Consortia Research Bibliography

Bibliography Consortia Research Bibliography August 2017

Lung Radiotherapy 2 Spine Radiosurgery 10 Oligometastatic Cancer 16 Stereotactic Lung Radiotherapy A collaborative analysis of stereotactic lung radiotherapy outcomes for early-stage non-small-cell lung cancer using daily online cone-beam computed tomography image-guided radiotherapy. J Thorac Oncol. 2012 Sep;7(9):1382-93 Grills IS, Hope AJ, Guckenberger M, Kestin LL, Werner-Wasik M, Yan D, Sonke JJ, Bissonnette JP, Wilbert J, Xiao Y, Belderbos J. We report lung stereotactic-body radiotherapy (SBRT) outcomes for a large pooled cohort treated using daily online cone-beam computed tomography. Five hundred and five stage I-IIB (T1-3N0M0) non-smallcell lung cancer (NSCLC) cases underwent SBRT using cone-beam computed tomography image guidance at five international institutions from 1998 to 2010. Median age was 74 years (range, 42-92) whereas median forced expiratory volume in 1 second/diffusing lung capacity for carbon monoxide were 1.4 liter (65%) and 10.8 ml/min/ mmhg (53%). Of the 505 cases, 64% were biopsy proven and 87% medically inoperable. Staging was: IA 63%, IB 33%, IIA 2%, and recurrent 1%. Median max tumor dimension was 2.6 cm (range, 0.9-8.5). Median heterogeneously calculated volumetric prescription dose (PD) was 54 Gy (range, 20-64 Gy) in three fractions (range, 1-15) over 8 days (range, 1-27). Median biologically equivalent PD biological equivalent doses (BED10) was 132 Gy (range, 60-180). With a median follow-up of 1.6 years (range, 0.1-7.3), the 2-year Kaplan-Meier local control (LC), regional control, and distant metastasis (DM) rates were 94%, 89%, and 20%, respectively, whereas cause-specific and overall survival were 87% and 60% (78% operable, 58% inoperable, p = 0.01), respectively. Stage, gross-tumor volume size ( 2.7 cm) and PD(BED10) predicted local relapse (LR) and DM. LR was 15% for BED10 less than 105 Gy versus 4% for BED10 of 105 Gy or more (p < 0.001); DM was 31% versus 18% for BED10 less than 105 versus 105 Gy or more (p = 0.01). On multivariate analysis, PD(BED10) and elapsed days during radiotherapy predicted LR; gross-tumor volume size predicted DM. Grade 2 or higher pneumonitis, rib fracture, myositis, and dermatitis were 7%, 3%, 1%, and 2%, respectively. In the largest early-stage NSCLC SBRT data set to date, a high rate of local control was achieved, which was correlated with a PD(BED10) of 105 Gy or more. Failures were primarily distant, severe toxicities were rare, and overall survival was encouraging in operable patients. 2

Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol. 2012 Mar;7(3):542-51. DOI: 10.1097/JTO.0b013e31824165d7 Guckenberger M, Kestin LL, Hope AJ, Belderbos J, Werner-Wasik M, Yan D, Sonke JJ, Bissonnette JP, Wilbert J, Xiao Y, Grills IS. To evaluate the influence of pretreatment pulmonary function (PF) on survival, early and late pulmonary toxicity after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer. Four hundred eighty-three patients with 505 tumors of early-stage non-small cell lung cancer ct1-3 cn0 were treated with image-guided SBRT at five international institutions (1998-2010). Sixty-four percent of the tumors were biopsy-proven and 18F-fluorodeoxyglucose-positron emission tomography was performed for staging in 84%. Image-guided SBRT was performed with a median of three fractions to a median total dose of 54 Gy. Pretreatment PF was available for 423 patients, and 617 posttreatment PF tests from 270 patients were available. A large variability of pretreatment PF was observed: the 90% range of forced expiratory volume in 1 second and diffusing capacity for carbon monoxide was 29 to 109% and 5.5 to 19.1 ml/min/mmhg, respectively. PF was significantly correlated with overall survival but not cause-specific survival: diffusing capacity for carbon monoxide of 11.2 ml/ min/mmhg differentiated between 3-year overall survival of 66% and 42%. Radiation-induced pneumonitis grade II occurred in 7% of patients and was not increased in patients with lower PF. A significant and progressive change of PF was observed after SBRT: PF decreased by 3.6% and 6.8% on average within 6 and 6 to 24 months after SBRT, respectively. Changes of PF after SBRT were significantly correlated with pretreatment PF: PF improved for worst pretreatment PF and the largest loss was observed for best pretreatment PF. Image-guided SBRT is safe in terms of acute and chronic pulmonary toxicity even for patients with severe pulmonary comorbidities. SBRT should be considered as a curative treatment option for inoperable patients with pretreatment PF as reported in this study. Lack of a dose-effect relationship for pulmonary function changes after stereotactic body radiation therapy for early-stage non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2013 Mar 15;85(4):1074-81. DOI: 10.1016/j.ijrobp.2012.09.016 Guckenberger M, Klement RJ, Kestin LL, Hope AJ, Belderbos J, Werner-Wasik M, Yan D, Sonke JJ, Bissonnette JP, Xiao Y, Grills IS. To evaluate the influence of tumor size, prescription dose, and dose to the lungs on posttreatment pulmonary function test (PFT) changes after stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC). The analysis is based on 191 patients treated at 5 international institutions: inclusion criteria were availability of pre- and post-sbrt PFTs and dose-volume histograms of the lung and planning target volume (PTV); patients treated with more than 1 SBRT course were excluded. Correlation between early (1-6 months, median 3 months) and late (7-24 months, median 12 months) PFT changes and tumor size, planning target volume (PTV) dose, and lung doses was assessed using linear regression analysis, receiver operating characteristics analysis, and Lyman s normal tissue complication probability model. The PTV doses were converted to biologically effective doses and lung doses to 2 Gy equivalent doses before correlation analyses. Up to 6 months after SBRT, forced expiratory volume in 1 second and carbon monoxide diffusion capacity changed by -1.4% (95% confidence interval [CI], -3.4% to 0) and -7.6% (95% CI, -10.2% to -3.4%) compared with pretreatment values, respectively. A modest decrease in PFTs was observed 7-24 months after SBRT, with changes of -8.1% (95% CI, -13.3% to -5.3%) and -12.4% (95% CI, -15.5% to -6.9%), respectively. Using linear regression analysis, receiver operating characteristic analysis, and normal tissue complication probability modeling, all evaluated parameters of tumor size, PTV dose, mean lung dose, and absolute and relative volumes of the lung exposed to minimum doses of 5-70 Gy were not correlated with early and late PFT changes. Subgroup analysis based on pre-sbrt PFTs (greater or equal and less than median) did not identify any dose-effect relationship. This study failed to demonstrate a significant doseeffect relationship for changes of pulmonary function after SBRT for early-stage non-small cell lung cancer. 3

