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Purpose: In robotic stereotactic radiosurgery (SRS), optimal selection of collimators from a set of fixed cones must be determined manually by trial and error. A unique and uniformly scaled metric to characterize plan quality could help identify Pareto-efficient treatment plans., Methods: The concept of dose-area product (DAP) was used to define a measure (DAP ratio ) of the targeting efficiency of a set of beams by relating the integral DAP of the beams to the mean dose achieved in the target volume. In a retrospective study of five clinical cases of brain metastases with representative target volumes (range: 0.5-5.68 ml) and 121 treatment plans with all possible collimator choices, the DAP ratio was determined along with other plan metrics (conformity index CI, gradient index R50%, treatment time, total number of monitor units TotalMU, radiotoxicity index f12, and energy efficiency index η50%), and the respective Spearman's rank correlation coefficients were calculated. The ability of DAP ratio to determine Pareto efficiency for collimator selection at DAP ratio  < 1 and DAP ratio  < 0.9 was tested using scatter plots., Results: The DAP ratio for all plans was on average 0.95 ± 0.13 (range: 0.61-1.31). Only the variance of the DAP ratio was strongly dependent on the number of collimators. For each target, there was a strong or very strong correlation of DAP ratio with all other metrics of plan quality. Only for R50% and η50% was there a moderate correlation with DAP ratio for the plans of all targets combined, as R50% and η50% strongly depended on target size. Optimal treatment plans with CI, R50%, f12, and η50% close to 1 were clearly associated with DAP ratio  < 1, and plans with DAP ratio  < 0.9 were even superior, but at the cost of longer treatment times and higher total monitor units., Conclusions: The newly defined DAP ratio has been demonstrated to be a metric that characterizes the target efficiency of a set of beams in robotic SRS in one single and uniformly scaled number. A DAP ratio  < 1 indicates Pareto efficiency. The trade-off between plan quality on the one hand and short treatment time or low total monitor units on the other hand is also represented by DAP ratio ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Stereotactic body radiotherapy is a locally effective treatment for lung metastases in patients with oligometastatic disease, a modern variant of which is robotic (rSBRT). Since it is unclear which factors determine the success of rSBRT, we investigated a cohort of patients with lung metastases treated with rSBRT., Patients and Methods: In our retrospective single-center analysis, we included patients with oligometastatic disease of different cancer types who underwent SBRT of lung metastases using an Accuray Cyberknife ® device between 2012 and 2019. We evaluated local control rate (LC), progression-free (PFS) and overall (OS) survival, and toxicity. Multivariate analysis was performed to identify independent factors associated with the efficacy and toxicity of rSBRT., Results: A total of 70 lung metastases of 54 patients were evaluated. The 4-year Kaplan-Meier estimate for LC, PFS and OS were 72.0%, 12.4% and 49.7%, respectively. Cox regression showed that LC of metastases of colorectal carcinoma and metastases treated with a biological effective dose at an α/β-ratio of 10 (BED 10 ) of <100 Gy was significantly worse than for other metastases. Patients suffered from grade I-II pneumonitis in 21.4% of cases treated with rSBRT (grade I: 20.0%; grade II: 1.4%)., Conclusion: rSBRT is an effective and safe therapy for lung metastases. A BED 10 of >100 Gy should be aimed for, especially for potentially radioresistant histologies such as colorectal carcinoma., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: In stereotactic radiosurgery (SRS), prescription isodoses and resulting dose homogeneities vary widely across different platforms and clinical entities. Our goal was to investigate the physical limitations of generating dose distributions with an intended level of homogeneity in robotic SRS., Methods: Treatment plans for non-isocentric irradiation of 4 spherical phantom targets (volume 0.27-7.70 ml) and 4 clinical targets (volume 0.50-5.70 ml) were calculated using Sequential (phantom) or VOLO TM (clinical) optimizers (Accuray, Sunnyvale, CA, USA). Dose conformity, volume of 12 Gy isodose (V12Gy) as a measure for dose gradient, and treatment time were recorded for different prescribed isodose levels (PILs) and collimator settings. In addition, isocentric irradiation of phantom targets was examined, with dose homogeneity modified by using different collimator sizes., Results: Dose conformity was generally high (nCI ≤ 1.25) and varied little with PIL. For all targets and collimator sets, V12Gy was highest for PIL ≥ 80% and lowest for PIL ≤ 65%. The impact of PIL on V12Gy was highest for isocentric irradiation and lowest for clinical targets (VOLO TM optimization). The variability of V12Gy as a function of collimator selection was significantly higher than that of PIL. V12Gy and treatment time were negatively correlated. Plans utilizing a single collimator with a diameter in the range of 70-80% of the target diameter were fastest, but showed the strongest dependence on PIL., Conclusion: Inhomogeneous dose distributions with PIL ≤ 70% can be used to minimize dose to normal tissue. PIL ≥ 90% is associated with a marked and significant increase in off-target dose exposure. Careful selection of collimators during planning is even more important., (© 2021. The Author(s).)

Background: Treatment decision for recurrent symptomatic brain metastases (BM) is challenging with scarce data regarding surgical resection. We therefore evaluated the efficacy of surgery for pretreated, recurrent BM in a comprehensive multidisciplinary treatment setting., Methods: In a retrospective single center study, patients were analyzed, who underwent surgical resection of recurrent BM between 2007 and 2019. Intracranial event-free survival (EFS) and overall survival (OS) were evaluated by Kaplan-Maier and Cox regression analysis., Results: We included 107 patients with different primary tumor entities and individual previous treatment for BM. Primary tumors comprised non-small cell lung cancer (NSCLC) (37.4%), breast cancer (19.6%), melanoma (13.1%), gastro-intestinal cancer (10.3%) and other, rare entities (19.6%). The number of previous treatments of BM ranged from one to four; the adjuvant treatment modalities comprised: none, focal or whole brain radiotherapy, brachytherapy and radiosurgery. The median pre-operative Karnofsky Performance Score (KPS) was 70% (range 40-100) and improved to 80% (range 0-100) after surgery. The complication rate was 26.2% and two patients died during the perioperative period. Sixty-seven (62.6%) patients received postoperative local radio-oncologic and/or systemic therapy. Median postoperative EFS and OS were 7.1 (95%CI 5.8-8.2) and 11.1 (95%CI 8.4-13.6) months, respectively. The clinical status (postoperative KPS ≥ 70 (HR 0.27 95%CI 0.16-0.46; p < 0.001) remained the only independent factor for survival in multivariate analysis., Conclusions: Surgical resection of recurrent BM may improve the clinical status and thus OS but is associated with a high complication rate; therefore a very careful patient selection is crucial., (© 2022. The Author(s).)

Background: Brain metastases show different patterns of contrast enhancement, potentially reflecting hypoxic and necrotic tumor regions with reduced radiosensitivity. An objective evaluation of these patterns might allow a prediction of response to radiotherapy. We therefore investigated the potential of MRI radiomics in comparison with the visual assessment of semantic features to predict early response to stereotactic radiosurgery in patients with brain metastases., Patients and Methods: In this retrospective study, 150 patients with 308 brain metastases from solid tumors (NSCLC in 53% of patients) treated by stereotactic radiosurgery (single dose of 17-20 Gy) were evaluated. The response of each metastasis (partial or complete remission vs. stabilization or progression) was assessed within 180 days after radiosurgery. Patterns of contrast enhancement in the pre-treatment T1-weighted MR images were either visually classified (homogenous, heterogeneous, necrotic ring-like) or subjected to a radiomics analysis. Random forest models were optimized by cross-validation and evaluated in a hold-out test data set (30% of metastases)., Results: In total, 221/308 metastases (72%) responded to radiosurgery. The optimal radiomics model comprised 10 features and outperformed the model solely based on semantic features in the test data set (AUC, 0.71 vs. 0.56; accuracy, 69% vs. 54%). The diagnostic performance could be further improved by combining semantic and radiomics features resulting in an AUC of 0.74 and an accuracy of 75% in the test data set., Conclusion: The developed radiomics model allowed prediction of early response to radiosurgery in patients with brain metastases and outperformed the visual assessment of patterns of contrast enhancement., Competing Interests: Conflicts of interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: The introduction of hypofractionated stereotactic radiosurgery (hSRS) extended the treatment modalities beyond the well-established single-fraction stereotactic radiosurgery and fractionated radiotherapy. Here, we report the efficacy and side effects of hSRS using Cyberknife ® (CK-hSRS) for the treatment of patients with critical brain metastases (BM) and a very poor prognosis. We discuss our experience in light of current literature., Methods: All patients who underwent CK-hSRS over 3 years were retrospectively included. We applied a surface dose of 27 Gy in 3 fractions. Rates of local control (LC), systemic progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related complications were rated using the Common Terminology Criteria for Adverse Events (CTCAE)., Results: We analyzed 34 patients with 75 BM. 53% of the patients had a large tumor, tumor location was eloquent in 32%, and deep seated in 15%. 36% of tumors were recurrent after previous irradiation. The median Karnofsky Performance Status was 65%. The actuarial rates of LC at 3, 6, and 12 months were 98%, 98%, and 78.6%, respectively. Three, 6, and 12 months PFS was 38%, 32%, and 15%, and OS was 65%, 47%, and 28%, respectively. Median OS was significantly associated with higher KPS, which was the only significant factor for survival. Complications CTCAE grade 1-3 were observed in 12%., Conclusion: Our radiation schedule showed a reasonable treatment effectiveness and tolerance. Representing an optimal salvage treatment for critical BM in patients with a very poor prognosis and clinical performance state, CK-hSRS may close the gap between surgery, stereotactic radiosurgery, conventional radiotherapy, and palliative care., (© 2021. The Author(s).)

