Jinyu Xue

Simple Factors Associated With Radiation-Induced Lung Toxicity After Stereotactic Body Radiation Therapy of the Thorax: A Pooled Analysis of 88 Studies

PURPOSEnTo study the risk factors for radiation-induced lung toxicity (RILT) after stereotactic body radiation therapy (SBRT) of the thorax.nnnMETHODS AND MATERIALSnPublished 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.nnnRESULTSnEighty-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 ratioxa0=xa00.43, 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.nnnCONCLUSIONSnThe 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.

Estimated Risk Level of Unified Stereotactic Body Radiation Therapy Dose Tolerance Limits for Spinal Cord

A literature review of more than 200 stereotactic body radiation therapy spine articles from the past 20 years found only a single article that provided dose-volume data and outcomes for each spinal cord of a clinical dataset: the Gibbs 2007 article (Gibbs et al, 2007(1)), which essentially contains the first 100 stereotactic body radiation therapy (SBRT) spine treatments from Stanford University Medical Center. The dataset is modeled and compared in detail to the rest of the literature review, which found 59 dose tolerance limits for the spinal cord in 1-5 fractions. We partitioned these limits into a unified format of high-risk and low-risk dose tolerance limits. To estimate the corresponding risk level of each limit we used the Gibbs 2007 clinical spinal cord dose-volume data for 102 spinal metastases in 74 patients treated by spinal radiosurgery. In all, 50 of the patients were previously irradiated to a median dose of 40Gy in 2-3Gy fractions and 3 patients developed treatment-related myelopathy. These dose-volume data were digitized into the dose-volume histogram (DVH) Evaluator software tool where parameters of the probit dose-response model were fitted using the maximum likelihood approach (Jackson et al, 1995(3)). Based on this limited dataset, for de novo cases the unified low-risk dose tolerance limits yielded an estimated risk of spinal cord injury of ≤1% in 1-5 fractions, and the high-risk limits yielded an estimated risk of ≤3%. The QUANTEC Dmax limits of 13Gy in a single fraction and 20Gy in 3 fractions had less than 1% risk estimated from this dataset, so we consider these among the low-risk limits. In the previously irradiated cohort, the estimated risk levels for 10 and 14Gy maximum cord dose limits in 5 fractions are 0.4% and 0.6%, respectively. Longer follow-up and more patients are required to improve the risk estimates and provide more complete validation.

Stereotactic body radiotherapy as an alternative to brachytherapy in gynecologic cancer.

Introduction. Brachytherapy plays a key role in the treatment of many gynecologic cancers. However, some patients are unable to tolerate brachytherapy for medical or other reasons. For these patients, stereotactic body radiotherapy (SBRT) offers an alternative form of treatment. Methods. Retrospective review of patients prospectively collected on SBRT database is conducted. A total of 11 gynecologic patients who could not have brachytherapy received SBRT for treatment of their malignancies. Five patients have been candidates for interstitial brachytherapy, and six have required tandem and ovoid brachytherapy. Median SBRT dose was 25u2009Gy in five fractions. Results. At last followup, eight patients were alive, and three patients had died of progressive disease. One patient had a local recurrence. Median followup for surviving patients was 420 days (median followup for all patients was 120 days). Two patients had acute toxicity (G2 dysuria and G2 GI), and one patient had late toxicity (G3 GI, rectal bleeding requiring cauterization). Conclusions. Our data show acceptable toxicity and outcome for gynecologic patients treated with SBRT who were unable to receive a brachytherapy boost. This treatment modality should be further evaluated in a phase II study.

Dose-volume effects on brainstem dose tolerance in radiosurgery

OBJECTnDose-volume data concerning the brainstem in stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN) were analyzed in relation to associated complications. The authors present their set of data and compare it with currently cited information on brainstem dose tolerance associated with conventional fractionated radiation therapy and hypofractionated radiation treatment of other diseases.nnnMETHODSnStereotactic radiosurgery for TN delivers a much higher radiation dose to the brainstem in a single fraction than doses delivered by any other procedures. A literature survey of articles on radiosurgery for TN revealed no incidences of severe toxicity, unlike other high-dose procedures involving the brainstem. Published data on brainstem dose tolerance were investigated and compared with dose-volume data in TN radiosurgery. The authors also performed a biological modeling study of dose-volume data involving the brainstem in cases of TN treated with the Gamma Knife, CyberKnife, and linear accelerator-based systems.nnnRESULTSnThe brainstem may receive a maximum dose as high as 45 Gy during radiosurgery for TN. The major complication after TN radiosurgery is mild to moderate facial numbness, and few other severe toxic responses to radiation are observed. The biologically effective dose of 45 Gy in a single fraction is much higher than any brainstem dose tolerance currently cited in conventional fractionation or in single or hypofractionated radiation treatments. However, in TN radiosurgery, the dose falloff is so steep and the delivery so accurate that brainstem volumes of 0.1-0.5 cm(3) or larger receive lower planned and delivered doses than those in other radiation-related procedures. Current models are suggestive, but an extensive analysis of detailed dose-volume clinical data is needed.nnnCONCLUSIONSnPatients whose TN is treated with radiosurgery are a valuable population in which to demonstrate the dose-volume effects of an extreme hypofractionated radiation treatment on the brainstem. The result of TN radiosurgery suggests that a very small volume of the brainstem can tolerate a drastically high dose without suffering a severe clinical injury. The authors believe that the steep dose gradient in TN radiosurgery plays a key role in the low toxicity experienced by the brainstem.