Improved modeling of radiation pneumonitis risk in lung SBRT by incorporating a local dose effect relation for perfusion reduction. Int J Radiat Oncol Biol Phys. 2013;87(suppl 2):S43. DOI: http://dx.doi.org/10.1016/j.ijrobp.2013.06.113 Scheenstra A, Grills I, Hope A, Guckenberg M, Werner-Wasik M, Bissonnette J, Xiao Y, Yan D, Belderbos J, Sonke J. The mean lung dose (MLD) has been shown to be associated with the risk of radiation pneumonitis (RP) in lung SBRT. There is, however, uncertainty whether the high biological dose levels present in heterogeneous SBRT dose distributions, proportionally contribute to the risk of RP. The low incidence of RP in SBRT limits the statistical power required to optimize the overall response parameter (ORP) as an alternative to the MLD. The purpose of this study was therefore to improve RP risk modeling by incorporating a local dose effect relation for perfusion loss as a weighting function into the ORP. All SBRT dose distributions were converted into normalized total dose (NTD) to account for fractionation effects according to the LQ model with a/ß = 3 Gy. The local reduction in lung perfusion was quantified using pre- and post SBRT SPECT-CT scans for a cohort of 42 patients and used as a surrogate for local lung damage. Perfusion loss was modeled as a function of the local NTD d using a logistic 3-parameter model M/(1 + (d50/d) k) with optimized parameters M = 42.6% (maximal effect), d50 = 28.7 Gy (dose for 50% complication probability) and k = 2.2 (steepness parameter). This model indicates that 90% of the maximum local damage was already observed at 78 Gy NTD. This logistic relation was subsequently incorporated as a weighting function to calculate the overall response parameter EUDlog. The EUDlog and the MLD were calculated from the Lungs- CTV dose volume histograms that were obtained from 385 patients with clinical stage T1-T2 N0 NSCLC that were treated with a variety of SBRT fractionation schemes at the 5 institutions participating in the Elekta lung research group. The MLD-RP and EUDlog-RP relations were modeled by the Lyman Normal Tissue Complication Probability (NTCP) model using D50 (dose for a 50% complication probability) and m (steepness parameter). The optimized NTCP models for the MLD and the EUDlog were compared by the Akaike information criterion (AIC). A clear relationship was found between RP and the MLD and EUDlog. Parameters for the optimized NTCP functions are given in the table. The AIC indicates that the EUDlog is 2.15 times as probable as the MLD to model RP. The prediction of RP over a variety of SBRT fractionation schemes can be improved by adding information on the local perfusion reduction as a function of local dose. 4