Objectives: To generate and validate state-of-the-art radiomics models for prediction of radiation-induced lung injury and oncologic outcome in non-small cell lung cancer (NSCLC) patients treated with robotic stereotactic body radiation therapy (SBRT)., Methods: Radiomics models were generated from the planning CT images of 110 patients with primary, inoperable stage I/IIa NSCLC who were treated with robotic SBRT using a risk-adapted fractionation scheme at the University Hospital Cologne (training cohort). In total, 199 uncorrelated radiomic features fulfilling the standards of the Image Biomarker Standardization Initiative (IBSI) were extracted from the outlined gross tumor volume (GTV). Regularized models (Coxnet and Gradient Boost) for the development of local lung fibrosis (LF), local tumor control (LC), disease-free survival (DFS) and overall survival (OS) were built from either clinical/ dosimetric variables, radiomics features or a combination thereof and validated in a comparable cohort of 71 patients treated by robotic SBRT at the Radiosurgery Center in Northern Germany (test cohort)., Results: Oncologic outcome did not differ significantly between the two cohorts (OS at 36 months 56% vs. 43%, p = 0.065; median DFS 25 months vs. 23 months, p = 0.43; LC at 36 months 90% vs. 93%, p = 0.197). Local lung fibrosis developed in 33% vs. 35% of the patients (p = 0.75), all events were observed within 36 months. In the training cohort, radiomics models were able to predict OS, DFS and LC (concordance index 0.77-0.99, p < 0.005), but failed to generalize to the test cohort. In opposite, models for the development of lung fibrosis could be generated from both clinical/dosimetric factors and radiomic features or combinations thereof, which were both predictive in the training set (concordance index 0.71- 0.79, p < 0.005) and in the test set (concordance index 0.59-0.66, p < 0.05). The best performing model included 4 clinical/dosimetric variables (GTV-D mean , PTV-D 95% , Lung-D 1ml , age) and 7 radiomic features (concordance index 0.66, p < 0.03)., Conclusion: Despite the obvious difficulties in generalizing predictive models for oncologic outcome and toxicity, this analysis shows that carefully designed radiomics models for prediction of local lung fibrosis after SBRT of early stage lung cancer perform well across different institutions.

Background: For meningiomas, complete resection is recommended as first-line treatment while stereotactic radiosurgery (SRS) is established for meningiomas of smaller size considered inoperable. If the patient´s medical condition or preference excludes surgery, SRS remains a treatment option. We evaluated the efficacy and safety of SRS in a cohort comprising these cases., Methods: In this retrospective single-centre analysis we included patients receiving single fraction SRS either by modified LINAC or robotic guidance by Cyberknife for potentially resectable intracranial meningiomas. Treatment-related adverse events as well as local and regional control rates were determined from follow-up imaging and estimated by the Kaplan-Meier method., Results: We analyzed 188 patients with 218 meningiomas. The median radiological, and clinical follow-up periods were 51.4 (6.2-289.6) and 55.8 (6.2-300.9) months. The median tumor volume was 4.2 ml (0.1-22), and the mean marginal radiation dose was 13.0 ± 3.1 Gy, with reference to the 80.0 ± 11.2% isodose level. Local recurrence was observed in one case (0.5%) after 239 months. The estimated 2-, 5-, 10- and 15-year regional recurrence rates were 1.5%, 3.0%, 6.6% and 6.6%, respectively. Early adverse events (≤ 6 months after SRS) occurred in 11.2% (CTCEA grade 1-2) and resolved during follow-up in 7.4% of patients, while late adverse events were documented in 14.4% (grade 1-2; one case grade 3). Adverse effects (early and late) were associated with the presence of symptoms or neurological deficits prior to SRS (p < 0.03) and correlated with the treatment volume (p < 0.02)., Conclusion: In this analysis SRS appears to be an effective treatment for patients with meningiomas eligible for complete resection and provides reliable long-term local tumor control with low rates of mild morbidity.

Background: Stereotactic radiosurgery (SRS) is widely accepted as a therapeutic option for meningiomas (M) and vestibular schwannomas (VS). However, data on outcome and toxicity in the elderly population have rarely been reported in detail., Methods: All patients aged ≥ 65 years with M or VS who underwent single fraction SRS were included. Patient data were analyzed in terms of clinical tumor control and incidence of early and late treatment related complications, which were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), RESULTS: We identified 245 patients with benign brain tumors (129 M and 116 VS, median tumor volume 2.9 ml, range 0.1-28). The median age was 71 years (range 65-86) and the mean follow-up times were 42 months (range 2-181). Tumors were irradiated with a median dose of 12.4 Gy. Actuarial clinical and radiological tumor control rates at 2, 5, and 10 years after SRS were 98%, 93%, and 88%, respectively. Recurrent tumors after previous treatment had a higher probability of post-radiosurgical progression (p < 0.001). Permanent toxicity (CTCAE I/II) were noted in 5.7%. No severe adverse events were observed during early and late follow up, although patients > 70 years had a slightly higher risk for toxicity (p = 0.027). The presence and extent of co-morbidities had no significant influence on local tumor control or toxicity., Conclusion: SRS provides favorable tumor control with low risk for treatment-related severe complications. Thus, SRS should always be considered as treatment option for benign intracranial tumors (meningiomas, schwannomas), especially in the group of elderly patients.

Stereotactic radiosurgery (SRS) has evolved as widely accepted treatment option for small-sized (Koos I up to II) vestibular schwannoma (VS). For larger tumors (prevalent Koos VI), microsurgery or combined treatment strategies are mostly recommended. However, in patients not suited for microsurgery, SRS might also be an alternative to balance tumor control, hearing preservation and adverse effects. The purpose of this analysis was to evaluate the efficacy and toxicity of SRS for VS with regard to different Koos grades. All patients with untreated VS who received SRS at our center were included. Outcome analysis included tumor control, preservation of serviceable hearing based on median pure tone averages (PTA), and procedure-related adverse events rated by the Common Terminology Criteria for Adverse Events (CTCAE; v4.03) classification. In total, 258 patients (median age 58 years, range 21-84) were identified with a mean follow-up of 52 months (range 3-228 months). Mean tumor volume was 1.8 ml (range 0.1-18.5). The mean marginal dose was 12.3 Gy ± 0.6 (range 11-13.5). The cohort was divided into two groups: A (Koos grades I and II, n = 186) and B (Koos grades III and IV, n = 72). The actuarial tumor control rate was 98% after 2 years and 90% after 5 and 10 years. Koos grading did not show a significant impact on tumor control (p = 0.632) or hearing preservation (p = 0.231). After SRS, 18 patients (7%) had new transient or permanent symptoms classified by the CTCAE. The actuarial rate of CTCAE-free survival was not related to Koos grading (p = 0.093). Based on this selected population of Koos grade III and IV VS without or with only mild symptoms from brainstem compression, SRS can be recommended as the primary therapy with the advantage of low morbidity and satisfactory tumor control. The overall hearing preservation rate and toxicity of SRS was influenced by age and cannot be predicted by tumor volume or Koos grading alone.

