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Background: Chemo-radioimmunotherapy with total radiation doses of 60-66 Gy in 2 Gy fractions is the standard of care for non-small cell lung cancer (NSCLC) UICC stage III. The Austrian radio-oncological lung cancer study association registry (ALLSTAR) is a prospective multicentre registry intended to document clinical practice at the beginning of the Durvalumab era., Patients and Methods: Patients were eligible if they had pathologically verified unresectable NSCLC stage III with a curative treatment option. Chemo-radiation combined with immunotherapy was performed according to local treatment practices. The endpoints were local control (LC), progression-free survival (PFS) and toxicity., Results: Between 2020/03 and 2023/04, 12/14 (86 %) Austrian radiation-oncology centres recruited 188 patients (median 17, range: 1-89). PD-L1 testing was performed in 173/188 (93 %) patients. The median interval between the end of chemoradiotherapy and start of Durvalumab was 14 days (range: 1-65). About 40 % (75/188) of the patients received a total radiation dose of > 66 Gy (range: 67.1-100), which improved 2-year LC (86 % versus 60 %, HR = 0.41; 95 %-CI: 0.17-0.98; log-rank p-value < 0.05). Median PFS for patients with Durvalumab was 25.8 months (95 %-CI: 21.9-not reached) compared to 15.7 months (95 %-CI: 13.2-27.8) for those without (HR = 1.88; 95 %-CI: 1.16-3.05; log-rank p-value < 0.01). The rates of esophageal and pulmonary toxicities were 34.6 % and 23.9 %, respectively, including one case of grade 4 pneumonitis. In the subcohort of 75 patients who received > 66 Gy, 19 (25 %) cases of pulmonary toxicity grades 1-3 were observed., Conclusion: While Durvalumab impacts PFS, LC can be improved by total radiation doses > 66 Gy without excess toxicity., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Treatment of patients with atypical teratoid/rhabdoid (AT/RT) is challenging, especially when very young (below the age of three years). Radiotherapy (RT) is part of a complex trimodality therapy. The purpose of this guideline is to provide appropriate recommendations for RT in the clinical management of patients not enrolled in clinical trials., Materials and Methods: Nine European experts were nominated to form a European Society for Radiotherapy and Oncology (ESTRO) guideline committee. A systematic literature search was conducted in PubMed/MEDLINE and Web of Science. They discussed and analyzed the evidence concerning the role of RT in the clinical management of AT/RT., Results: Recommendations on diagnostic imaging, therapeutic principles, RT considerations regarding timing, dose, techniques, target volume definitions, dose constraints of radiation-sensitive organs at risk, concomitant chemotherapy, and follow-up were considered. Treating children with AT/RT within the framework of prospective trials or prospective registries is of utmost importance., Conclusion: The present guideline summarizes the evidence and clinical-based recommendations for RT in patients with AT/RT. Prospective clinical trials and international, large registries evaluating modern treatment approaches will contribute to a better understanding of the best treatment for these children in future., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Irradiation of the vertebrae in prepubertal patients, if non-homogenous, can result in future growth deformities including kyphoscoliosis. Vertebral delineation and dosimetry were assessed for 101 paediatric cases reviewed within QUARTET-affiliated trials. Despite the availability of published consensus guidelines, a high variability in vertebral delineation was observed, with impact on dosimetry., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: SIOP Europe's QUARTET project launched in 2016; aiming to improve access to high-quality radiotherapy for children and adolescents treated within clinical trials across Europe. The aim of this report is to present the profile of institutions participating in six QUARTET-affiliated trials and a description of the initial individual case review (ICR) outcomes., Methods: This is a two-part analysis. Firstly, using facility questionnaires, beam output audit certificates, and advanced technique credentialing records to create a profile of approved institutions, and secondly, collating trial records for ICRs submitted prior to 31/10/2022. Trials included are: SIOPEN HR-NBL1, SIOPEN-LINES, SIOPEN- VERITAS, SIOP-BTG HRMB, EpSSG-FaR-RMS, and SIOPEN HR-NBL2., Results: By 31/10/2022, a total of 103 institutions had commenced QUARTET site approval procedures to participate in QUARTET-affiliated trials; 66 sites across 20 countries were approved. These participating institutions were often paediatric referral sites with intensity modulated radiotherapy or proton beam therapy, designated paediatric radiation oncologists, and paediatric adapted facilities and imaging protocols available. In total, 263 patient plans were submitted for ICR, 254 ICRs from 15 countries were completed. ICRs had a rejection rate of 39.8%, taking an average of 1.4 submissions until approval was achieved. Target delineation was the most frequent reason for rejection., Conclusion: The QUARTET facility questionnaire is a valuable tool for mapping resources, personnel, and technology available to children and adolescents receiving radiotherapy. Prospective ICR is essential for paediatric oncology clinical trials and should be prioritised to reduce protocol violations., 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 B.V. All rights reserved.)