Required target margins for image-guided lung SBRT: Assessment of target position intrafraction and correction residuals. Pract Radiat Oncol. 2013 Jan-Mar;3(1):67-73. DOI: 10.1016/j.prro.2012.03.004 Shah C, Kestin LL, Hope AJ, Bissonnette JP, Guckenberger M, Xiao Y, Sonke JJ, Belderbos J, Yan D, Grills IS. With increased use of stereotactic body radiotherapy (SBRT) for early-stage lung cancer, quantification of intrafraction variation (IFV) is required to develop adequate target margins. A total of 409 patients with 427 tumors underwent 1593 fractions of lung SBRT between 2005 and 2010. Translational target position correction of the mean target position (MTP) was performed via onboard cone-beam computed tomography (CBCT). IFV was measured as the difference in MTP between the post-correction CBCT and the posttreatment CBCT and was calculated on 1337 fractions. Mean IFV-MTP was 0.0 ± 1.7 mm, 0.6 ± 2.2 mm, and -1.0 ± 2.0 mm in the mediolateral (ML), anteroposterior (AP), and craniocaudal (CC) dimensions, and the vector was 3.1 ± 2.0 mm; 67.8% of fractions had an IFV vector greater than 2 mm, and 14.3% greater than 5 mm. Weight, excursion, forced expiratory volume in the first second of expiration, diffusing capacity of the lung for carbon monoxide, and treatment time were found to be significant predictors of IFV-MTP greater than 2 mm and 5 mm. Significant differences in IFV-MTP were seen between immobilization devices with a mean IFV of 2.3 ± 1.4 mm, 2.7 ± 1.6 mm, 3.0 ± 1.7 mm, 3.0 ± 2.5 mm, 3.3 ± 1.7 mm, and 3.3 ± 2.2 mm for the body frame, hybrid device, alpha cradle, body fix, wing board, and no immobilization, respectively (P <.001). Estimated required target margins for the entire cohort were 4.3, 6.1, and 6.0 mm in the ML, AP, and CC dimensions, with differences in margins based on immobilization. IFV is dependent on several factors: immobilization device, treatment time, pulmonary function, and bodyweight. These factors are responsible for a significant portion of target margins with a mean IFV vector of 3 mm. Target margins of 6 mm or greater are required to encompass IFV in all dimensions when using four-dimensional CT with CBCT without respiratory gating or compression. 5

Dose-response relationship with clinical outcome for lung stereotactic body radiotherapy (SBRT) delivered via online image guidance. Radiother Oncol. 2014 Mar;110(3):499-504. DOI: 10.1016/j.radonc.2014.02.002. Epub 2014 Mar 11. Kestin L, Grills I, Guckenberger M, Belderbos J, Hope AJ, Werner-Wasik M, Sonke JJ, Bissonnette JP, Xiao Y, Yan D. To examine potential dose-response relationships with various non-small-cell lung cancer (NSCLC) SBRT fractionation regimens delivered with online CT-based image guidance. 505 tumors in 483 patients with clinical stage T1-T2N0 NSCLC were treated with SBRT using on-line conebeam-ct-based image guidance at 5 institutions (1998-2010). Median maximum tumor dimension was 2.6 cm (range 0.9-8.5 cm). Dose fractionation prescription was according to each institution s protocol with the most common schedules of 18-20 GyX3, 12 GyX4, 12 GyX5, 12.5 GyX3, 7.5 GyX8 (median = 54 Gy, 3 fractions). Median prescription (Rx) BED10 = 132 Gy (50.4-180). Median values (Gy) of 3D planned doses for BED10 were GTV(min) = 164.1, GTV(mean) = 188.4, GTV(max) = 205.9, PTV(min) = 113.9, PTV D99 = 123.9, PTV(mean) = 164.7, PTV D1 = 197.3, PTV(max) = 210.7. Mean follow-up = 1.6 years. 26 cases (5%) had local recurrence (LR) for a 2-year rate of 6% and 3-year rate of 9%. All BED10 GTV&PTV endpoints were associated with LR as continuous variables on univariate analysis (p<0.05). Rx and PTV(mean) dose appeared to have the highest correlation with LR with area under ROC curve of 0.69 and 0.65 respectively and optimal cut points of 105 and 125 Gy, respectively. 2-year LR was 4% for PTV(mean)>125 vs 17% for <125 Gy (p<0.01) with sensitivity = 84% and specificity = 57% for predicting LR. 2-year LR for Rx BED10>105 was 4% vs 15% for <105 Gy (p<0.01). Longer treatment duration ( 11 elapsed days) demonstrated a 2-year LR of 14% vs 4% for 10 days (p<0.01). GTV size was associated with LR on univariate analysis as a continuous variable (p = 0.02) with 2-year LR = 3% for <2.7 cm vs 9% for 2.7 cm (p = 0.03). BED10 (p = 0.01) and elapsed days during RT (p = 0.05) were independent predictors on multivariate analysis as continuous variables. There is a substantial dose-response relationship for local control of NSCLC following image-guided SBRT with optimal PTV(mean) BED10>125 Gy. Shorter treatment duration was also associated with better local control in this dataset. 6