Objectives: To predict radiation-induced lung injury and outcome in non-small cell lung cancer (NSCLC) patients treated with robotic stereotactic body radiation therapy (SBRT) from radiomic features of the primary tumor., Methods: In all, 110 patients with primary stage I/IIa NSCLC were analyzed for local control (LC), disease-free survival (DFS), overall survival (OS) and development of local lung injury up to fibrosis (LF). First-order (histogram), second-order (GLCM, Gray Level Co-occurrence Matrix) and shape-related radiomic features were determined from the unprocessed or filtered planning CT images of the gross tumor volume (GTV), subjected to LASSO (Least Absolute Shrinkage and Selection Operator) regularization and used to construct continuous and dichotomous risk scores for each endpoint., Results: Continuous scores comprising 1-5 histogram or GLCM features had a significant (p = 0.0001-0.032) impact on all endpoints that was preserved in a multifactorial Cox regression analysis comprising additional clinical and dosimetric factors. At 36 months, LC did not differ between the dichotomous risk groups (93% vs. 85%, HR 0.892, 95%CI 0.222-3.590), while DFS (45% vs. 17%, p < 0.05, HR 0.457, 95%CI 0.240-0.868) and OS (80% vs. 37%, p < 0.001, HR 0.190, 95%CI 0.065-0.556) were significantly lower in the high-risk groups. Also, the frequency of LF differed significantly between the two risk groups (63% vs. 20% at 24 months, p < 0.001, HR 0.158, 95%CI 0.054-0.458)., Conclusion: Radiomic analysis of the gross tumor volume may help to predict DFS and OS and the development of local lung fibrosis in early stage NSCLC patients treated with stereotactic radiotherapy.

Importance: Brain metastases are a common source of morbidity for patients with cancer, and limited data exist to support the local therapeutic choice between surgical resection and stereotactic radiosurgery (SRS)., Objective: To evaluate local control of brain metastases among patients treated with SRS vs surgical resection within the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial., Design, Setting, and Participants: This unplanned, exploratory analysis of the international, multi-institutional randomized clinical trial EORTC 22952-26001 (conducted from 1996-2007) was performed from February 9, 2017, through July 25, 2018. The EORTC 22952-26001 trial randomized patients with 1 to 3 brain metastases to whole-brain radiotherapy vs observation after complete surgical resection or before SRS. Patients in the present analysis were stratified but not randomized according to local modality (SRS or surgical resection) and treated per protocol with 1 to 2 brain metastases and tumors with a diameter of no greater than 4 cm., Interventions: Surgical resection or SRS., Main Outcomes and Measures: The primary end point was local recurrence of treated lesions. Cumulative incidence of local recurrence was calculated according to modality (surgical resection vs SRS) with competing risk regression to adjust for prognostic factors and competing risk of death., Results: A total of 268 patients were included in the analysis (66.4% men; median age, 60.7 years [range, 26.9-81.1 years]); 154 (57.5%) underwent SRS and 114 (42.5%) underwent surgical resection. Median follow-up time was 39.9 months (range, 26.0-1982.0 months). Compared with the SRS group, patients undergoing surgical resection had larger metastases (median 28 mm [range, 10-40 mm] vs 20 mm [range, 4-40 mm]; P < .001), more frequently had 1 brain metastasis (112 [98.2%] vs 114 [74.0%]; P < .001), and differed in location (parietal, 21 [18.4%] vs 61 [39.6%]; posterior fossa, 30 [26.3%] vs 12 [7.8%]; P < .001). In adjusted models, local recurrence was similar between the SRS and surgical resection groups (hazard ratio [HR], 1.15; 95% CI, 0.72-1.83). However, when stratified by interval, patients with surgical resection had a much higher risk of early (0-3 months) local recurrence compared with those undergoing SRS (HR, 5.94; 95% CI, 1.72-20.45), but their risk decreased with time (HR for 3-6 months, 1.37 [95% CI, 0.64-2.90]; HR for 6-9 months, 0.75 [95% CI, 0.28-2.00]). At 9 months or longer, the surgical resection group had a lower risk of local recurrence (HR, 0.36; 95% CI, 0.14-0.93)., Conclusions and Relevance: In this exploratory analysis, local control of brain metastases was similar between SRS and surgical resection groups. Stereotactic radiosurgery was associated with improved early local control of treated lesions compared with surgical resection, although the relative benefit decreased with time., Trial Registration: ClinicalTrials.gov Identifier: NCT00002899.

Combination concepts of radiotherapy and immune checkpoint inhibition are currently of high interest. We examined imaging findings, acute toxicity, and local control in patients with melanoma brain metastases receiving programmed death 1 (PD-1) inhibitors and/or robotic stereotactic radiosurgery (SRS). Twenty-six patients treated with SRS alone ( n = 13; 20 lesions) or in combination with anti-PD-1 therapy ( n = 13; 28 lesions) were analyzed. Lesion size was evaluated three and six months after SRS using a volumetric assessment based on cranial magnetic resonance imaging (cMRI) and acute toxicity after 12 weeks according to the Common Terminology Criteria for Adverse Events (CTCAE). Local control after six months was comparable (86%, SRS + anti-PD-1, and 80%, SRS). All toxicities reported were less than or equal to grade 2. One metastasis (5%) in the SRS group and six (21%) in the SRS + anti-PD-1 group increased after three months, whereas four (14%) of the six regressed during further follow-ups. This was rated as pseudoprogression (PsP). Three patients (23%) in the SRS + anti-PD-1 group showed characteristics of PsP. Treatment with SRS and anti-PD-1 antibodies can be combined safely in melanoma patients with cerebral metastases. Early volumetric progression of lesions under simultaneous treatment may be related to PsP; thus, the evaluation of combined radioimmunotherapy remains challenging and requires experienced teams.

Objective: To determine the clinical and radiologic outcome of patients with acoustic neuroma (AN) treated with linear accelerator (LINAC) or CyberKnife-based stereotactic radiosurgery with respect to tumor control, preservation of serviceable hearing, and toxicity., Methods: A retrospective monocentric analysis including all patients who underwent single-fraction LINAC- or CyberKnife-based radiosurgery for AN between 1991 and 2015. Patient data were analyzed in terms of radiologic and clinical tumor control (no further intervention needed), treatment-related complications, preservation of serviceable hearing, and objectified hearing loss using pure tone average levels., Results: We included 335 patients (median age 58.2 years, treated either by LINAC-based [n = 270] or CyberKnife [n = 65] stereotactic radiosurgery). The median tumor volume was 1.1 mL (0.1-23.7 mL). The median radiation dose was 12 Gy (LINAC 12 Gy, 11-20 Gy; CyberKnife 13 Gy, 12-13 Gy) at an isodose level of 71.7% (LINAC 68.3%, 31.9%-86.2%; CyberKnife 80%, 65%-81%). The median follow-up was 30 months (LINAC 43 months, 2-224 months; CyberKnife 13 months, 4-37 months). Clinical tumor control was 98%, 89%, and 88% at 2, 5, and 10 years. The objective actuarial hearing preservation rate was 89%, 80%, and 55% at 1, 2, and 5 years. New symptoms were observed in 11.3% and classified as Common Terminology Criteria for Adverse Events grade 1/2, apart from 4 patients (1.2%), who developed Common Terminology Criteria for Adverse Events grade 3., Conclusions: Our study shows that in AN, high tumor control and considerable hearing preservation rates can be achieved by single-dose radiosurgery at low toxicity rates, resulting in a positive impact on long-term clinical outcome., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To evaluate efficacy and toxicity of stereotactic body radiation therapy (SBRT) with CyberKnife® (Accuray, Sunnyvale, CA, USA) in a selected cohort of primary, medically inoperable early-stage non-small cell lung cancer (NSCLC) patients., Methods: From 2012 to 2016, 106 patients (median age 74 years, range 50-94 years) with primary NSCLC were treated with SBRT using CyberKnife®. Histologic confirmation was available in 87 patients (82%). For mediastinal staging, 92 patients (87%) underwent 18 F-fluorodeoxyglucose positron-emission tomography (18-FDG-PET) and/or endobronchial ultrasound (EBUS)-guided lymph node biopsy or mediastinoscopy. Tumor stage (UICC8, 2017) was IA/B (T1a-c, 1-3 cm) in 86 patients (81%) and IIA (T2a/b, 3-5 cm) in 20 patients (19%). Depending on tumor localization, three different fractionation schedules were used: 3 fractions of 17Gy, 5 fractions of 11Gy, or 8 fractions of 7.5 Gy. Tracking was based on fiducial implants in 13 patients (12%) and on image guidance without markers in 88%., Results: Median follow-up was 15 months (range 0.5-46 months). Acute side effects were mild (fatigue grade 1-2 in 20% and dyspnea grade 1-2 in 17%). Late effects were observed in 4 patients (4%): 3 patients developed pneumonitis requiring therapy (grade 2) and 1 patient suffered a rib fracture (grade 3). In total, 9/106 patients (8%) experienced a local recurrence, actuarial local control rates were 88% (95% confidence interval, CI, 80-96%) at 2 years and 77% (95%CI 56-98%) at 3 years. The median disease-free survival time was 27 months (95%CI 23-31 months). Overall survival was 77% (95%CI 65-85%) at 2 years and 56% (95%CI 39-73%) at 3 years., Conclusion: CyberKnife® lung SBRT which allows for real-time tumor tracking and risk-adapted fractionation achieves satisfactory local control and low toxicity rates in inoperable early-stage primary lung cancer patients.