Background and Purpose: To establish an international quality standard for contouring and planning for high-risk neuroblastoma within the prospective High-Risk Neuroblastoma Study 2 of SIOP-Europe-Neuroblastoma (SIOPEN HR-NBL2), which includes a randomized question on dose escalation for residual disease., Materials and Methods: Data on four patients with high-risk neuroblastoma were selected and distributed to the radiotherapy committee of the HR-NBL2 study for independent contouring and planning. Differences in contouring were analyzed using apparent and kappa-corrected agreement. Plans were analyzed regarding the dose-volume histogram metrics. Results were discussed among experts and agreement was obtained., Results: Substantial agreement was found for contouring of the heart (0.64), liver (0.70), left lung (0.74), and right lung (0.74). For contouring of the gastrointestinal tract (0.54), left kidney (0.60), and right kidney (0.59) moderate agreement was obtained. For target volume delineation, agreement for preoperative tumour extent was moderate (0.42), for CTV fair (0.35) and only low (0.06) for residual tumour, respectively. The dose planning strategies appeared to be relatively homogeneous among all experts., Conclusion: Considerable variability was found for the delineation of target volumes, particularly the boost volume, whereas the contouring of the organs at risk and the planning strategy were reasonably consistent. In order to obtain reliable results from the randomized HR-NBL2 trial, standardization of target volume delineation based on adequate imaging is crucial., 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. Published by Elsevier B.V.)

Introduction: The success of intensification and personalisation of the curative treatment of non-small cell lung cancer (NSCLC) is strongly associated with the precision in radiotherapy. Here, we evaluate the impact of radiotherapy protocol adherence in a prospective multicentre trial., Methods: In the open-label, randomised, controlled PET-Plan trial, patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume delineation informed by 1 F-FDG PET and CT plus elective nodal irradiation (arm A) or target volumes informed by PET alone (arm B) and received iso-toxically dose-escalated concurrent chemoradiation. The prospectively organised quality assurance program (RTQA) included individual case review by predefined criteria. For evaluation, protocol adherence was scored as per protocol (pP), with minor (miD), intermediate (inD) and major (maD) deviations. In order to exclude biases through patients who discontinued treatment, patients who received ≥60 Gy were additionally analysed., Results: Between 05/2009-11/2016, 205 patients were randomized, 204 patients started treatment according to protocol of which 31 (15%) patients had maD. Patients with maD had an inferior overall survival (OS) (HR 2.9, 95% CI 1.8-4.4, p < 0.0001) and a higher risk of loco-regional progression (HR 5.7, 95% CI 2.7-11.1, p < 0.0001). These results were significant also in the subgroup of patients receiving ≥ 60 Gy. Patients with maD concerning normal tissue delineation and/or dose constraints had a worse OS (p = 0.006) although no higher incidence of grade ≥ 3 toxicities., Conclusions: Non-adherence to the radiotherapy protocol was associated with an inferior OS and loco-regional control. These results underline the importance of RTQA., (Copyright © 2021. Published by Elsevier B.V.)

Background: Whole brain radiotherapy (WBRT) is a common treatment option for brain metastases secondary to non-small cell lung cancer (NSCLC). Data from the QUARTZ trial suggest that WBRT can be omitted in selected patients and treated with optimal supportive care alone. Nevertheless, WBRT is still widely used to treat brain metastases secondary to NSCLC. We analysed decision criteria influencing the selection for WBRT among European radiation oncology experts., Methods: Twenty-two European radiation oncology experts in lung cancer as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) for previous projects and by the Advisory Committee on Radiation Oncology Practice (ACROP) for lung cancer were asked to describe their strategies in the management of brain metastases of NSCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies., Results: Eight decision criteria (suitability for SRS, performance status, symptoms, eligibility for targeted therapy, extra-cranial tumour control, age, prognostic scores and "Zugzwang" (the compulsion to treat)) were identified. WBRT was recommended by a majority of the European experts for symptomatic patients not suitable for radiosurgery or fractionated stereotactic radiotherapy. There was also a tendency to use WBRT in the ALK/EGFR/ROS1 negative NSCLC setting., Conclusion: Despite the results of the QUARTZ trial WBRT is still widely used among European radiation oncology experts., 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 © 2020 Elsevier B.V. All rights reserved.)

