gy in 2 fractions, 33 Gy in 3 fractions, and (with extrapolation) 40 Gy in 5 fractions. The estimated TCP for common fractionation schemes was 82% at 18 Gy, 90% for 20 Gy, and 96% for 24 Gy in a single fraction, 82% for 24 Gy in 2 fractions, and 78% for 27 Gy in 3 fractions., Conclusions: Spinal SBRT with the most common fractionation schemes yields 2-year estimates of local control of 82% to 96%. Given the heterogeneity in the tumor control estimates extracted from the literature, with variability in reporting of dosimetry data and the definition of and statistical methods of reporting tumor control, care should be taken interpreting the resultant model-based estimates. Depending on the clinical intent, the improved TCP with higher dose regimens should be weighed against the potential risks for greater toxicity. We encourage future reports to provide full dosimetric data correlated with tumor local control to allow future efforts of modeling pooled data., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: As part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy, tumor control probability (TCP) after stereotactic radiosurgery (SRS) and fractionated stereotactic radiosurgery (fSRS) for brain metastases was modeled based on pooled dosimetric and clinical data from published English-language literature., Methods and Materials: PubMed-indexed studies published between January 1995 and September 2017 were used to evaluate dosimetric and clinical predictors of TCP after SRS or fSRS for brain metastases. Eligible studies had ≥10 patients and included detailed dose-fractionation data with corresponding ≥1-year local control (LC) data, typically evaluated as a >20% increase in diameter of the targeted lesion using the pre-SRS diameter as a reference., Results: Of 2951 potentially eligible manuscripts, 56 included sufficient dose-volume data for analyses. Accepting that necrosis and pseudoprogression can complicate the assessment of LC, for tumors ≤20 mm, single-fraction doses of 18 and 24 Gy corresponded with >85% and 95% 1-year LC rates, respectively. For tumors 21 to 30 mm, an 18 Gy single-fraction dose was associated with 75% LC. For tumors 31 to 40 mm, a 15 Gy single-fraction dose yielded ∼69% LC. For 3- to 5-fraction fSRS using doses in the range of 27 to 35 Gy, 80% 1-year LC has been achieved for tumors of 21 to 40 mm in diameter., Conclusions: TCP for SRS and fSRS are presented. For small lesions ≤20 mm, single doses of ≈18 Gy appear generally associated with excellent rates of LC; for melanoma, higher doses seem warranted. For larger lesions >20 mm, local control rates appear to be ≈ 70% to 75% with usual doses of 15 to 18 Gy, and in this setting, fSRS regimens should be considered. Greater consistency in reporting of dosimetric and LC data is needed to facilitate future pooled analyses. As systemic and biologic therapies evolve, updated analyses will be needed to further assess the necessity, efficacy, and toxicity of SRS and fSRS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Dosimetric and clinical predictors of radiation-induced optic nerve/chiasm neuropathy (RION) after single-fraction stereotactic radiosurgery (SRS) or hypofractionated (2-5 fractions) radiosurgery (fSRS) were analyzed from pooled data that were extracted from published reports (PubMed indexed from 1990 to June 2015). This study was undertaken 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., Methods and Materials: Eligible studies described dose delivered to optic nerve/chiasm and provided crude or actuarial toxicity risks, with visual endpoints (ie, loss of visual acuity, alterations in visual fields, and/or blindness/complete vision loss). Studies of patients with optic nerve sheath tumors, optic nerve gliomas, or ocular/uveal melanoma were excluded to obviate direct tumor effects on visual outcomes, as were studies not specifying causes of vision loss (ie, tumor progression vs RION)., Results: Thirty-four studies (1578 patients) were analyzed. Histologies included pituitary adenoma, cavernous sinus meningioma, craniopharyngioma, and malignant skull base tumors. Prior resection (76% of patients) did not correlate with RION risk (P = .66). Prior irradiation (6% of patients) was associated with a crude 10-fold increased RION risk versus no prior radiation therapy. In patients with no prior radiation therapy receiving SRS/fSRS in 1-5 fractions, optic apparatus maximum point doses resulting in <1% RION risks include 12 Gy in 1 fraction (which is greater than our recommendation of 10 Gy in 1 fraction), 20 Gy in 3 fractions, and 25 Gy in 5 fractions. Omitting multi-fraction data (and thereby eliminating uncertainties associated with dose conversions), a single-fraction dose of 10 Gy was associated with a 1% RION risk. Insufficient details precluded modeling of NTCP risks after prior