Background: As irradiated brain volume at 12 Gy (V12) is a predictor for radionecrosis, the purpose of the study was to develop a model for Cyberknife (CK) plans that is able to predict the lowest achievable V12 at a given tumor size and prescription dose (PD), and to suggest a new quality index regarding V12 for optimizing the treatment planning of brain metastases., Method: In our model V12 was approximated as a spherical shell around the tumor volume. The radial distance between tumor surface and the 12 Gy isodose line was calculated using an approximation of the mean dose gradient in that area. Assuming a radially symmetrical irradiation from the upper half space, the dose distribution is given by the superposition of single fields. The dose profiles of a single field were derived by the measured off-center ratios (OCR) of the CK system. Using the calculated gradients of the sum dose profiles, minimal-V12 was estimated for different tumor sizes. The model calculation was tested using a phantom dataset and retrospectively applied on clinical cases., Results: Our model allows the prediction of a best-case scenario for V12 at a given tumor size and PD which was confirmed by the results of the isocentric phantom plans. The results of the non-isocentric phantom plans showed that an optimization of coverage caused an increase in V12. This was in accordance with the results of the retrospective analysis. V12 s of the clinical cases were on average twice that of the predicted model calculation. A good agreement was achieved for plans with an optimal conformity index (nCI). Re-planning of cases with high V12 showed that lower values could be reached by selecting smaller collimators and by allowing a larger number of total MU and more MU per beam., Conclusions: V12 is a main parameter for assessing plan quality in terms of radiotoxicity. The index f12 defined as the ratio of V12 from the actual plan with the evaluated V12 from our model describes the conformity of an optimally possible V12 and thus can be used as a new quality index for optimizing treatment plans.

Background: The management of solely intracanalicular acoustic neurinoma (iAN) includes observation, microsurgical resection and radiation therapy. Treatment goals are long-term tumor control, hearing preservation and concurrently low side-effects. Stereotactic radiosurgery (SRS) has evolved as an alternative first-line treatment for small AN. Here we report about the long-term follow-up of a unique cohort of patients with iAN after LINAC or Cyberknife® based SRS., Methods: In this single center retrospective analysis, we included all patients with iAN who underwent single session LINAC or Cyberknife® based SRS between 1993 and 2015, and who had a minimum follow-up period of six weeks. Patient data were analyzed in terms of radiological and clinical tumor control (no further treatment necessary), subjective preservation of serviceable hearing, objective change in pure tone averages (PTA), and adverse events rated by the Common Terminology Criteria for Adverse Events (CTCAE; v4.03)., Results: Forty-nine patients (f/m = 21/28, median age 54 ± 12, range 20-77 years) were identified. Mean tumor volumes were 0.24 ± 0.12 cm 3 (range, 0.1-0.68 cm 3 ), the mean marginal dose was 12.6 ± 0.6 Gy (range, 11.0-14.0 Gy) and the prescription isodose was 75 ± 7.4% (range, 47-86%). Mean follow-up time was 65 months (range, 4-239 months). Radiological tumor control was 100% during further follow-up. 17 (35%) out of 49 patients had lost serviceable hearing prior to SRS. Those with preserved serviceable hearing remained stable in 78% (n = 25/32) at the last follow-up (LFU). The median PTA (n = 16) increased from 25.6 dB prior to SRS to 43.8 dB at LFU. Mild adverse events were observed temporarily in two patients (4%): one with CTCAE grade 1 facial nerve disorder after 3 months, resolving three months later, and one with CTCAE grade 2 facial muscle weakness resolving after 12 months. Three patients described permanent mild symptoms CTCAE grade 1 without limiting daily life (facial weakness n = 1, vertigo n = 2)., Conclusion: SRS for iAN shows long-term reliable tumor control with a high rate of hearing preservation without considerable permanent side effects, and can be proposed as a safe and effective treatment alternative to microsurgical resection.

The irradiation of tumors in the brain is challenging due to the proximity of radiation sensitive critical structures and the tumors to be treated. In addition, irradiation above a certain level can cause irreversible damage to nerve tissue. The irradiation of benign and malignant brain tumors requires precise techniques to preserve critical structures while simultaneously administering a high radiation dose for maximum effectiveness. Therefore, stereotaxy, as a subspecialty of neurosurgery, has developed various irradiation techniques, e. g., intracerebral application of interstitial brachytherapy (SBT; stereotactic brachytherapy) and stereotactic radiosurgery (SRS). Due to the development of computer-controlled radiation techniques (e. g., Cyberknife) over the last 20 years, SRS has gained increasing importance.

Purpose: The efficacy and safety of stereotactic radiosurgery (SRS) for treatment of intracranial meningiomas has been demonstrated in numerous studies with short- and intermediate-term follow-up. In this retrospective single-center study, we present long-term outcomes of SRS performed with a linear accelerator (LINAC) for typical intracranial meningiomas., Patients and Methods: Between August 1990 and December 2007, 148 patients with 168 typical intracranial meningiomas were treated with stereotactic LINAC-SRS, either as primary treatment or after microsurgical resection. A median tumor surface dose of 12 Gy (range 7-20 Gy) and a median maximum dose of 24.1 Gy (range 11.3-58.6 Gy) was applied. The median target volume was 4.7 ml (range 0.2-32.8 ml, SD ± 4.8 ml)., Results: Overall mean radiological follow-up was 12.6 years. Tumor shrinkage was seen in 75 (44.6 %) and stable disease in 85 (50.6 %) cases. Eight of 168 meningiomas (4.8 %) showed local tumor progression. The tumor control rate (TCR) after 5, 10, and 15 years was 93.6 % at each time point, and the progression-free survival (PSF) rates were 92, 89, and 89 %, respectively. The neurological symptoms existing prior to LINAC-SRS improved in 77 patients (59.7 %), remained unchanged in 42 (32.6 %), and deteriorated in 10 (7.8 %) patients., Conclusion: Our study emphasizes the efficacy of LINAC-SRS for de novo, residual and recurrent typical intracranial meningiomas. A high long-term local TCR with a low morbidity rate could be achieved. LINAC-SRS should thus be considered as a primary treatment option, as one arm of a combined treatment approach for incompletely resected meningiomas, or as a salvage therapy for recurrences.

Background: The optimal treatment of glomus jugulare tumors (GJTs) remains controversial. Due to the critical location, microsurgery still provides high treatment-related morbidity and a decreased quality of life. Thus, we performed stereotactical radiosurgery (SRS) for the treatment of GJTs and evaluated the long-term outcome., Methods: Between 1991 and 2011, 32 patients with GJTs underwent SRS using a linear accelerator (LINAC) either as primary or salvage therapy. Twenty-seven patients (median age 59.9 years, range 28.7-79.9 years) with a follow-up greater than five years (median 11 years, range 5.3-22.1 years) were selected for retrospective analysis. The median therapeutic single dose applied to the tumor surface was 15 Gy (range 11-20 Gy) and the median tumor volume was 9.5 ml (range 2.8-51 ml)., Results: Following LINAC-SRS, 10 of 27 patients showed a significant improvement of their previous neurological complaints, whereas 12 patients remained unchanged. Five patients died during follow-up due to old age or other, not treatment-related reasons. MR-imaging showed a partial remission in 12 and a stable disease in 15 patients. No tumor progression was observed. The actuarial overall survival rates after five, ten and 20 years were 100%, 95.2% and 79.4%, respectively., Conclusions: Stereotactic LINAC-Radiosurgery can achieve an excellent long-term tumor control beside a low rate of morbidity in the treatment of GJTs. It should be considered as an alternative therapy regime to surgical resection or fractionated external beam radiation either as primary, adjuvant or salvage therapy.

Background and Purpose: Stereotactic radiosurgery with an adapted linear accelerator (linac-SRS) is an established therapy option for brain metastases, benign brain tumors, and arteriovenous malformations. We intended to investigate whether the dosimetric quality of treatment plans achieved with a CyberKnife (CK) is at least equivalent to that for linac-SRS with circular or micromultileaf collimators (microMLC)., Patients and Methods: A random sample of 16 patients with 23 target volumes, previously treated with linac-SRS, was replanned with CK. Planning constraints were identical dose prescription and clinical applicability. In all cases uniform optimization scripts and inverse planning objectives were used. Plans were compared with respect to coverage, minimal dose within target volume, conformity index, and volume of brain tissue irradiated with ≥ 10 Gy., Results: Generating the CK plan was unproblematic with simple optimization scripts in all cases. With the CK plans, coverage, minimal target volume dosage, and conformity index were significantly better, while no significant improvement could be shown regarding the 10 Gy volume. Multiobjective comparison for the irradiated target volumes was superior in the CK plan in 20 out of 23 cases and equivalent in 3 out of 23 cases. Multiobjective comparison for the treated patients was superior in the CK plan in all 16 cases., Conclusion: The results clearly demonstrate the superiority of the irradiation plan for CK compared to classical linac-SRS with circular collimators and microMLC. In particular, the average minimal target volume dose per patient, increased by 1.9 Gy, and at the same time a 14% better conformation index seems to be an improvement with clinical relevance.