Objective: To derive evidence-based recommendations for the optimal utilisation of resources during unexpected shortage of radiotherapy capacity., Methods and Materials: We have undertaken a rapid review of published literature on the role of radiotherapy in the multimodality treatment of paediatric cancers governing the European practise of paediatric radiotherapy. The derived data has been discussed with expert paediatric radiation oncologists to derive a hierarchy of recommendations., Results: The general recommendations to mitigate the potential detriment of an unexpected shortage of radiotherapy facilities include: (1) maintain current standards of care as long as possible (2) refer to another specialist paediatric radiotherapy department with similar level of expertise (3) prioritise use of existing radiotherapy resources to treat patients with tumours where radiotherapy has the most effect on clinical outcome (4) use chemotherapy to defer the start of radiotherapy where timing of radiotherapy is not expected to be detrimental (5) active surveillance for low-grade tumours if appropriate and (6) consider iso-effective hypofractionated radiotherapy regimens only for selected patients with predicted poor prognosis. The effectiveness of radiotherapy and recommendations for prioritisation of its use for common and challenging paediatric tumours are discussed., Conclusion: This review provides evidence-based treatment recommendations during unexpected shortage of paediatric radiotherapy facilities. It has wider applications for the optimal utilisation of facilities, to improve clinical outcome in low- and middle-income countries, where limited resources continue to be a challenge., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Purpose: In 2017 the ACROP guideline on SBRT for peripherally located early stage NSCLC was published. Later that year ICRU-91 about prescribing, recording and reporting was published. The purpose of this study is to quantify the current variation in prescription practice in the institutions that contributed to the ACROP guideline and to establish the link between the ACROP and ICRU-91 recommendations., Material and Methods: From each of the eight participating centres, 15 SBRT plans for stage I NSCLC were analyzed. Plans were generated following the institutional protocol, centres prescribed 3 × 13.5 Gy, 3 × 15 Gy, 3 × 17 Gy or 3 × 18 Gy. Dose parameters of the target volumes were reported as recommended by ICRU-91 and also converted to BED 10Gy ., Results: The intra-institutional variance in D98%, Dmean and D2% of the PTV and GTV/ITV is substantially smaller than the inter-institutional spread, indicating well protocollised planning procedures are followed. The median values per centre ranged from 56.1 Gy to 73.1 Gy (D2%), 50.4 Gy to 63.3 Gy (Dmean) and 40.5 Gy to 53.6 Gy (D98%) for the PTV and from 57.1 Gy to 73.6 Gy (D2%), 53.7 Gy to 68.7 Gy (Dmean) and 48.5 Gy to 62.3 Gy (D98%) for the GTV/ITV. Comparing the variance in PTV D98% with the variance in GTV Dmean per centre, using an F-test, shows that four centres have a larger variance in GTV Dmean, while one centre has a larger variance in PTV D98% (p values <0.01). This shows some centres focus on achieving a constant PTV coverage while others aim at a constant GTV coverage., Conclusion: More detailed recommendations for dose planning and reporting of lung SBRT in line with ICRU-91 were formulated, including a minimum PTV D98% of 100 Gy BED 10Gy and minimum GTV/ITV mean dose of 150 Gy BED 10Gy and a D2% in the range of 60-70 Gy., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: High-dose hypofractionated radiotherapy should theoretically result in a deviation from the typical linear-quadratic shape of the cell survival curve beyond a certain threshold dose, yet no evidence for this hypothesis has so far been found in clinical data of stereotactic body radiotherapy treatment (SBRT) for early-stage non-small cell lung cancer (NSCLC). A pragmatic explanation is a larger α/β ratio than the conventionally assumed 10 Gy. We here attempted an estimation of the α/β ratio for NSCLC treated with SBRT using individual patient data., Materials and Methods: We combined two large retrospective datasets, yielding 1294 SBRTs (≤10 fractions) of early stage NSCLC. Cox proportional hazards regression, a logistic tumor control probability model and a biologically motivated Bayesian cure rate model were used to estimate the α/β ratio based on the observed number of local recurrences and accounting for tumor size., Results: A total of 109 local progressions were observed after a median of 17.7 months (range 0.6-76.3 months). Cox regression, logistic regression of 3 year tumor control probability and the cure rate model yielded best-fit estimates of α/β = 12.8 Gy, 14.9 Gy and 12-16 Gy (depending on the prior for α/β), respectively, although with large uncertainties that did not rule out the conventional α/β = 10 Gy., Conclusions: Clinicians can continue to use the simple LQ formalism to compare different SBRT treatment schedules for NSCLC. While α/β = 10 Gy is not ruled out by our data, larger values in the range 12-16 Gy are more probable, consistent with recent meta-regression