radiation therapy., Conclusions: Optic apparatus NTCP and tolerance doses after single- and multi-fraction stereotactic radiosurgery are presented. Additional standardized dosimetric and toxicity reporting is needed to facilitate future pooled analyses and better define RION NTCP after SRS/fSRS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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 cm 3 , 10 cm 3 , or >15 cm 3 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 cm 3 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Dose escalation improves localized prostate cancer disease control, and moderately hypofractionated external beam radiation is noninferior to conventional fractionation. The evolving treatment approach of ultrahypofractionation with stereotactic body radiation therapy (SBRT) allows possible further biological dose escalation (biologically equivalent dose [BED]) and shortened treatment time., Methods and Materials: The American Association of Physicists in Medicine Working Group on Biological Effects of Hypofractionated Radiation Therapy/SBRT included a subgroup to study the prostate tumor control probability (TCP) with SBRT. We performed a systematic review of the available literature and created a dose-response TCP model for the endpoint of freedom from biochemical relapse. Results were stratified by prostate cancer risk group., Results: Twenty-five published cohorts were identified for inclusion, with a total of 4821 patients (2235 with low-risk, 1894 with intermediate-risk, and 446 with high-risk disease, when reported) treated with a variety of dose/fractionation schemes, permitting dose-response modeling. Five studies had a median follow-up of more than 5 years. Dosing regimens ranged from 32 to 50 Gy in 4 to 5 fractions, with total BED (α/β = 1.5 Gy) between 183.1 and 383.3 Gy. At 5 years, we found that in patients with low-intermediate risk disease, an equivalent doses of 2 Gy per fraction (EQD2) of 71 Gy (31.7 Gy in 5 fractions) achieved a TCP of 90% and an EQD2 of 90 Gy (36.1 Gy in 5 fractions) achieved a TCP of 95%. In patients with high-risk disease, an EQD2 of 97 Gy (37.6 Gy in 5 fractions) can achieve a TCP of 90% and an EQD2 of 102 Gy (38.7 Gy in 5 fractions) can achieve a TCP of 95%., Conclusions: We found significant variation in the published literature on target delineation, margins used, dose/fractionation, and treatment schedule. Despite this variation, TCP was excellent. Most prescription doses range from 35 to 40 Gy, delivered in 4 to 5 fractions. The literature did not provide detailed dose-volume data, and our dosimetric analysis was constrained to prescription doses. There are many areas in need of continued research as SBRT continues to evolve as a treatment modality for prostate cancer, including the durability of local control with longer follow-up across risk groups, the efficacy and safety of SBRT as a boost to intensity modulated radiation therapy (IMRT), and the impact of incorporating novel imaging techniques into treatment planning., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We sought to investigate the tumor control probability (TCP) of vestibular schwannomas after single-fraction stereotactic radiosurgery (SRS) or hypofractionated SRS over 2 to 5 fractions (fSRS)., Methods and Materials: Studies (PubMed indexed from 1993-2017) were eligible for data extraction if they contained dosimetric details of SRS/fSRS correlated with local tumor control. The rate of tumor control at 5 years (or at 3 years if 5-year data were not available) were collated. Poisson modeling estimated the TCP per equivalent dose in 2 Gy per fraction (EQD2) and in 1, 3, and 5 fractions., Results: Data were extracted from 35 publications containing a total of 5162 patients. TCP modeling was limited by the absence of analyzable data of <11 Gy in a single-fraction, variability in definition of "tumor control," and by lack of significant increase in TCP for doses >12 Gy. Using linear-quadratic-based dose conversion, the 3- to 5-year TCP was estimated at 95% at an EQD2 of 25 Gy, corresponding to 1-, 3-, and 5-fraction doses of 13.8 Gy, 19.2 Gy, and 21.5 Gy, respectively. Single-fraction doses of 10 Gy, 11 Gy, 12 Gy, and 13 Gy predicted a TCP of 85.0%, 88.4%, 91.2%, and 93.5%, respectively. For fSRS, 18 Gy in 3 fractions (EQD2 of 23.0 Gy) and 25 Gy in 5 fractions (EQD2 of 30.2 Gy) corresponded to TCP of 93.6% and 97.2%. Overall, the quality of dosimetric reporting was poor; recommended reporting guidelines are presented., Conclusions: With current typical SRS doses of 12 Gy in 1 fraction, 18 Gy in 3 fractions, and 25 Gy in 5 fractions, 3- to 5-year TCP exceeds 91%. To improve pooled data analyses to optimize treatment outcomes for patients with vestibular schwannoma, future reports of SRS should include complete dosimetric details with