Purpose: To perform an individual patient data (IPD) meta-analysis of randomized controlled trials evaluating stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT) for patients presenting with 1 to 4 brain metastases., Method and Materials: Three trials were identified through a literature search, and IPD were obtained. Outcomes of interest were survival, local failure, and distant brain failure. The treatment effect was estimated after adjustments for age, recursive partitioning analysis (RPA) score, number of brain metastases, and treatment arm., Results: A total of 364 of the pooled 389 patients met eligibility criteria, of whom 51% were treated with SRS alone and 49% were treated with SRS plus WBRT. For survival, age was a significant effect modifier (P=.04) favoring SRS alone in patients ≤50 years of age, and no significant differences were observed in older patients. Hazard ratios (HRs) for patients 35, 40, 45, and 50 years of age were 0.46 (95% confidence interval [CI] = 0.24-0.90), 0.52 (95% CI = 0.29-0.92), 0.58 (95% CI = 0.35-0.95), and 0.64 (95% CI = 0.42-0.99), respectively. Patients with a single metastasis had significantly better survival than those who had 2 to 4 metastases. For distant brain failure, age was a significant effect modifier (P=.043), with similar rates in the 2 arms for patients ≤50 of age; otherwise, the risk was reduced with WBRT for patients >50 years of age. Patients with a single metastasis also had a significantly lower risk of distant brain failure than patients who had 2 to 4 metastases. Local control significantly favored additional WBRT in all age groups., Conclusions: For patients ≤50 years of age, SRS alone favored survival, in addition, the initial omission of WBRT did not impact distant brain relapse rates. SRS alone may be the preferred treatment for this age group., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This report from the Working Group on Stereotaktische Radiotherapie of the German Society of Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) provides recommendations for the use of stereotactic radiosurgery (SRS) on patients with brain metastases. It considers existing international guidelines and details them where appropriate., Results and Discussion: The main recommendations are: Patients with solid tumors except germ cell tumors and small-cell lung cancer with a life expectancy of more than 3 months suffering from a single brain metastasis of less than 3 cm in diameter should be considered for SRS. Especially when metastases are not amenable to surgery, are located in the brain stem, and have no mass effect, SRS should be offered to the patient. For multiple (two to four) metastases--all less than 2.5 cm in diameter--in patients with a life expectancy of more than 3 months, SRS should be used rather than whole-brain radiotherapy (WBRT). Adjuvant WBRT after SRS for both single and multiple (two to four) metastases increases local control and reduces the frequency of distant brain metastases, but does not prolong survival when compared with SRS and salvage treatment. As WBRT carries the risk of inducing neurocognitive damage, it seems reasonable to withhold WBRT for as long as possible., Conclusion: A single (marginal) dose of 20 Gy is a reasonable choice that balances the effect on the treated lesion (local control, partial remission) against the risk of late side effects (radionecrosis). Higher doses (22-25 Gy) may be used for smaller (< 1 cm) lesions, while a dose reduction to 18 Gy may be necessary for lesions greater than 2.5-3 cm. As the infiltration zone of the brain metastases is usually small, the GTV-CTV (gross tumor volume-clinical target volume) margin should be in the range of 0-1 mm. The CTV-PTV (planning target volume) margin depends on the treatment technique and should lie in the range of 0-2 mm. Distant brain recurrences fulfilling the aforementioned criteria can be treated with SRS irrespective of previous WBRT.

Purpose: To find out whether the use of stereotactic techniques for fractionated radiotherapy reduces toxicity to the endocrine and visual system in patients with benign perioptic tumors., Patients and Methods: From 1993 to 2009, 29 patients were treated with fractionated stereotactic radiotherapy. The most frequent tumor types were grade I meningioma (n = 11) and pituitary adenoma (n = 10, 7 nonfunctioning, 3 growth hormone-producing). Patients were immobilized with the GTC frame (Radionics, USA) and the planning target volume (PTV; median 24.7, 4.6-58.6 ml) was irradiated with a total dose of 52.2 Gy (range, 45.0-55.8 Gy) in 1.8-Gy fractions using a linear accelerator (6 MeV photons) equipped with a micro-multileaf collimator. Maximum doses to the optic system and pituitary gland were 53.4 Gy (range, 11.5-57.6 Gy) and 53.6 Gy (range, 12.0-57.9 Gy)., Results: Median follow-up was 45 months (range, 10-105 months). Local control was achieved in all but 1 patient (actuarial rate 92% at 5 years and 10 years). In 9 of 29 patients (31%), partial remission was observed (actuarial response rate 40% at 5 years and 10 years). In 4 of 26 patients (15%) with at least partial pituitary function, new hormonal deficits developed (actuarial rate 21% at 5 years and 10 years). This rate was significantly higher in patients treated for a larger PTV (< /> 25 ml: 0% vs. 42% at 5 years and 10 years, p = 0.028). Visual function improved in 4 of 15 patients (27%) who had prior impairment. None of the patients developed treatment-related optic neuropathy, but 2 patients experienced new disease-related visual deficits., Conclusion: Fractionated stereotactic radiotherapy for benign tumors of the perioptic and sellar region results in satisfactory response and local control rates and does not affect the visual system. The assumption that patients can be spared hypophyseal insufficiency only holds for small tumors.

Purpose: This phase III trial compared adjuvant whole-brain radiotherapy (WBRT) with observation after either surgery or radiosurgery of a limited number of brain metastases in patients with stable solid tumors. Here, we report the health-related quality-of-life (HRQOL) results., Patients and Methods: HRQOL was a secondary end point in the trial. HRQOL was assessed at baseline, at 8 weeks, and then every 3 months for 3 years with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and Brain Cancer Module. The following six primary HRQOL scales were considered: global health status; physical, cognitive, role, and emotional functioning; and fatigue. Statistical significance required P ≤ .05, and clinical relevance required a ≥ 10-point difference., Results: Compliance was 88.3% at baseline and dropped to 45.0% at 1 year; thus, only the first year was analyzed. Overall, patients in the observation only arm reported better HRQOL scores than did patients who received WBRT. The differences were statistically significant and clinically relevant mostly during the early follow-up period (for global health status at 9 months, physical functioning at 8 weeks, cognitive functioning at 12 months, and fatigue at 8 weeks). Exploratory analysis of all other HRQOL scales suggested worse scores for the WBRT group, but none was clinically relevant., Conclusion: This study shows that adjuvant WBRT after surgery or radiosurgery of a limited number of brain metastases from solid tumors may negatively impact some aspects of HRQOL, even if these effects are transitory. Consequently, observation with close monitoring with magnetic resonance imaging (as done in the EORTC trial) is not detrimental for HRQOL.

Background and Purpose: Stereotactic linear accelerator-based radiosurgery (LINAC-RS) is increasingly used for microsurgically inaccessible or recurrent pituitary adenomas. This single-center study evaluates the long-term follow-up after LINAC-RS of nonsecreting pituitary adenomas (NSA)., Patients and Methods: Between 1992 and August 2008, 65 patients with NSA were treated. Patient treatment and follow-up were conducted according to a prospective protocol. Indications for LINAC-RS were (1) tumor recurrence or (2) residual tumor. Three patients were treated primarily. For analysis of prognostic factors, patients were grouped according to epidemiological or treatment-associated characteristics., Results: A total of 61 patients with a follow-up ≥ 12 months (median 83 months, range 15-186 months, longest follow-up of published radiosurgery series) were evaluated with regard to their clinical, radiological, and endocrinological course. The median tumor volume was 3.5 ml (± 4.3 ml, range 0.3-17.3 ml) treated with a median surface and maximum dose of 13.0 Gy and 29.7 Gy, respectively. Local tumor control was achieved in 98%. One patient died of unrelated cause after 36 months and 1 patient developed a radiation-induced seizure disorder. Visual complications did not occur. In 37 of 41 patients (90.2%), pituitary function remained stable. Maximum dose to the pituitary ≤ 16 Gy and female gender were positive prognostic factors for the preservation of pituitary function., Conclusion: LINAC-RS is a minimally invasive, safe, and effective treatment for recurrent NSA or microsurgically inaccessible residual tumor. LINAC-RS yielded a high rate of local long-term tumor control with a small number of radiation-induced side effects.