Biological implications of whole-brain radiotherapy versus stereotactic radiosurgery of multiple brain metastases

OBJECTnThe efficacy and safety of treatment with whole-brain radiotherapy (WBRT) or with stereotactic radiosurgery (SRS) for multiple brain metastases (> 10) are topics of ongoing debate. This study presents detailed dosimetric and biological information to investigate the possible clinical outcomes of these 2 modalities.nnnMETHODSnFive patients with multiple brain metastases (n = 11-23) underwent SRS. Whole-brain radiotherapy plans were retrospectively designed with the same MR image set and the same structure set for each patient, using the standard opposing lateral beams and fractionation (3 Gy × 10). Physical radiation doses and biologically effective doses (BEDs) in WBRT and SRS were calculated for each lesion target and for the normal brain tissues for comparison of the 2 modalities in the context of clinical efficacy and published toxicities.nnnRESULTSnThe BEDs targeted to the tumor were higher in SRS than in WBRT by factors ranging from 2.4- to 3.0- fold for the mean dose and from 3.2- to 5.3-fold for the maximum dose. In the 5 patients, mean BEDs in SRS (calculated as percentages of BEDs in WBRT) were 1.3%-34.3% for normal brain tissue, 0.7%-31.6% for the brainstem, 0.5%-5.7% for the chiasm, 0.2%-5.7% for optic nerves, and 0.6%-18.1% for the hippocampus.nnnCONCLUSIONSnThe dose-volume metrics presented in this study were essential to understanding the safety and efficacy of WBRT and SRS for multiple brain metastases. Whole-brain radiotherapy results in a higher incidence of radiation-related toxicities than SRS. Even in patients with > 10 brain metastases, the normal CNS tissues receive significantly lower doses in SRS. The mean normal brain dose in SRS correlated with the total volume of the lesions rather than with the number of lesions treated.

Factors that may determine the targeting accuracy of image-guided radiosurgery

PURPOSEnThe AAPM TG-135 report is a landmark recommendation for the quality assurance (QA) of image-guided robotic radiosurgery. The purpose of this paper is to present results pertaining to intentionally offsetting the phantom as recommended by TG-135 and to present data on targeting algorithm accuracy as a function of imager parameters in less than ideal circumstances, which had not been available at the time of publication of TG-135.nnnMETHODSnAll tests in this study were performed at the Cooper University Hospital CyberKnife Center in Mt. Laurel, NJ. For intentional offsets, initial tests were performed on the Accuray-supplied anthropomorphic head and neck phantom, whereas for subsequent tests, the Accuray-supplied alignment quality assurance (AQA) phantom was used. To simulate the effects of imager parameters for larger patients, slabs of Blue Water (Standard Imaging, Inc., Middleton, WI) were added to attenuate the x-ray images in some of the tests. In conjunction with attenuated x-ray tests, the number of fiducials was varied by systematically deselecting them one at a time at the CyberKnife console.nnnRESULTSnTests using the AQA phantom verified that submillimeter alignments were consistently achieved even with intentional shifts and rotations of up to 10.0 mm and 1.0°, respectively. An analysis of 17 months of daily QA alignment tests showed that submillimeter alignments were achieved more than 99% of the time even with such intentional shifts and rotations of the phantom. When additional slabs of Blue Water were added to simulate patient attenuation of the x-ray images, targeting errors could be induced depending on imager parameters and the amount of Blue Water used. A series of consecutive tests showed that two helpful variables to ensure good accuracy of the system were (1) the fiducial extraction confidence level (FECL) system parameter and (2) the number of targeted fiducials. When fewer than four fiducials were used, the FECL reported by the CyberKnife was sometimes high even when a false lock occurred, so using multiple fiducials helped to ensure reliable targeting.nnnCONCLUSIONSnRadiosurgery requires the highest degree of targeting accuracy, and in our experience, the CyberKnife has been able to maintain submillimeter accuracy consistently. It has been verified that our CyberKnife can correct for phantom shifts of up to 10.0 mm and rotations of up to 1.0°. It has also been discovered that false locks are more likely to occur with a single fiducial than with multiple fiducials. Although targeting accuracy can only be measured on a phantom, the insight gained from analyzing the QA tests can help us in devising better strategies for achieving the best treatment for our patients.