well-defined tumor control and toxicity endpoints., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) and stereotactic ablative body radiation therapy is being increasingly used for pancreatic cancer (PCa), particularly in patients with locally advanced and borderline resectable disease. A wide variety of dose fractionation schemes have been reported in the literature. This HyTEC review uses tumor control probability models to evaluate the comparative effectiveness of the various SBRT treatment regimens used in the treatment of patients with localized PCa., Methods and Materials: A PubMed search was performed to review the published literature on the use of hypofractionated SBRT (usually in 1-5 fractions) for PCa in various clinical scenarios (eg, preoperative [neoadjuvant], borderline resectable, and locally advanced PCa). The linear quadratic model with α/β= 10 Gy was used to address differences in fractionation. Logistic tumor control probability models were generated using maximum likelihood parameter fitting., Results: After converting to 3-fraction equivalent doses, the pooled reported data and associated models suggests that 1-year local control (LC) without surgery is ≈79% to 86% after the equivalent of 30 to 36 Gy in 3 fractions, showing a dose response in the range of 25 to 36 Gy, and decreasing to less than 70% 1-year LC at doses below 24 Gy in 3 fractions. The 33 Gy in 5 fraction regimen (Alliance A021501) corresponds to 28.2 Gy in 3 fractions, for which the HyTEC pooled model had 77% 1-year LC without surgery. Above an equivalent dose of 28 Gy in 3 fractions, with margin-negative resection the 1-year LC exceeded 90%., Conclusions: Pooled analyses of reported tumor control probabilities for commonly used SBRT dose-fractionation schedules for PCa suggests a dose response. These findings should be viewed with caution given the challenges and limitations of this review. Additional data are needed to better understand the dose or fractionation-response of SBRT for PCa., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To review the radiobiological mechanisms of stereotactic body radiation therapy stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS)., Methods and Materials: We reviewed previous reports and recent observations on the effects of high-dose irradiation on tumor cell survival, tumor vasculature, and antitumor immunity. We then assessed the potential implications of these biological changes associated with SBRT and SRS., Results: Irradiation with doses higher than approximately 10 Gy/fraction causes significant vascular injury in tumors, leading to secondary tumor cell death. Irradiation of tumors with high doses has also been reported to increase the antitumor immunity, and various approaches are being investigated to further elevate antitumor immunity. The mechanism of normal tissue damage by high-dose irradiation needs to be further investigated., Conclusions: In addition to directly killing tumor cells, high-dose irradiation used in SBRT and SRS induces indirect tumor cell death via vascular damage and antitumor immunity. Further studies are warranted to better understand the biological mechanisms underlying the high efficacy of clinical SBRT and SRS and to further improve the efficacy of SBRT and SRS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) in the management of adrenal metastases is emerging as a well-tolerated, effective method of treatment for patients with limited metastatic disease. SBRT planning and treatment utilization are widely variable, and publications report heterogeneous radiation dose fractionation schemes and treatment outcomes. The objective of this analysis was to review the current literature on SBRT for adrenal metastases and to develop treatment guidelines and a model for tumor control probability of SBRT for adrenal metastases based on these publications., Methods and Materials: A literature search of all studies on SBRT for adrenal metastases published from 2008 to 2017 was performed, and outcomes in these studies were reviewed. Local control (LC) rates were fit to a statistically significant Poisson model using maximum likelihood estimation techniques., Results: One-year LC greater than 95% was achieved at an approximated biological equivalent dose with α/β = 10 Gy of 116.4 Gy., Conclusions: While respecting normal tissue tolerances, tumor doses greater than or equal to a biological equivalent dose with α/β = 10 Gy of 116.4 Gy are recommended to achieve high LC. Further studies following unified reporting standards are needed for more robust prediction., (Published by Elsevier Inc.)