Background: The optimal management of subtotally resected or recurrent malignant meningiomas remains controversial. We evaluated the efficacy of linear accelerator (LINAC) radiosurgery for atypical and anaplastic meningiomas after incomplete resection or treatment of recurrences., Methods: Between August 1990 and December 2003, 16 patients with 28 meningiomas WHO II and III were treated by stereotactic LINAC radiosurgery at our institution. The median radiological follow-up was 60.3 months, respectively (range: 7.2-173.9 months). Fourteen tumors in nine patients were classified as WHO II and 14 tumors in seven patients as WHO III. The median surface dose was 14 Gy (range: 10-15 Gy) with a median tumor volume of 4.8 ml (range: 0.51-51.4 ml)., Results: Clinical condition improved in four patients, remained unchanged in nine and deteriorated in one. Tumor shrinkage was seen in eight of 28 meningiomas and a stable disease in 12. Eight of 28 meningiomas showed local tumor progression. The overall tumor control rate (TCR) was 84%, 70%, 70% after 3, 5, 10 years. According to grading the corresponding TCR after 3, 5, 10 years was 91%, 81%, 81% for grade II and 77%, 60%, 60% for grade III meningiomas. Overall progression-free survival (PFS) was 74%, 67%, 58% after 3, 5, 10 years. According to grading the PFS after 3, 5, 10 years was 88%, 75%, 75% for grade II meningiomas and 57%, 57%, 43% for grade III meningiomas., Conclusion: Our results show the efficacy and safety of LINAC radiosurgery for incompletely resected or recurrent malignant meningiomas with a relatively high local tumor control and low morbidity.

Purpose: To compare stereotactic brachytherapy (SBT) with stereotactic radiosurgery (SRS) for treating singular cerebral metastases, regarding feasibility, complications, cerebral disease control, and survival., Patients and Methods: For this retrospective, single-center study, all patients treated for newly diagnosed, untreated singular cerebral metastasis with SBT using (125)iodine seeds (cumulative tumor surface dose 50 Gy, applied for 42 days) were compared with patients receiving LINAC-based SRS for the same indication. Survival and actuarial local and distant disease control were evaluated using univariate Kaplan-Meier estimates and Cox regression. Results were compared using Student's t test and the χ2 test., Results: A total of 142 patients treated with SRS were compared with 77 patients undergoing SBT. No significant differences were observed between epidemiological and disease-related features (p > 0.05), except a lower KPS (p < 0.007) and a larger tumor volume (p < 0.001) in the SBT group. Neither median survival (LINAC-SRS vs. SBT = 8.1 vs. 8.0 months, respectively) nor actuarial local/distant cerebral disease control after 12 months showed significant differences (93.6% vs. 96.7% / 42.4% vs. 46.4%). There was no treatment-related mortality and no permanent grade 3 or 4 CNS toxicity (RTOG/EORTC CNS toxicity criteria)., Conclusion: For the treatment of singular cerebral metastasis, SBT represents a safe, minimally invasive, and effective local treatment option with results comparable to SRS regarding survival and cerebral disease control. Its advantage is that it allows histological (re-)evaluation and treatment within one stereotactic procedure and, compared to microneurosurgery, is almost unrestricted regarding tumor localization. Furthermore, larger metastases can be treated than with SRS. SBT, therefore, represents an alternative local treatment in selected cases.

Purpose: To evaluate the efficacy of interstitial radiosurgery (IRS) for pineal parenchymal tumors (PPTs)., Patients and Methods: 18 consecutively admitted patients (twelve male and six female, age range 6-68 years, median age 34 years) with PPTs (eight pineocytomas, ten malignant PPTs) were treated at the authors' institution with IRS using stereotactically guided iodine-125 seed implantation ((125)I-IRS) as either primary or salvage therapy. The cumulative tumor surface dose ranged from 40 to 64 Gy. Adjuvant radiotherapy of the whole brain or the craniospine was done in patients with grade III and grade IV PPT. The median follow-up period was 57.4 months (range 6-134 months)., Results: Overall actuarial 5- and 8-year survival rates after IRS were 100% and 86% for pineocytomas, and the overall actuarial 5-year survival rate was 78% for high-grade PPTs. Follow-up magnetic resonance imaging showed complete remission in 72% (13/18) and partial remission in 28% (5/18) of the cases. One patient developed an out-of-field relapse 4 years after partial remission of a pineocytoma, which had already been treated with IRS. There was no treatment-related mortality. Treatment-related morbidity occurred in two patients only., Conclusion: This study indicates that stereotactic (125)I-IRS for the management of PPTs is quite efficient and safe. Due to the low rate of side effects, IRS may develop into an attractive alternative to microsurgery in de novo diagnosed pineocytomas. In malignant PPTs, IRS may be routinely applied in a multimodality treatment schedule supplementary to conventional irradiation.

Objective: Determination of the impact of inaccuracies in the determination and setup of the target point in stereotactic radiosurgery (SRS) on the expectable complication and control probabilities., Methods: Two randomized samples of patients with arteriovenous malformation (AVM) (n=20) and with brain metastases (n=20) treated with SRS were formed, and the probability for complete obliteration (COP) or complete remission (CRP), the size of the 10 Gy-volume in the brain tissue (VOI10), and the probability for radiation necrosis (NTCP) were calculated. The dose-effect relations for COP and CRP were fitted to clinical data. Target point deviations were simulated through random vectors and the resulting probabilities and volumes were calculated and compared with the values of the treatment plan., Results: The decrease of the relative value of the control probabilities at 1mm target point deviation was up to 4% for AVMs and up to 10% for metastases. At 2 mm the median decrease was 5% for AVMs and 9% for metastases. The value for the target point deviation, at which COP and CRP decreased about 0.05 in 90% of the cases, was 1.3 mm. The increase of NTCP was maximally 0.0025 per mm target point deviation for AVMs and 0.0035/mm for metastases. The maximal increase of VOI10 was 0.7 cm(3)/mm target point deviation in both patient groups., Conclusions: The upper limit for tolerable target point deviations is at 1.3mm. If this value cannot be achieved during the system test, a supplementary safety margin should be applied for the definition of the target volume. A better accuracy level is desirable, in order to ensure optimal chances for the success of the treatment. The target point precision is less important for the minimization of the probability of radiation necroses.

Background: A prospective study was conducted to assess the efficacy and side effects of linear accelerator (LINAC)-based radiosurgery (RS) performed with a reduced dose of therapeutic radiation for patients with surgically inaccessible pituitary macroadenomas., Methods: From August 1990 through January 2004, 175 patients with pituitary macroadenomas were treated with LINAC-RS according to a prospective protocol. To minimize the risk for radiation-induced damage of the pituitary function, the therapeutic dose to be applied was limited to 20 grays., Results: Among 175 patients, 142 patients who had a minimum follow-up of 12 months (mean +/- standard deviation, 81.9 +/- 37.2 months) were included in the current study. The local tumor control rate was 96.5%, and the tumor response rate was 32.4%. The mean time (+/- standard deviation) from LINAC-RS to normalization of pathologic hormone secretion was 36.2 +/- 24.0 months. The probability for normalization was 34.3% at 3 years and 51.1% at 5 years. The frequency of endocrine cure (defined as the normalization of hormone secretion without specific medication intake) was 35.2% (mean +/- standard deviation time to cure, 42.1 +/- 25.0 months). Patients with Cushing disease had a statistically significant greater chance of achieving a cure (P = .001). Side effects of LINAC-RS were deterioration of anterior pituitary function (12.3%), radiation-induced tissue damage (2.8%), and radiation-induced neuropathy (1.4%)., Conclusions: LINAC-RS using a lower therapeutic radiation dose achieved local tumor control and normalization or cure of hormone secretion comparable to the results achieved with gamma-knife RS. Compared with the latter, the time to normalization or endocrine cure was delayed, most probably as a result of dose reduction. However, the lower therapeutic radiation dose did not prevent radiation-induced damage of pituitary function completely., ((c) 2006 American Cancer Society.)