Predictors and Patterns of Regional Recurrence Following Lung SBRT: A Report From the Elekta Lung Research Group. Clin Lung Cancer. 2017 Mar; 18(2):162-168 Giuliani ME, Hope A, Mangona V, Guckenberger M, Mantel F, Peulen H, Sonke JJ, Belderbos J, Werner-Wasik M, Ye H, Grills IS. The objective of this study was to determine the predictors and patterns of regional recurrence (RR) following stereotactic body radiotherapy (SBRT) for primary lung cancers. Details of patient factors, treatment, and outcome factors were extracted from a multi-institutional (5) database. All events were calculated from the end of radiotherapy. Estimates of local recurrence, RR, and distant metastases (DM) were calculated using the competing risk method. Cause-specific and overall survival were calculated using the Kaplan-Meier method. Details of locations and number of simultaneous RRs were categorized by lymph node anatomic station. A total of 734 patients were analyzed. The median follow-up was 3.0 years in surviving patients. Four hundred seventysix (65%) patients had pathologic proof of disease. There were 64 patients with RR. The 2-year local recurrence, RR, and distant metastases rates were 5.6%, 9.0%, and 14.6% respectively. The 2-year cause-specific and overall survival were 89.9% and 63.7%, respectively. There were 136 simultaneous sites of RR. There were 21 recurrences in stations 4R (15.4%), 9 (6.6%) in 4L, 30 (22%) in 7, 19 (13.9%) in 10R, and 14 (10.3%) in 10L. The most common stations for isolated recurrence (n = 19) were station 7 (n = 5; 26.3%) and station 10R (n = 6; 31.6%). The most common RR levels were stations 4 and 7 for right and left upper lobe, stations 5, 7, and 10 for left lower lobe tumors, and stations 7 and 10 for right lower lobe tumors. Stations 4, 7, and 10 were the most common stations for RR. These patterns of recurrence may guide nodal staging procedures prior to SBRT. Validation of High-Risk Computed Tomography Features for Detection of Local Recurrence After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2016 Sep 01; 96(1):134-41 Peulen H, Mantel F, Guckenberger M, Belderbos J, Werner-Wasik M, Hope A, Giuliani M, Grills I, Sonke JJ. Fibrotic changes after stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC) are difficult to distinguish from local recurrences (LR), hampering proper patient selection for salvage therapy. This study validates previously reported highrisk computed tomography (CT) features (HRFs) for detection of LR in an independent patient cohort. From a multicenter database, 13 patients with biopsyproven LR were matched 1:2 to 26 non-lr control patients based on dose, planning target volume (PTV), follow-up time, and lung lobe. Tested HRFs were enlarging opacity, sequential enlarging opacity, enlarging opacity after 12 months, bulging margin, linear margin disappearance, loss of air bronchogram, and craniocaudal growth. Additionally, 2 new features were analyzed: the occurrence of new unilateral pleural effusion, and growth based on relative volume, assessed by manual delineation. All HRFs were significantly associated with LR except for loss of air bronchogram. The best performing HRFs were bulging margin, linear margin disappearance, and craniocaudal growth. Receiver operating characteristic analysis of the number of HRFs to detect LR had an area under the curve (AUC) of 0.97 (95% confidence interval [CI] 0.9-1.0), which was identical to the performance described in the original report. The best compromise (closest to 100% sensitivity and specificity) was found at 4 HRFs, with a sensitivity of 92% and a specificity of 85%. A model consisting of only 2 HRFs, bulging margin and craniocaudal growth, resulted in a sensitivity of 85% and a specificity of 100%, with an AUC of 0.96 (95% CI 0.9-1.0) (HRFs 2). Pleural effusion and relative growth did not significantly improve the model. We successfully validated CT-based HRFs for detection of LR after SBRT for early-stage NSCLC. As an alternative to number of HRFs, we propose a simplified model with the combination of the 2 best HRFs: bulging margin and craniocaudal growth, although validation is warranted. 7

Prediction of early death in patients with early-stage NSCLC-Can we select patients without a potential benefit of SBRT as a curative treatment approach? J Thorac Oncol. 2016 Jul;11(7):1132-9. DOI: 10.1016/j.jtho.2016.03.016. Epub 2016 Apr 7. Klement RJ, Belderbos J, Grills I, Werner-Wasik M, Hope A, Giuliani M, Ye H, Sonke JJ, Peulen H, Guckenberger M. Stereotactic body radiotherapy (SBRT) is the guidelinerecommended treatment for medically inoperable patients with peripheral stage I non-small cell lung cancer (NSCLC). This study analyzed whether short-term (<6 months) death can be predicted reliably to select a subgroup of patients who will not have a benefit from SBRT. A total of 779 patients with early-stage NSCLC who had been treated with cone beam computed tomography-guided SBRT in five institutes and for whom information on overall survival during the first 6 months after treatment was available were included in this analysis. The probability of dying within 6 months after treatment was defined as the end point early death and modeled by multivariate logistic regression. Model fitting was performed using the least absolute shrinkage and selection operator method, and model test performance was estimated using double 10-fold cross validation. The variables age, sex, Eastern Cooperative Oncology Group performance status, operability, forced expiratory volume in 1 second, and Charlson comorbidity index were considered for model building. Eastern Cooperative Oncology Group performance status and (to a lesser extent) operability were the most important predictors of early death, whereas the Charlson comorbidity index was associated only with the overall survival time. On the basis of the best expected test performance (area under the curve = 0.699), the risk for early death would be 8.8% (range 8.2%-13.7%) and 4.1% (3.0%-4.3%) for the 10% of patients with the highest and lowest risk, respectively. Overall, predictive performance was too low for clinical application. SBRT should be offered to all patients irrespective of their comorbidities, unless the performance status of the patients and the comorbidities prevent accurate SBRT planning and delivery. 8