Purpose: Stereotactic body radiation therapy (SBRT) has become the standard of care for inoperable early-stage non-small cell lung cancer and is often used for recurrent lung cancer and pulmonary metastases. Radiation-induced lung toxicity (RILT), including radiation pneumonitis and pulmonary fibrosis, is a major concern for which it is important to understand dosimetric and clinical predictors., Methods and Materials: This study was undertaken through the American Association of Physicists in Medicine's Working Group on Biological Effects of Stereotactic Body Radiotherapy. Data from studies of lung SBRT published through the summer of 2016 that provided detailed information about RILT were analyzed., Results: Ninety-seven studies were ultimately considered. Definitions of the risk organ and complication endpoints as well as dose-volume information presented varied among studies. The risk of RILT, including radiation pneumonitis and pulmonary fibrosis, was reported to be associated with the size and location of the tumor. Patients with interstitial lung disease appear to be especially susceptible to severe RILT. A variety of dosimetric parameters were reported to be associated with RILT. There was no apparent threshold "tolerance dose-volume" level. However, most studies noted safe treatment with a rate of symptomatic RILT of <10% to 15% after lung SBRT with a mean lung dose (MLD) of the combined lungs ≤8 Gy in 3 to 5 fractions and the percent of total lung volume receiving more than 20 Gy (V 20 ) <10% to 15%., Conclusions: To allow more rigorous analysis of this complication, future studies should standardize reporting by including standardized endpoint and volume definitions and providing dose-volume information for all patients, with and without RILT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: In patients with spinal instability, cord compression, or neurologic deficits, the standard of care is surgery followed by radiation therapy (RT). Recurrence rates after conventional RT remain high. The purpose of this study is to prospectively examine the efficacy of postoperative stereotactic body RT (SBRT) in patients who have undergone surgical intervention for spine metastases. We hypothesize that postoperative SBRT to the spine would be associated with higher local control than historical rates after conventional RT., Methods and Materials: Thirty-five adult patients with a Karnofsky Performance Status score ≥40 and spine metastases from solid tumors with no prior overlapping RT and target volumes ≤3 consecutive vertebral levels were enrolled. Thirty-three patients were treated. Two patients underwent treatment to 2 target volumes for a total of 35 target volumes. All patients received SBRT 30 Gy in 5 fractions. Patients were followed with neurological examinations and computed tomography and/or magnetic resonance imaging every 3 months. Neurologic function was assessed at the same time points using the American Spinal Injury Association (ASIA) impairment score. Pain was rated according to the 10-point visual analogue scale and MD Anderson Cancer Center brief pain index. Toxicity was recorded according to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4. The primary objective was the rate of radiographic local recurrence at 12 months after completion of SBRT., Results: Patient characteristics were as follows: 34.3% had radioresistant primaries; 71.4% were ASIA E and the remainder ASIA D; and the median baseline Karnofsky Performance Status score was 70 (range, 50-100). Radiographic and symptomatic local control at 1 year were 90% (95% confidence interval, 76%-98%). The median time to recurrence in these 3 patients was 3.5 months (range, 3.4-5.8 months), all had radiosensitive tumors, and all recurrences were epidural. No patients experienced wound dehiscence, hardware failure, or spinal cord myelopathy. The median time to return to systemic therapy was 0.5 months (range, 0-9.4 months)., Conclusions: This prospective study of postoperative spine SBRT demonstrates excellent local control with low toxicity. These data suggest superior rates of local control compared with conventional RT; however, a formal comparative study is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Treatment effect or radiation necrosis after stereotactic radiosurgery (SRS) for brain metastases is a common phenomenon often indistinguishable from true progression. Radiomics is an emerging field that promises to improve on conventional imaging. In this study, we sought to apply a radiomics-based prediction model to the problem of diagnosing treatment effect after SRS., Methods and Materials: We included patients in the Johns Hopkins Health System who were treated with SRS for brain metastases who subsequently underwent resection for symptomatic growth. We also included cases of likely treatment effect in which lesions grew but subsequently regressed spontaneously. Lesions were segmented semiautomatically on preoperative T1 postcontrast and T2 fluid-attenuated inversion recovery magnetic resonance imaging, and