Background and Purpose: Stereotactic radiosurgery of intracranial tumors and vascular malformations can be performed by either a linear accelerator (Linac) or gamma knife. The aim of this first study on patients was to determine the radiation exposure of organs at risk and assess the risk for late effects including secondary tumors and/or hereditary disorders after stereotactic Linac radiosurgery., Material and Methods: Thermoluminescent dosimetry (TLD) measurements were done on 21 consecutively admitted patients with various intracranial lesions scheduled for Linac radiosurgery. The TLD chips were placed on the eyelid, thyroid, breast and the regions of the ovary or testes., Results: The mean doses in organs at risk were 276 +/- 200 mGy (eye lens), 155 +/- 83 mGy (thyroid), 47 +/- 22 mGy (breast), 20 +/- 12 mGy (ovary), and 9 +/- 3 mGy (testes). The doses decreased significantly with a larger distance from the isocenter., Conclusion: The absorbed doses to the extracranial organs at risk in patients undergoing Linac radiosurgery were very low, ranging from 0.025% (testes) to 0.76% (eye lens) of the mean maximum target dose (36 Gy). Nevertheless, while the majority of radiosurgery patients have benign tumors or arteriovenous malformations and their life expectancy is long, all doses should be kept as low as reasonably achievable. This could be accomplished by the use of modern irradiation techniques including conformal beams with micro-multileaf collimator and avoiding beams directed to the trunk.

The authors evaluated the efficacy of radiosurgery (RS) for cerebral arteriovenous malformations in hereditary hemorrhagic telangiectasia (HHT AVMs). Two patients with seven HHT AVMs were treated by linear accelerator-RS. Complete obliteration was achieved 18 to 24 months post-treatment without side effects. Because HHT AVMs are small and multiple, RS is superior to microsurgery because it is noninvasive and all AVMs can be treated in one session regardless of their location.

Background and Purpose: For patients with inoperable brain metastases, whole brain radiotherapy (WBRT) has been the standard treatment for decades. Radiosurgery is an effective alternative strategy, but has failed to show a substantial survival benefit so far. The prognostic factors derived from the RTOG recursive partitioning analysis (RPA) provide a framework that allows a nonrandomized comparison of the two modalities., Patients and Methods: From 1991 to 1998, 117 patients with one to three previously untreated cerebral metastases underwent single-dose linac radiosurgery (median dose 20 Gy) without adjuvant WBRT. After radiosurgery, 26/117 patients (22%) had salvage WBRT, radiosurgery or neurosurgical resection of recurrent (4/117) and/or new (24/117) metastases. Survival of these patients was compared to a historical group of 138 patients with one to three lesions treated by WBRT (30-36 Gy/3-Gy fractions) from 1978 to 1991; only nine of these patients (7%) had salvage WBRT. All patients were classified into the three RPA prognostic classes based on age, performance score, and presence of extracranial tumor manifestations., Results: In RPA class I (Karnofsky performance score > or = 70, primary tumor controlled, no other metastases, age < 65 years), radiosurgery resulted in a median survival of 25.4 months (n = 23, confidence interval [CI] 5.8-45.0) which was significantly longer than for WBRT (n = 9, 4.7 months, CI 3.8-5.5; p < 0.0001). In RPA class III (Karnofsky performance score < 70), no significant difference in survival between radiosurgery (n = 20, 4.2 months, CI 3.2-5.3) and WBRT (n = 68, 2.5 months, CI 2.2-2.8) was found. In RPA class II (all other patients), radiosurgery produced a small, but significant survival advantage (radiosurgery: n = 74, 5.9 months, CI 3.2-8.5, WBRT: n = 61, 4.1 months, CI 3.4-4.9; p < 0.04)., Conclusion: Radiosurgery in patients with one to three cerebral metastases results in a substantial survival benefit only in younger patients with a low systemic tumor burden when compared to WBRT alone. It cannot be excluded that this effect is partially caused by the available salvage options after radiosurgery.

Background and Purpose: Results from single-dose radiosurgery have failed to yield reasonable alpha/beta ratios for obliteration rates of arteriovenous malformations (AVMs) in the framework of the linear-quadratic approach. We used outcome data from single-dose and fractionated radiotherapy for AVM to approach this problem., Patients and Methods: AVM obliteration rates observed in an updated historical series of fractionated radiotherapy and from six recent series of single-dose stereotactic radiosurgery were analyzed. Reciprocal total doses (1/D) and fraction sizes (d) of isoeffective fractionation schemes were entered into the rearranged form of the linear-quadratic equation: 1/D = (alpha/E) + (beta/E)d, and alpha/beta-ratios were calculated from the parameters of the regression line., Results: Fractionated radiotherapy with 20 Gy/4 Gy fractions, 50 Gy/2 Gy fractions and single-dose radiosurgery of approximately 13 Gy were isoeffective with crude obliteration rates of 13%. The analysis yielded an alpha/beta-ratio of 3.5 Gy. For small-sized AVMs (<3 cm), alpha/beta-ratios of 4.6-6.4 Gy were obtained., Conclusion: These results support the view that radiosurgery for AVM can be understood as a typical late tissue effect with a high fractionation sensitivity. Fractionated radiotherapy is ineffective for AVMs and should be evaluated carefully in other benign targets.

A micro-multileaf collimator (microMLC) for stereotactic radiosurgery is used for determination of the spatial intensity distribution of the photon source of a linear accelerator. The method is based on grid field dose measurements using film dosimetry and is easy to perform. Since the microMLC does not allow 'direct' imaging of the photon source, special software has been developed to analyse grid field measurements. Besides the source-density function, grid field analysis yields the position of the focal spot in the room laser coordinate system of the linear accelerator and the position of the treatment head rotation axis and the inclination angle of the leaf bank. Thus the method can be used for base dosimetry and for quality assurance in radiosurgery using a microMLC.

Background: The optimal treatment for patients with glomus jugulare tumor (GJT) of the skull base remains controversial. Surgical excision is associated with a high incidence of cranial nerve injury, decreased quality of life, and high mortality. Fractionated radiotherapy is used to control the majority of these tumors, but disadvantages are a prolonged therapy interval and exposition of adjacent brain tissue to irradiation. The authors present the results of a study on 12 of 14 consecutively admitted patients who were treated using linear accelerator-based radiosurgery (LINAC-RS), an innovative method for the treatment of GJT., Methods: From May 1991 to March 2001, 14 patients with GJT were treated with stereotactic LINAC-RS for continued growth of tumor or of remaining tumor after surgery. Twelve patients (9 women and 3 men; age range, 28-71 years; median age, 59 years) with a median follow-up of 4 years (range, 0.8-9,0 years), were selected for retrospective analysis. A median single dose of 15 grays (Gy; range, 11-20 Gy) was applied to the surface of the tumor., Results: After undergoing LINAC-RS, 8 of 12 patients (67%) reported partial or complete subjective improvement, whereas complaints remained unchanged in 4 patients (33%). Neurologic status improved in 3 patients (25%) and remained unchanged in 8 patients (67%). Magnetic resonance images showed tumor shrinkage in 8 patients (67%) and no further progression in 4 patients (33%)., Conclusions: LINAC-RS is an effective and safe therapy for patients with GJT and may be used as an alternative to surgical resection. Compared with fractionated radiotherapy, LINAC-RS has some advantages. However, to clarify the question of long-term tumor control, longer observation times are required., (Copyright 2003 American Cancer Society)

Background: Pituitary tumors are relatively uncommon, comprising 10-12% of all intracranial tumors. The treatment consisting of surgery, radiotherapy and drug therapy or a combination of these modalities is aimed at the control of tumor cell proliferation and--in endocrine active tumors--the reduction of hormone secretion. However, the slow proliferation characteristics of pituitary tumors necessitate long-term studies for the evaluation of the treatment results. In the last decade there has been continuous improvement in surgical procedures, radiotherapy techniques and drug generation. In this paper, literature will be reviewed to assess the role of modern radiotherapy and radiosurgery in the management of pituitary adenomas., Material and Methods: Nowadays, magnetic resonance imaging for the definition of the target volume and a real three-dimensional (3-D) treatment planning with field conformation and the possibility for non-coplanar irradiation has to be recommended. Most groups irradiate these benign tumors with single doses of 1.8-2.0 Gy up to a total dose of 45 Gy or 50.4 Gy in extensive parasellar adenomas. Adenomas are mostly small, well circumscribed lesions, and have, therefore, attracted the use of stereotactically guided high-precision irradiation techniques which allow extreme focussing and provide steep dose gradients with selective treatment of the target and optimal protection of the surrounding brain tissue., Results: Radiation therapy controls tumor growth in 80-98% of patients with non-secreting adenomas and 67-89% for endocrine active tumors. Reviewing the recent literature including endocrine active and non-secreting adenomas, irradiated postoperatively or in case of recurrence the 5-, 10- and 15-year local control rates amount 92%, 89% and 79%. In cases of microprolactinoma primary therapy consists of dopamine agonists. Irradiation should be preferred in patients with macroprolactinomas, when drug therapy and/or surgery failed or for patients medically unsuitable for surgery. Reduction and control of prolactin secretion can be achieved in 44-70% of patients. After radiotherapy in acromegaly patients somatomedin-C and growth hormone concentrations decrease to normal levels in 70-90%, with a decrease rate of 10-30% per year. Hypercortisolism is controlled in 50-83% of adults and 80% of children with Cushing's disease, generally in less than 9 months. Hypopituitarism is the most common side effect of pituitary irradiation with an incidence of 13-56%. Long-term overall risk for brain necrosis in a total of 1,388 analyzed patients was estimated to be 0.2%. Other side effects are rare too, and do also depend on the damage produced by tumor itself or preceding surgery. They include deterioration of vision in 1.7% of all cases, vascular changes in 6.3%, neuropsychological disorders such as dementia in 0.7% and secondary malignancies in 0.8%, if single doses of 2.0 Gy and total doses of 50 Gy are not exceeded., Conclusion: Conventional radiation therapy of pituitary adenoma is highly effective. It is recommended after subtotal resection of primary tumors such as macroadenomas, after gross total resection from endocrine active adenomas with postsurgical hormone secretion and for recurrent tumors. Radiosurgery seems to be a possible treatment alternative in experienced centers, and only in patients with adenomas smaller than 25-30 mm with a minimum distance of 2-3 mm to the chiasm.