Stereotactic body radiotherapy in octo-and nonagenarians for the treatment of early stage lung cancer. Int J Radiat Oncol Biol Phys. Vol. 98, No. 4, pp. 893-899, 2017. DOI: 10.1016/j.ijrobp.2017.01.019. Epub 2017 Jan 2. Giuliani M, Hope A, Guckenberger M, Mantel F, Peulen H, Sonke JJ, Belderbos J, Werner-Wasik M, Ye H, Grills IS. To determine the safety and efficacy of lung stereotactic body radiation therapy (SBRT) in octo- and nonagenarians and to compare their outcomes with those of younger patients. Patients with primary lung cancer treated with SBRT were identified from a multi-institutional (5 institutions) database of 1083 cases. Details of patient factors, treatment specifics, toxicity, and clinical outcomes were extracted from the database. All events were calculated from the end of radiation therapy. Estimates of local recurrence, regional recurrence, and distant metastases were calculated using the competing risk method. Cause-specific survival (CSS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcomes were compared for those aged <70, 70 to 79, and 80 years. Univariable and multivariable analyses were performed to determine associations with CSS and OS in patients aged 80 years. The median (range) follow-up was 1.7 (1-10) years, and median age was 75 (41-94) years. There were 305 patients aged <70 years (28%), 448 aged 70 to 79 years (41%), and 330 aged 80 years (30%). There was no difference in 2-year local recurrence (4.2% vs 5.4% vs 3.7%, respectively, P=.7), regional recurrence (10.4% vs 7.8% vs 5.3%, P=.1), distant metastases (12.2% vs 7.7% vs 9.5%, P=.2), or CSS (90.6% vs 90.3% vs 90.4%, P=.6). Those aged 80 years had significantly lower 2-year OS (73.6% vs 67.2% vs 63.3%, P<.01). The grade 3+ pneumonitis rate was 1.3% versus 1.6% versus 1.5% (P=1.0) in patients aged <70, 70 to 79, and 80 years, respectively. The 90-day mortality rates for patients aged <70, 70 to 79, and 80 years were 1.3%, 2.5%, and 2.4% (P=.01), respectively. In patients aged 80 years OS was associated with T category (hazard ratio 1.7; P<.01). Stereotactic body radiation therapy is a safe treatment modality in elderly patients (aged 80 years). Despite larger tumor volumes, the tumor control outcomes were comparable to those in younger patients treated with SBRT. All patients with early-stage lung cancer, regardless of age, should be considered for treatment with SBRT. 9

Spine Radiosurgery Clinical practice of image-guided spine radiosurgery - results from an international research consortium. Radiat Oncol. 2011 Dec 15;6:172. DOI: 10.1186/1748-717X-6-172 Guckenberger M, Sweeney RA, Flickinger JC, Gerszten PC, Kersh R, Sheehan J, Sahgal A. Spinal radiosurgery is a quickly evolving technique in the radiotherapy and neurosurgical communities. However, the methods of spine radiosurgery have not been standardized. This article describes the results of a survey about the methods of spine radiosurgery at five international institutions. All institutions are members of the Elekta Spine Radiosurgery Research Consortium and have a dedicated research and clinical focus on image-guided radiosurgery. The questionnaire consisted of 75 items covering all major steps of spine radiosurgery. Strong agreement in the methods of spine radiosurgery was observed. In particular, similarities were observed with safety and quality assurance playing an important role in the methods of all institutions, cooperation between neurosurgeons and radiation oncologists in case selection, dedicated imaging for target- and organ-at-risk delineation, application of proper safety margins for the target volume and organs-at-risk, conformal planning and precise image-guided treatment delivery, and close clinical and radiological followup. In contrast, three major areas of uncertainty and disagreement were identified: 1) Indications and contraindications for spine radiosurgery; 2) treatment dose and fractionation and 3) tolerance dose of the spinal cord. of this study reflect the current practice of spine radiosurgery in large academic centers. Despite close agreement was observed in many steps of spine radiosurgery, further research in form of retrospective and especially prospective studies is required to refine the details of spinal radiosurgery in terms of safety and efficacy. 10