analyses., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: So far, the development and course of therapy-induced deficiencies in hypothalamic-pituitary hormones in adult patients with malignant gliomas has not received much attention. However, such deficiencies may impact patient's quality of life substantially., Methods: In this monocentric longitudinal trial, we examined hormonal levels of TSH, T3, T4, fT3, fT4, FSH, LH, testosterone, estradiol and prolactin in patients with malignant high grade gliomas before the start of radiochemotherapy (RCT), at the end of RCT and then every three months for newly diagnosed patients and every six months in patients diagnosed more than two years before study inclusion. Growth hormone was not measured in this trial., Results: 436 patients (198 female, 238 male) with high-grade gliomas, aged 19-83 years (median 50 years), were included in this study. Low levels of thyroid hormones were observed in around 10% of patients within the first six months of follow up and increasingly after 36 months. Half of premenopausal women at study entry developed premature menopause, 35% showed hyperprolactinemia. Low testosterone levels were measured in 37% of men aged less than 50 years and in 35/63 (55%) of men aged 50 years or older., Discussion: The results of this study show that a significant percentage of patients with malignant gliomas develop hormonal deficiencies mandating regular clinical follow up, state of the art counseling and if clinically necessary substitution therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Purpose: During extended follow-up (of up to 15 years), approximately fifty percent of patients with choroidal melanoma will develop metastatic disease and eventually die. Thus, continuing research on prognostic factors, early detection and treatment is necessary. Height regression rates both after plaque brachytherapy and proton beam irradiation have been shown to have prognostic value. The purpose of this study was to analyze the influence of early tumor regression rate after treatment of choroidal melanoma with LINAC stereotactic fractionated radiotherapy (SFRT) as an independent risk factor for metastasis., Material and Methods: 256 patients with choroidal melanoma treated with LINAC SFRT were included. Follow-up included standardized echography yielding apical height, smallest and largest basal linear diameter, tumor volume and mean reflectivity. The influence of baseline measurements and of a longitudinal, normalized area under the curve coefficient (NAC) of the latter marker on metastasis risk was assessed., Results: NAC for tumor thickness at months 3, 6, and 12 had a statistically significant (p < 0.001) non-linear effect on risk of metastasis. Additionally, ultrasonographic baseline tumor dimensions, but not internal reflectivity were found to be statistically significant risk factors for metastasis., Conclusions: Our results demonstrate a non-linear influence of regression rate of choroidal melanoma as independent risk factor of metastatic disease after LINAC SFRT. These prove the clinical experience that, in comparison to rather slow regressions, very quick and very slow early tumor responses to LINAC SFRT are associated with a significantly higher metastasis risk., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The importance of QoL and neurocognitive functions in patients with glioblastoma (GB) is above controversy by now. We followed newly diagnosed GB patients treated with radio-chemotherapy during their course of disease by continuously evaluating their quality of life (QoL) and cognitive functions., Methods: We included consecutive patients with newly diagnosed GB from 2010 to 2013 at the Medical University of Vienna. To assess QoL the EORTC QLQ C30 and BN20 questionnaire were used. Neurocognition was measured with the NeuroCog FX. The evaluations were done 6 times every three months, beginning at the beginning of radio-chemotherapy., Results: 42 patients participated in this study. We also recorded QoL and neurocognition in 23 patients after the first disease progression. Patients maintained their cognitive summary score until relapse. Patients with left-sided tumors showed significant lower scores in the subscale verbal fluency than patients with right-sided tumors. The global health score of QoL decreased after the fifth evaluation (13months after diagnosis) whereas a peak of fatigue symptoms was obtained at the third evaluation. Furthermore, fatigue symptoms increased strongly 7months after diagnosis and patients' financial difficulties were mentioned more frequently by younger patients and in patients with lower education levels., Conclusions: QoL and cognitive long-term assessments are feasible also in some patients with GB after a symptomatic progression. Our study demonstrates maintenance of QoL and cognitive summary scales before tumor progression. Moreover, it highlights subgroups according to tumor location and socioeconomic factors., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Stereotactic body radiotherapy (SBRT) has become the standard of care for medically inoperable patients with peripherally located, early stage non-small cell lung cancer (NSCLC), and for those refusing surgical resection. Despite