Single- and Multi-Fraction Stereotactic Radiosurgery Dose Tolerances of the Optic Pathways

PURPOSEnDosimetric 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.nnnMETHODS AND MATERIALSnEligible 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).nnnRESULTSnThirty-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 (Pxa0=xa0.66). 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 25xa0Gy in 5 fractions. Omitting multi-fraction data (and thereby eliminating uncertainties associated with dose conversions), a single-fraction dose of 10xa0Gy was associated with a 1% RION risk. Insufficient details precluded modeling of NTCP risks after prior radiation therapy.nnnCONCLUSIONSnOptic 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.

Head and Neck Tumor Control Probability: Radiation Dose-Volume Effects in Stereotactic Body Radiation Therapy for Locally Recurrent Previously-Irradiated Head and Neck Cancer: Report of the AAPM Working Group

PURPOSEnStereotactic 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.nnnMATERIAL & METHODSnA 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.nnnRESULTSnData 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 45xa0Gy (in 5 fractions) compared with <30xa0Gy.nnnCONCLUSIONnStereotactic body radiation therapy doses equivalent to 5-fraction doses of 40 to 50xa0Gy are suggested for retreatment.

Improved Dose Conformity for Adjacent Targets: A Novel Planning Technique for Gamma Knife Stereotactic Radiosurgery

Purpose In the current Gamma Knife (GK) planning system (GammaPlan, version 10.2, Elekta AB, Stockholm, Sweden), multiple adjacent brain metastasis (BMs) had to be planned sequentially if BMs were drawn separately, leading to less conformal target dose in the composite plan due to inter-target dose contribution and fine-tuning of the shots being quite tedious. We proposed a method to improve target dose conformality and planning efficiency for such cases. Methods and Materials Fifteen patients with multiple BMs treated on the Leksell GK Perfexion system were retrospectively replanned in the Institutional Review Board (IRB) approved study. The recruitment criterion was all the BMs should be entirely encompassed within the maximum dose grid allowed in the GammaPlan. The BMs were first planned sequentially as routine clinic cases. The contours of the BMs were then exported to the VelocityAI (Varian, CA, USA) to generate a composite contour after a union operation, and all the BMs were planned again simultaneously using this composite contour in the GammaPlan. The inverse planning (IP) was employed in both methods with the same treatment time allowed for a fair plan comparison. Dose evaluation was performed in the VelocityAI with all planning magnetic resonance (MR) images, structure set and dose were exported to the VelocityAI. The dosimetery parameters, including conformality index (CI), V20Gy, V16Gy, V12Gy, and V5Gy, were compared between the two methods. Results The planning results from both methods were reviewed qualitatively and quantitatively. The proposed method exhibited superior CI, except for an outlier case with very tiny BMs. The mean and standard deviation (std.) of the Paddick CI for all patients were 0.76±0.11 for the proposed method, comparing to 0.69±0.13 for the sequential method. The V20Gy, V16Gy, V12Gy, and V5Gy for the proposed method were 10.9±0.9%, 9.5±10.2%, 6.2±16.4% and 3.3±21.8%, all lower than those from the sequential method. Conclusions The proposed method showed improved target dose conformality for all cases except for very tiny BMs. Planning efficiency is considerably better with the combined target technique. The improved dose conformality will be beneficial to patients in long term with lowered risk of radiation necrosis after GK stereotactic radiosurgery (SRS).

Dosimetric assessment of tumor control probability in intensity and volumetric modulated radiotherapy plans

OBJECTIVE:nRadiobiological models have been used to calculate the outcomes of treatment plans based on dose-volume relationship. This study examines several radiobiological models for the calculation of tumor control probability (TCP) of intensity modulated radiotherapy plans for the treatment of lung, prostate, and head and neck (H&N) cancers.nnnMETHODS:nDose volume histogram (DVH) data from the intensity modulated radiotherapy plans of 36 lung, 26 prostate, and 87 u2009H&N cases were evaluated. The Poisson, Niemierko, and Marsden models were used to calculate the TCP of each disease group treatment plan. The calculated results were analyzed for correlation and discrepancy among the three models, as well as different treatment sites under study.nnnRESULTS:nThe median value of calculated TCP in lung plans was 61.9% (34.1-76.5%), 59.5% (33.5-73.9%) and 32.5% (0.0-93.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in prostate plans was 85.1% (56.4-90.9%), 81.2% (56.1-88.7%) and 62.5% (28.2-75.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in H&N plans was 94.0% (44.0-97.8%) and 94.3% (0.0-97.8%) with the Poisson and Niemierko models, respectively. There were significant differences between the calculated TCPs with the Marsden model in comparison with either the Poisson or Niemierko model (p < 0.001) for both lung and prostate plans. The TCPs calculated by the Poisson and Niemierko models were significantly correlated for all three tumor sites.nnnCONCLUSION:nThere are variations with different radiobiological models. Understanding of the correlation and limitation of a TCP model with dosimetric parameters can help develop the meaningful objective functions for plan optimization, which would lead to the implementation of outcome-based planning. More clinical data are needed to refine and consolidate the model for accuracy and robustness.nnnADVANCES IN KNOWLEDGE:nThis study has tested three radiobiological models with varied disease sites. It is significant to compare different models with the same data set for better understanding of their clinical applicability.