Radiosurgery for benign tumors of the spine using the Synergy S with cone-beam computed tomography image guidance. J Neurosurg. 2012 Dec;117 Suppl:197-202. DOI: 10.3171/2012.8.GKS12981 Gerszten PC, Chen S, Quader M, Xu Y, Novotny J Jr, Flickinger JC. There is a growing body of evidence to support the safe and effective use of spine radiosurgery. However, there is much less experience regarding the use of radiosurgery for the treatment of benign as opposed to malignant spine tumors. This study represents an evaluation of, and reporting on, the technical aspects of using a dedicated radiosurgery system for the treatment of benign spine tumors. Forty-five consecutive benign spine tumors were treated using the Elekta Synergy S 6-MV linear accelerator with a beam modulator and cone-beam computed tomography (CBCT) image guidance technology for target localization. The study cohort included 16 men and 29 women, ranging in age from 23 to 88 years (mean age 52 years). There were 14 cervical, 12 thoracic, 14 lumbar, and 5 sacral tumors. Forty-one lesions (91%) were intradural. The most common histological types of tumor were schwannoma, neurofibroma, and meningioma. Indications for radiosurgery included primary treatment in 24 cases (53%) and treatment of recurrent or residual tumor after open resection in 21 cases (47%). No subacute or long-term spinal cord or cauda equina toxicity occurred during the follow-up period (median 32 months). The mean maximum dose received by the gross tumor volume (GTV) was 16 Gy (range 12-24 Gy) delivered in a single fraction in 39 cases. The mean lowest dose received to the GTV was 12 Gy (range 8-16 Gy). The GTV ranged from 0.37 to 94.5 cm(3) (mean 13.7 cm(3), median 5.9 cm(3)). In the majority of cases, a planning target volume expansion of 2 mm was employed (38 cases; 84%). The mean maximum point dose delivered to the spinal cord was 8.7 Gy (range 4-11.5 Gy); the mean volume of the spinal cord that received greater than 8 Gy was 0.9 cm(3) (range 0.0-5.1 cm(3)); and the mean dose delivered to 0.1 cm(3) of the spinal cord was 7.5 Gy (range 3-10.5 Gy). The mean maximum point dose delivered to the cauda equina was 10 Gy (range 0-13 Gy); the mean volume of the cauda equina that received greater than 8 Gy was 1.45 cm(3) (range 0.0-10.6 cm(3)); and the mean dose delivered to 0.1 cm(3) of the cauda equina was 8 Gy (range 0.5-11 Gy). In this study the authors describe the contouring and prescribed dose techniques used in the treatment planning and delivery of radiosurgery for benign neoplasms of the spine using CBCT image guidance. This technique may serve as an important reference for the performance of radiosurgery when one believes it is clinically indicated as a treatment modality for a benign spine tumor that is associated with both a high safety profile and a strong positive clinical outcome. 11

A multi-national report on methods for institutional credentialing for spine radiosurgery. Radiat Oncol. 2013 Jun 27;8:158. DOI: 10.1186/1748-717X-8-158 Gerszten PC, Sahgal A, Sheehan JP, Kersh R, Chen S, Flickinger JC, Quader M, Fahim D, Grills I, Shin JH, Winey B, Oh K, Sweeney RA, Guckenberger M. Stereotactic body radiotherapy and radiosurgery are rapidly emerging treatment options for both malignant and benign spine tumors. Proper institutional credentialing by physicians and medical physicists as well as other personnel is important for the safe and effective adoption of spine radiosurgery. This article describes the methods for institutional credentialing for spine radiosurgery at seven highly experienced international institutions. All institutions (n = 7) are members of the Elekta Spine Radiosurgery Research Consortium and have a dedicated research and clinical focus on image-guided spine radiosurgery. A questionnaire consisting of 24 items covering various aspects of institutional credentialing for spine radiosurgery was completed by all seven institutions. Close agreement was observed in most aspects of spine radiosurgery credentialing at each institution. A formal credentialing process was believed to be important for the implementation of a new spine radiosurgery program, for patient safety and clinical outcomes. One institution has a written policy specific for spine radiosurgery credentialing, but all have an undocumented credentialing system in place. All institutions rely upon an in-house proctoring system for the training of both physicians and medical physicists. Four institutions require physicians and medical physicists to attend corporate sponsored training. Two of these 4 institutions also require attendance at a noncorporate sponsored academic society radiosurgery course. Corporate as well as non-corporate sponsored training were believed to be complimentary and both important for training. In 5 centers, all cases must be reviewed at a multidisciplinary conference prior to radiosurgery treatment. At 3 centers, neurosurgeons are not required to be involved in all cases if there is no evidence for instability or spinal cord compression. Backup physicians and physicists are required at only 1 institution, but all institutions have more than one specialist trained to perform spine radiosurgery. All centers believed that credentialing should also be device specific, and all believed that professional societies should formulate guidelines for institutions on the requirements for spine radiosurgery credentialing. Finally, in 4 institutions radiation therapists were required to attend corporatesponsored device specific training for credentialing, and in only 1 institution were radiation therapists required to also attend academic society training for credentialing. This study represents the first multi-national report of the current practice of institutional credentialing for spine radiosurgery. Key methodologies for safe implementation and credentialing of spine radiosurgery have been identified. There is strong agreement among experienced centers that credentialing is an important component of the safe and effective implementation of a spine radiosurgery program. 12