the availability of national and international guidelines, there exists substantial variability in many aspects of SBRT practice., Methods: The ESTRO ACROP guideline is based on a questionnaire covering all aspects of SBRT implementation and practice (n=114 items). The questionnaire was answered by the 11 faculty members of the ESTRO course "Clinical practice and implementation of image-guided SBRT" and their 8 institutions., Results: Agreement by >50% of the institutions was achieved in 72% of all items. Only 8/57 technologies and techniques were identified as mandatory for SBRT while 32/57 were considered as optional. In contrast, quality-assurance related elements were considered as mandatory in 12/24 items. A consensus of risk-adapted SBRT fractionation was achieved with 3×15Gy for peripherally located lesions and 4×12Gy (PTV D95-D99; D max <125% to <150%) for lesions with broad chest wall contact. For patients free from severe comorbidities and with favourable long-term OS expectancy, use of the maximum tolerated dose of 3×18Gy should be considered., Conclusions: This ACROP guideline achieved detailed recommendations in all aspects of SBRT implementation and practice, which will contribute to further standardization of SBRT for peripherally located early stage NSCLC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Paediatric malignancies are a challenge for the radiation oncologist due to their rarity, the great variety of histological types, and the complexity of treatment concepts that evolve over time. The Paediatric Radiation Oncology Society (PROS) is the only internationally operating society for paediatric radiation oncology. The objectives of PROS are to set a world-wide standard of excellence with respect to radiation oncology aspects in curing children and adolescents with cancer, to provide a forum for communication between radiation oncologists, and to exchange information with all professionals involved in the management of paediatric and adolescent cancer. Challenges include the need to promote education and support practice in low and middle income countries (LMIC) as well as the cost and availability of modern treatment technologies for all but most especially these countries. Collaborations with other societies that include for example the education programmes provided jointly with ESTRO, and the upgraded technical platform of the PROS web site offer new possibilities to enhance the efficacy of PROS in education and support of paediatric radiation oncology practice world-wide. PROS has made an important contribution to the management of childhood malignancies over the past decade and new and developing collaborations between PROS and other societies or organizations will ultimately lead to a reduction in world-wide health care inequalities., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background and Purpose: To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors., Materials and Methods: A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison., Results: After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort., Conclusions: Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To compare photons, protons and carbon ions and their combinations for treatment of atypical and anaplastical skull base meningioma., Material and Methods: Two planning target volumes (PTVinitial/PTVboost) were delineated for 10 patients (prescribed doses 50 Gy(RBE) and 10 Gy(RBE)). Plans for intensity modulated photon (IMXT), proton (IMPT) and carbon ion therapy ((12)C) were generated assuming a non-gantry scenario for particles. The following combinations were compared: IMXT+IMXT/IMPT/(12)C; IMPT+IMPT/(12)C; and (12)C+(12)C. Plan quality was evaluated by target conformity and homogeneity (CI, HI), V95%, D2% and D50% and dose-volume-histogram (DVH) parameters for organs-at-risk (OAR). If dose escalation was possible, it was performed until OAR tolerance levels were reached., Results: CI was worst for IMXT. HI<0.05±0.01 for (12)C was significantly better than for IMXT. For all treatment options dose escalation above 60 Gy(RBE) was possible for four patients, but impossible for six patients. Compared to IMXT+IMXT, ion beam therapy showed an improved sparing for most OARs, e.g. using protons and carbon ions D50% was reduced by more than 50% for the ipsilateral eye and the brainstem., Conclusion: Highly conformal IMPT and (12)C plans could be generated with a non-gantry scenario. Improved OAR sparing favors both sole (12)C and/or IMPT plans., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC)., Materials and Methods: This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs)., Results: There was strong evidence for a dose-response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p=0.07, BF=2.1 and p=0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs>20)., Conclusion: Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To identify modifying factors and dose-/volume-response relationships for the retina and optic nerve related to highly conformal hypofractionated radiotherapy., Patients and Methods: Seventy-three patients undergoing hypofractionated stereotactic photon radiotherapy of choroidal melanoma were included in this retrospective