radiomic features were extracted with software developed in-house. Top-performing features on univariate logistic regression were entered into a hybrid feature selection/classification model, IsoSVM, with parameter optimization and further feature selection performed using leave-one-out cross-validation. Final model performance was assessed by 10-fold cross-validation with 100 repeats. All cases were independently reviewed by a board-certified neuroradiologist for comparison., Results: We identified 82 treated lesions across 66 patients, with 77 lesions having pathologic confirmation. There were 51 radiomic features extracted per segmented lesion on each magnetic resonance imaging sequence. An optimized IsoSVM classifier based on top-ranked radiomic features had sensitivity and specificity of 65.38% and 86.67%, respectively, with an area under the curve of 0.81 on leave-one-out cross-validation. Only 73% of cases were classifiable by the neuroradiologist, with a sensitivity of 97% and specificity of 19%., Conclusions: Radiomics holds promise for differentiating between treatment effect and true progression in brain metastases treated with SRS. A predictive model built on radiomic features from an institutional cohort performed well on cross-validation testing. These results warrant further validation in independent datasets. Such work could prove invaluable for guiding management of individual patients and assessing outcomes of novel interventions., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Potential dosimetric and clinicopathologic predictors of radiation-induced brain edema after single-fraction or multifraction stereotactic radiosurgery (SRS) for non-base of skull (non-BOS) meningiomas are summarized based on a systematic review of the published literature., Methods and Materials: Reviewed studies (PubMed indexed from 1998 through 2017) included all or some non-BOS meningioma patients, reported risks of edema after SRS, and correlated dosimetric and/or nondosimetric measures with the magnitude of risk., Results: Twenty-six studies reporting risks of edema after SRS for meningioma are reviewed. The treatment techniques as well as distribution of tumor locations, target dosing, and target volume varied across studies. Among 13 studies that included only non-BOS tumors or separately grouped non-BOS tumors, symptomatic edema occurred in 5% to 43% of patients and any edema occurred in 28% to 50%. The reported average time to onset of edema ranged from approximately 3 to 9 months in most studies. Factors reported to significantly correlate with increased risks of edema and/or symptomatic edema after SRS for meningioma include the following: greater tumor margin and/or maximum dose, greater tumor size and/or volume, non-BOS (particularly parasagittal) location, no prior resection for meningioma, and presence of pretreatment edema. Nevertheless, the extent and significance of these factors were inconsistent across studies. Potentially important dosimetric factors, such as volume of brain or tissue receiving single-fraction doses > 10 to 12 Gy, are not well studied., Conclusions: The variability in risks of edema and in factors impacting those risks is likely a result of differences across studies in the clinicopathologic characteristics of the patient populations, as well as differences in treatment modalities and SRS planning and delivery parameters. More studies on pooled populations, grouped by potential prognostic factors such as tumor location and prior therapy, are needed to better understand dosimetric and nondosimetric factors predictive of edema risk after SRS for meningioma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To study the risk factors for radiation-induced lung toxicity (RILT) after stereotactic body radiation therapy (SBRT) of the thorax., Methods and Materials: Published studies on lung toxicity in patients with early-stage non-small cell lung cancer (NSCLC) or metastatic lung tumors treated with SBRT were pooled and analyzed. The primary endpoint was RILT, including pneumonitis and fibrosis. Data of RILT and risk factors were extracted from each study, and rates of grade 2 to 5 (G2+) and grade 3 to 5 (G3+) RILT were computed. Patient, tumor, and dosimetric factors were analyzed for their correlation with RILT., Results: Eighty-eight studies (7752 patients) that reported RILT incidence were eligible. The pooled rates of G2+ and G3+ RILT from all 88 studies were 9.1% (95% confidence interval [CI]: 7.15-11.4) and 1.8% (95% CI: 1.3-2.5), respectively. The median of median tumor sizes was 2.3 (range, 1.4-4.1) cm. Among the factors analyzed, older patient age (P=.044) and larger tumor size (the greatest diameter) were significantly correlated with higher rates of G2+ (P=.049) and G3+ RILT (P=.001). Patients with stage IA versus stage IB NSCLC had