Safety and efficacy of stereotactic body radiotherapy as primary treatment for vertebral metastases: a multi-institutional analysis. Radiat Oncol. 2014 Oct 16;9(1):226. DOI: 10.1186/s13014-014-0226-2 Guckenberger M, Mantel F, Gerszten PC, Flickinger JC, Sahgal A, Letourneau D, Grills IS, Jawad M, Fahim DK, Shin JH, Winey B, Sheehan J, Kersh R. To evaluate patient selection criteria, methodology, safety and clinical outcomes of stereotactic body radiotherapy (SBRT) for treatment of vertebral metastases. Eight centers from the United States (n=5), Canada (n=2) and Germany (n=1) participated in the retrospective study and analyzed 301 patients with 387 vertebral metastases. No patient had been exposed to prior radiation at the treatment site. All patients were treated with linac-based SBRT using cone-beam CT image-guidance and online correction of set-up errors in six degrees of freedom. 387 spinal metastases were treated and the median followup was 11.8 months. The median number of consecutive vertebrae treated in a single volume was one (range, 1-6), and the median total dose was 24 Gy (range 8-60 Gy) in 3 fractions (range 1-20). The median EQD210 was 38 Gy (range 12-81 Gy). Median overall survival (OS) was 19.5 months and local tumor control (LC) at two years was 83.9%. On multivariate analysis for OS, male sex (p<0.001; HR=0.44), performance status <90 (p<0.001; HR=0.46), presence of visceral metastases (p=0.007; HR=0.50), uncontrolled systemic disease (p=0.007; HR=0.45), >1 vertebra treated with SBRT (p=0.04; HR=0.62) were correlated with worse outcomes. For LC, an interval between primary diagnosis of cancer and SBRT of 30 months (p=0.01; HR=0.27) and histology of primary disease (NSCLC, renal cell cancer, melanoma, other) (p=0.01; HR=0.21) were correlated with worse LC. Vertebral compression fractures progressed and developed de novo in 4.1% and 3.6%, respectively. Other adverse events were rare and no radiation induced myelopathy reported. This multi-institutional cohort study reports high rates of efficacy with spine SBRT. At this time the optimal fractionation within high dose practice is unknown. Re-irradiation stereotactic body radiotherapy for spinal metastases: a multi-institutional outcome analysis. J Neurosurg Spine. 2016 Nov;25(5):646-653. Epub 2016 Jun 24. DOI: 10.3171/2016.4.SPINE151523 Hashmi A, Guckenberger M, Kersh R, Gerszten PC, Mantel F, Grills IS, Flickinger JC, Shin JH, Fahim DK, Winey B, Oh K, John Cho BC, Letourneau D, Sheehan J, Sahgal A. This study is a multi-institutional pooled analysis specific to imaging-based local control of spinal metastases in patients previously treated with conventional external beam radiation therapy (cebrt) and then treated with re-irradiation stereotactic body radiotherapy (SBRT) to the spine as salvage therapy, the largest such study to date. The authors reviewed cases involving 215 patients with 247 spinal target volumes treated at 7 institutions. Overall survival was calculated on a patient basis, while local control was calculated based on the spinal target volume treated, both using the Kaplan-Meier method. Local control was defined as imaging-based progression within the SBRT target volume. Equivalent dose in 2-Gy fractions (EQD2) was calculated for the cebrt and SBRT course using an a/ß of 10 for tumor and 2 for both spinal cord and cauda equina. The median total dose/number of fractions of the initial cebrt was 30 Gy/10. The median SBRT total dose and number of fractions were 18 Gy and 1, respectively. Sixty percent of spinal target volumes were treated with single-fraction SBRT (median, 16.6 Gy and EQD2/10 = 36.8 Gy), and 40% with multiple-fraction SBRT (median 24 Gy in 3 fractions, EQD2/10 = 36 Gy). The median time interval from cebrt to re-irradiation SBRT was 13.5 months, and the median duration of patient follow-up was 8.1 months. Kaplan-Meier estimates of 6- and 12-month overall survival rates were 64% and 48%, respectively; 13% of patients suffered a local failure, and the 6- and 12-month local control rates were 93% and 83%, respectively. Multivariate analysis identified Karnofsky Performance Status (KPS) < 70 as a significant prognostic factor for worse overall survival, and singlefraction SBRT as a significant predictive factor for better local control. There were no cases of radiation myelopathy, and the vertebral compression fracture rate was 4.5%. Re-irradiation spine SBRT is effective in yielding imaging-based local control with a clinically acceptable safety profile. A randomized trial would be required to determine the optimal fractionation. 13