study. The volumes of the optic nerve receiving doses of more than 7.5 or 12 Gy, respectively, were defined. Optic nerve circumference included in the 30%, 40%, 50%, or 80% isodose (ON%) and retina included in 30% or 40% were determined as quantal effects. Univariate and multivariate analyses were performed for clinical variables as well as probit analysis to define EDx (doses where a positive response is expected in x% of the cases)., Results: Median follow-up was 90.0 (interquartile range 69.0-98.0) months. Fifty-two (71%) and 49 (67%) patients developed radiation retinopathy and optic neuropathy (any grade). Age, length of follow-up and diabetes were significant parameters regarding retinopathy. Optic neuropathy was significantly influenced by age, length of follow-up, and ON30. The probability of optic neuropathy (any grade and grade ≥ 2) significantly increases with the dose (p ranges from 0.0126 to 0.0211)., Conclusion: Treatment planning should aim at minimizing encompassing isodoses particularly in the low dose region, without compromising PTV coverage., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To evaluate long-term safety and efficacy of hypofractionated stereotactic photon radiotherapy with 5 five fractions at 10 Gy each in patients with centrally located choroidal melanoma., Materials and Methods: Ninety-one patients with centrally located choroidal melanoma were treated stereotactically at a linear accelerator with 6 MV photon beams with 5 fractions at 10 Gy each. Examinations were performed at baseline and every 3 months in the first 2 years, then every 6 months until 5 years and yearly thereafter. Median follow-up was 37.8 months (IQR 19.2-49.9). They included visual acuity assessment, routine ophthalmological examinations with fundoscopy, echography for measurement of tumor dimensions, medical examinations and, if necessary, fluorescein angiography., Results: Initial tumor base diameters, height and volume were 11.20mm (IQR 9.10-13.70), 9.80 mm (IQR 7.80-11.70), 4.53 mm (IQR 3.33-6.43) and 253.8mm(3) (IQR 127.5-477.0). Local tumor control and eye retention rates were 97.7% and 86.4% after 5 years, respectively. Eight patients developed metastatic disease and 3 of them died due to metastatic disease during the follow-up period. Median visual acuity decreased from 0.67 initially to 0.05 at the last individual follow-up (p<0.001). The most common toxicities (any grade) were radiation retinopathy (n=39), optic neuropathy (n=32), radiogenic cataract (n=21), neovascular glaucoma (n=15) and dry eye syndrome (n=10). The 5 year probabilities to remain free of these side effects (any grade) were 26.0%, 45.4%, 55.4%, 72.6% and 80.5%, respectively. The most important prognostic factors for toxicities were the largest tumor base diameter, tumor height and tumor distance to the optic disk., Conclusion: Hypofractionated stereotactic photon radiotherapy with a total dose of 50 Gy delivered in 5 fractions is a highly effective treatment option in patients with centrally located choroidal melanoma and has a moderate toxicity profile., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Quality assurance of radiotherapy is an important determinant of outcome in some cancers. SIOPEN-R-NET developed a computerised remote data entry system for recording imaging and treatment parameters for its multimodality high risk neuroblastoma study. This will enable investigation of the relationship between radiotherapy quality and local control., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Evaluation of dosimetric benefits of advanced radiotherapy techniques for the treatment of abdominal lesions during early childhood., Patients and Methods: Treatment planning was performed for five Neuroblastoma (NBL) and four Wilms Tumor (WT) patients. Opposing fields (2F), photon intensity modulated radiotherapy (IMXT) and two proton techniques (passively scattered (PT) and scanned beams (IMPT)) were considered. Averaged dose-volume histograms, associated dosimetric parameters and a radiobiological model for the estimation of the therapy related carcinogenic effect were evaluated., Results: With respect to the 2F technique, both proton techniques enabled to reduce mean liver and kidney dose by 40-60%; Organ fractions irradiated at the level of the tolerance dose were reduced by 65% for kidneys and 75% for the liver in NBL patients and by additional 10% for WT patients. IMXT enabled to reduce parameters related to the steep high-dose gradient, e.g., V(15Gy) for the kidneys was reduced by a factor 2-3 compared to 2F. V(12Gy) was reduced by 40% in the liver. On the other side, the improvement of those parameters characterizing the low isodose domain was limited for IMXT. The risk for radiation-induced secondary cancer was doubled for IMXT and even more increased for PT if secondary neutrons were taken into account, while this risk remained the same or was reduced by IMPT with respect to 2F., Conclusions: Proton beams improved all dosimetric parameters for NBL and WT patients compared to photon techniques. This improvement was limited for IMXT mainly to parameters related to the steep high-dose gradient. Further research is needed to minimize uncertainties for secondary cancer estimations.