significantly lower risks of G2+ RILT (8.3% vs 17.1%, odds ratio = 0.43, 95% CI: 0.29-0.64, P<.0001). Among studies that provided detailed dosimetric data, the pooled analysis demonstrated a significantly higher mean lung dose (MLD) (P=.027) and V20 (P=.019) in patients with G2+ RILT than in those with grade 0 to 1 RILT., Conclusions: The overall rate of RILT is relatively low after thoracic SBRT. Older age and larger tumor size are significant adverse risk factors for RILT. Lung dosimetry, specifically lung V20 and MLD, also significantly affect RILT risk., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: To quantify rigid and nonrigid motion of liver tumors using reconstructed 3-dimensional (3D) fiducials from stereo imaging during CyberKnife-based stereotactic body radiation therapy (SBRT)., Methods and Materials: Twenty-three liver patients treated with 3 fractions of SBRT were used in this study. After 2 orthogonal kilovoltage images were taken during treatment, the 3D locations of the fiducials were generated by the CyberKnife system and validated using geometric derivations. A total of 4824 pairs of kilovoltage images from start to end of treatment were analyzed. For rigid motion, the rotational angles and translational shifts were reported by aligning 3D fiducial groups from different image pairs, using least-squares fitting. For nonrigid motion, we quantified interfractional tumor volume variations by using the proportional volume derived from the fiducials, which correlates to the sum of interfiducial distances. The individual fiducial displacements were also reported (1) after rigid corrections and (2) without angle corrections., Results: The proportional volume derived by the fiducials demonstrated a volume-increasing trend in the second (101.9% ± 3.6%) and third (101.0 ± 5.9%) fractions among most patients, possibly due to radiation-induced edema. For all patients, the translational shifts in left-right, anteroposterior, and superoinferior directions were 2.1 ± 2.3 mm, 2.9 ± 2.8 mm, and 6.4 ± 5.5 mm, respectively. The greatest translational shifts occurred in the superoinferior direction, likely due to respiratory motion from the diaphragm. The rotational angles in roll, pitch, and yaw were 1.2° ± 1.8°, 1.8° ± 2.4°, and 1.7° ± 2.1°, respectively. The 3D individual fiducial displacements with rigid corrections were 0.2 ± 0.2 mm and increased to 0.5 ± 0.4 mm without rotational corrections., Conclusions: Accurate 3D locations of internal fiducials can be reconstructed from stereo imaging during treatment. As an effective surrogate to tumor motion, fiducials provide a close estimation of both rigid and nonrigid motion of liver tumors. The reported displacements could be further utilized for tumor margin definition and motion management in conventional linear accelerator-based liver SBRT., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To perform an independent validation of an anatomy-based inverse planning simulated annealing (IPSA) algorithm in obtaining superior target coverage and reducing the dose to the organs at risk., Method and Materials: In a recent prostate high-dose-rate brachytherapy protocol study by the Radiation Therapy Oncology Group (0321), our institution treated 20 patients between June 1, 2005 and November 30, 2006. These patients had received a high-dose-rate boost dose of 19 Gy to the prostate, in addition to an external beam radiotherapy dose of 45 Gy with intensity-modulated radiotherapy. Three-dimensional dosimetry was obtained for the following optimization schemes in the Plato Brachytherapy Planning System, version 14.3.2, using the same dose constraints for all the patients treated during this period: anatomy-based IPSA optimization, geometric optimization, and dose point optimization. Dose-volume histograms were generated for the planning target volume and organs at risk for each optimization method, from which the volume receiving at least 75% of the dose (V(75%)) for the rectum and bladder, volume receiving at least 125% of the dose (V(125%)) for the urethra, and total volume receiving the reference dose (V(100%)) and volume receiving 150% of the dose (V(150%)) for the planning target volume were determined. The dose homogeneity index and conformal index for the planning target volume for each optimization technique were compared., Results: Despite suboptimal needle position in some implants, the IPSA algorithm was able to comply with the tight Radiation Therapy Oncology Group dose constraints for 90% of the patients in this study. In contrast, the compliance was only 30% for dose point optimization and only 5% for geometric optimization., Conclusions: Anatomy-based IPSA optimization proved to be the superior technique and also the fastest for reducing the dose to the organs at risk without compromising the target coverage.