We have developed a densitometric method for measuring the isocentric accuracy and the accuracy of marking the isocentre position for linear accelerator based radiosurgery with circular collimators and room lasers. Isocentric shots are used to determine the accuracy of marking the isocentre position with room lasers and star shots are used to determine the wobble of the gantry and table rotation movement, the effect of gantry sag, the stereotactic collimator alignment, and the minimal distance between gantry and table rotation axes. Since the method is based on densitometric measurements, beam spot stability is implicitly tested. The method developed is also suitable for quality assurance and has proved to be useful in optimizing isocentric accuracy. The method is simple to perform and only requires a film box and film scanner for instrumentation. Thus, the method has the potential to become widely available and may therefore be useful in standardizing the description of linear accelerator based radiosurgical systems.

Purpose: Solid and necrotic brain tumors respond to radiosurgery, although necrotic lesions often contain a significant proportion of hypoxic cells which cannot become reoxygenated during the short overall treatment time of single dose application. In addition to the direct cytotoxic action, delayed vascular occlusion followed by ischemic tumor cell death could contribute to the effect of radiosurgery., Materials and Methods: In order to determine the impact of the two possible effects on tumor response, a 3-dimensional computer simulation was developed and fitted to response data obtained from 90 patients who were treated by LINAC radiosurgery for 1-3 brain metastases with median marginal doses of 20 Gy. Complete response rates were as follows: small, solid lesions (diameter 0.4-1 cm), 52% (12/23); large solid lesions (1.1-5.2 cm), 28% (17/60); large necrotic lesions, 12% (6/50). The 3-dimensional computer model simulated the growth of small solid and large, solid or necrotic tumors situated in a vascularized stroma. Oxygen supply, tumor cell division (cell cycle time 5 days), neovascularization, tumor cell kill by single dose irradiation (linear-quadratic model, alpha/beta=10 Gy, oxygen enhancement ratio 3.0) and time-dependent vascular occlusion (alpha/beta=3 Gy) were modeled by Monte-Carlo simulation techniques., Results: In the presence of neovascularization, solid tumors with a hypoxic fraction of 1-2% developed. Without neoangiogenesis, central necrosis occurred, and tumors had a hypoxic fraction of 20-25%. Assuming a pure cytotoxic effect of radiosurgery, neither the dose-response relationship for the solid lesions of different size nor that for the large lesions with solid or necrotic appearance could be reproduced for any given level of radiosensitivity. This was only possible by introducing a vascular effect that led to the occlusion of >/=99% of the vessels at the border of the target volume within 1 year after irradiation. In the presence of the vascular effect, the apparent radiosensitivity of the tumor cells was increased by 50-100%. Calculations of the dose-equivalent for the vascular effect show that it contributes 19-33% of the overall effect of single dose radiosurgery., Conclusion: This simulation study suggests that the therapeutic effect of single radiosurgery in malignant brain tumors cannot be understood without the consideration of vascular effects. The computer model might serve as a basis for exploring new treatment modalities that modify both cytotoxic and vascular effects of radiosurgery.

The efficacy of linear accelerator-based radiosurgery for patients who have preirradiated recurrent nasopharyngeal carcinomas and unresectable recurrent sarcomas invading the base of skull was assessed. Thirteen patients were treated: 8 patients had carcinomas arising from the nasopharynx (lymphoepithelioma, 4; squamous cell carcinoma, 2; adenoid-cystic, 2); 5 patients had sarcomas (rhabdomyosarcoma, 1; chordoma, 1; chondrosarcoma, 1; hemangiopericytoma, 2). All patients had had repeated tumor resections or irradiation, hindering any further conventional fractionated radiotherapy or surgery. Convergent-beam irradiation was performed with a modified linear accelerator (8-MeV photons). Because of irregular tumor configuration, multiple (up to seven) isocenters had to be used in 10 of 13 patients to match the target volume with the reference isodose (60%-80%). Each isocenter was irradiated with 6 to 10 arcs. The median planning target volume was 33 mL (4-128 mL) and the median dose was 15 Gy (9-24 Gy). Median survival time was 9 months in 8 patients who had recurrent nasopharyngeal carcinomas. Three patients who had complete or partial tumor remission survived 1.5 to 3.5 years. All of the sarcoma patients responded to radiosurgery. After a follow-up of 28 to 67 months, 4 of 5 patients are alive. This investigation demonstrates that radiosurgery is an effective tool in palliative treatment for patients who have recurrent, extensively pretreated nasopharyngeal cancer. Patients who have recurrent sarcomas of the base of skull may be treated for long-term palliation or even for cure.

The purposes of this analysis were the evaluation of the toxicity of stereotactic single dose irradiation in patients with an arteriovenous malformation (AVM) and the comparison of the authors' own results with already existing risk prediction models. Computed-tomography (CT) or magnetic-resonance (MR) images, and clinical data of patients treated with linear accelerator radiosurgery for an AVM were analysed retrospectively. Using the Cox proportional hazards model (1), the relevance of treatment parameters and dose-volume relationships to the occurrence of radiation-induced tissue changes (oedema and localised blood-brain-barrier breakdown) were assessed. The 81 patients selected for analysis had a mean follow-up of 28.9 months (range: 9.0-65.7 months). Radiation-induced tissue changes (22 out of 81 i.e. 27.2%) were documented on CT or MR images 6.3-33.8 months after radiosurgery (median time: 12.8 months). The actuarial risk at 2 years was 32.1% for the development of neuroradiological changes and 20.1% for the development of symptomatic tissue alteration. The coefficient of total volume receiving a minimum dose of 10 Gy (VTREAT10) reached statistical significance in a Cox proportional hazards model. These results demonstrate the particular vulnerability of normal brain tissue to single dose irradiation. Optimal conformation of the therapeutic isodose line to the 3D configuration of the target volume may help to reduce side effects.

Purpose: To evaluate the toxicity of stereotactic single-dose irradiation and to compare the own results with already existing risk prediction models., Methods and Materials: Computed tomography (CT) or magnetic-resonance (MR) images, and clinical data of 133 consecutive patients treated with linear accelerator radiosurgery were analyzed retrospectively. Using the Cox proportional hazards model the relevance of treatment parameters and dose-volume relationships on the occurrence of radiation-induced tissue changes (edema, localized blood-brain barrier breakdown) were assessed., Results: Sixty-two intraparenchymal lesions (arteriovenous malformation (AVM): 56 patients, meningioma: 6 patients) and 73 skull base tumors were selected for analysis. The median follow-up was 28.1 months (range: 9.0-58.9 months). Radiation-induced tissue changes (32 out of 135, 23.7%) were documented on CT or MR images 3.6-58.7 months after radiosurgery (median time: 17.8 months). The actuarial risk at 2 years for the development of neuroradiological changes was 25.8% for all evaluated patients, 38.4% for intraparenchymal lesions, and 14.6% for skull base tumors. The coefficient: total volume recieving a minimum dose of 10 Gy (VTREAT10) reached statistical significance in a Cox proportional hazards model calculated for all patients, intraparenchymal lesions, and AVMs. In skull base tumors, the volume of normal brain tissue covered by the 10 Gy isodose line (VBRAIN10) was the only significant variable., Conclusions: These results demonstrate the particular vulnerability of normal brain tissue to single dose irradiation. Optimal conformation of the therapeutic isodose line to the 3D configuration of the target volume may help to reduce side effects.

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