Variability in spine radiosurgery treatment planning results of an international multi-institutional study. Radiat Oncol. 2016 Apr 18; 1157. DOI: 10.1186/s13014-016-0631-9 Toussaint A, Richter A, Mantel F, Flickinger JC, Grills IS, Tyagi N, Sahgal A, Letourneau D, Sheehan JP, Schlesinger DJ, Gerszten PC, Guckenberger M. The aim of this study was to quantify the variability in spinal radiosurgery (SRS) planning practices between five international institutions, all member of the Elekta Spine Radiosurgery Research Consortium. Four institutions provided one representative patient case each consisting of the medical history, CT and MR imaging. A step-wise planning approach was used where, after each planning step a consensus was generated that formed the basis for the next planning step. This allowed independent analysis of all planning steps of CT-MR image registration, GTV definition, CTV definition, PTV definition and SRS treatment planning. In addition, each institution generated one additional SRS plan for each case based on intra-institutional image registration and contouring, independent of consensus results. Averaged over the four cases, image registration variability ranged between translational 1.1 mm and 2.4 mm and rotational 1.1 and 2.0 in all three directions. GTV delineation variability was 1.5 mm in axial and 1.6 mm in longitudinal direction averaged for the four cases. CTV delineation variability was 0.8 mm in axial and 1.2 mm in longitudinal direction. CTV-to-PTV margins ranged between 0 mm and 2 mm according to institutional protocol. Delineation variability was 1 mm in axial directions for the spinal cord. Average PTV coverage for a single fraction18 Gy prescription was 87 ± 5 %; Dmin to the PTV was 7.5 ± 1.8 Gy averaged over all cases and institutions. Average Dmax to the PRV_SC (spinal cord + 1 mm) was 10.5 ± 1.6 Gy and the average Paddick conformity index was 0.69 ± 0.06. of this study reflect the variability in current practice of spine radiosurgery in large and highly experienced academic centers. Despite close methodical agreement in the daily workflow, clinically significant variability in all steps of the treatment planning process was demonstrated. This may translate into differences in patient clinical outcome and highlights the need for consensus and established delineation and planning criteria. 14

Vertebral compression fractures after stereotactic body radiation therapy: a large, multi-institutional, multinational evaluation. J Neurosurg Spine. 2016 Jun; 24(6):928-36. DOI: 10.3171/2015.10.SPINE141261 Jawad MS, Fahim DK, Gerszten PC, Flickinger JC, Sahgal A, Grills IS, Sheehan J, Kersh R, Shin J, Oh K, Mantel F, Guckenberger M. The purpose of this study was to identify factors contributing to an increased risk for vertebral compression fracture (VCF) following stereotactic body radiation therapy (SBRT) for spinal tumors. A total of 594 tumors were treated with spinal SBRT as primary treatment or re-irradiation at 8 different institutions as part of a multi-institutional research consortium. Patients underwent LINAC-based, imageguided SBRT to a median dose of 20 Gy (range 8-40 Gy) in a median of 1 fraction (range 1-5 fractions). Median patient age was 62 years. Seventy-one percent of tumors were osteolytic, and a preexisting vertebral compression fracture (VCF) was present in 24% of cases. Toxicity was assessed following treatment. Univariate and multivariate analyses were performed using a logistic regression method to determine parameters predictive for post-sbrt VCF. At a median follow-up of 10.1 months (range 0.03-57 months), 80% of patients had local tumor control. At the time of last imaging follow-up, at a median of 8.8 months after SBRT, 3% had a new VCF, and 2.7% had a progressive VCF. For development of any (new or progressive) VCF following SBRT, the following factors were predictive for VCF on univariate analysis: short interval from primary diagnosis to SBRT (less than 36.8 days), solitary metastasis, no additional bone metastases, no prior chemotherapy, preexisting VCF, no MRI used for target delineation, tumor volume of 37.3 cm(3) or larger, equivalent 2-Gy-dose (EQD2) tumor of 41.8 Gy or more, and EQD2 spinal cord Dmax of 46.1 Gy or more. Preexisting VCF, solitary metastasis, and prescription dose of 38.4 Gy or more were predictive on multivariate analysis. The following factors were predictive of a new VCF on univariate analysis: solitary metastasis, no additional bone metastases, and no MRI used for target delineation. Presence of a solitary metastasis and lack of MRI for target delineation remained significant on multivariate analysis. A VCF following SBRT is more likely to occur following treatment for a solitary spinal metastasis, reflecting a more aggressive treatment approach in patients with adequately controlled systemic disease. Higher prescription dose and a preexisting VCF also put patients at increased risk for post- SBRT VCF. In these patients, pre-sbrt cement augmentation could be considered to decrease the risk of subsequent VCF. 15

Oligometastatic Cancer A multinational report of technical factors on stereotactic body radiotherapy for oligometastases. Future Oncol. 2017 Feb 3. DOI: 10.2217/fon-2016-0479 Redmond KJ, Lo SS, Dagan R, Poon I, Foote MC, Erler D, Lee Y, Lohr F, Biswas T, Ricardi U, Sahgal A. Oligometastatic cancer is being increasingly managed with aggressive local therapy using stereotactic body radiation therapy (SBRT). However, few guidelines exist. We summarize the results of an international survey reviewing technical factors for extracranial SBRT for oligometastatic disease to guide safe management. Seven high-volume centers contributed. Levels of agreement were categorized as strong (6 7 common responses), moderate (4 5), low (2 3) or no agreement. We present the results of a multi-national and multiinstitutional survey of technical factors of SBRT for extracranial oligometastases. Key methods including target delineation, prescription doses, normal tissue constraints, imaging and set-up for safe implementation and practice of SBRT for oligometastasis have been identified. This manuscript will serve as a foundation for future clinical evaluations. 16

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