Background and Purpose: The aim of the present study was to investigate potential dosimetric benefits of proton therapy for hypofractionated stereotactic body radiotherapy (SBRT)., Materials and Method: Twelve patients undergoing hypofractionated SBRT at the Medical University Vienna were selected. Passively scattered protons (PT) and intensity modulated proton therapy (IMPT) were evaluated against a conformal photon technique (3D-CRT), assuming a fractionation of 3x15Gy, prescribed to the 65% isodose. For all treatment techniques shallow breathing with abdominal compression (SB+AC) was compared with a deep inspiration breath hold technique (DIBH). Treatment planning was done with XiO (CMS, USA). Target conformity, dose-volume histograms (DVH) and various associated dosimetric parameters were considered for the planning target volume (PTV), lung, heart and esophagus., Results: For both breathing conditions conformity indices were very similar. They were between 0.75 and 0.78 for IMPT and 3D-CRT and around 0.55 for PT using 2-3 beams. Irrespective of treatment modality, DVHs for the ipsilateral lung were improved with the DIBH technique. For the PT technique, the 2Gy isodose (V2Gy) covered on average 7-9% less lung volume compared to 3D-CRT, for IMPT this reduction was more than 10%. Volumes covered the 4 and 6Gy isodoses were 2-4% smaller for IMPT, but very similar for PT and 3D-CRT. Both proton techniques achieved full sparing of the contralateral lung and superior sparing of the heart. Maximum doses to the heart and esophagus were on average around 3Gy for 3D-CRT and almost 0Gy for both proton techniques. For 3D-CRT average V2Gy values for the heart could be reduced from 64% in shallow breathing to 34% in DIBH. V2Gy for protons was negligible., Conclusions: Only small dosimetric differences were found between photons and protons for SBRT of lung lesions. Whether these small dosimetric benefits translate in reduced side effects or have the potential to improve local control rates remains to be demonstrated in clinical studies.

Purpose: To evaluate the dosimetric consequences for irradiated lung tissue for different respiration conditions for hypofractionated stereotactic body radiotherapy (SBRT)., Methods and Materials: Thirteen patients with lung lesion undergoing SBRT treatment in shallow breathing with abdominal compression (SB+AP) underwent additional multislice CT studies in free breathing (FB), deep inspiration and expiration breath hold (DIBH, DEBH). For each patient 6 different treatment plans were designed for the various respiration conditions applying standard (7/7/10 mm), reduced (5/5/5 mm) and individual margins. The FB plan with standard margins was used as a reference. The percentage of volume of the ipsilateral lung receiving total doses > or=12, 15> or= and > or=18 Gy, mean lung dose (D(mean)), NTCP corrected for fractionation effects and the total monitor units (MU) were evaluated., Results: With DIBH it was possible to reduce all lung dose parameters by about 20%. Applying reduced margins in DIBH, this reduction was even increased to about 40%. The standard technique (SB+AP) with individual margins showed similar results as DIBH with standard margins. DEBH showed some improvement over FB only when reduced margins were applied. Only for 5/13 patients NTCP values >1% were obtained. For these patients a significant NTCP reduction was achieved with DIBH techniques., Conclusions: In SBRT shallow breathing with abdominal compression produces acceptable results concerning lung DVHs. DIBH, especially with reduced margins, showed the best lung sparing. For the clinical implementation of such a technique some form of gating is advisable. However, there are some practical limitations due to high fractional doses.

Background: Brain metastases have evolved from a rare to a frequently encountered event in advanced breast cancer due to advances in palliative systemic treatment., Patients and Methods: All Patients treated at our centre from 1994 to 2004 with WBRT for brain metastases from breast cancer were included. We performed a multivariate analysis (Cox regression) to explore which factors are able to influence significantly cerebral time to progression (TTP) and overall survival (metastatic sites [visceral versus non-visceral], Karnofsky performance score [KPS], age, intensified local treatment [boost irradiation, neuro-surgical resection] further systemic treatment)., Results: Overall 174 patients, median age 51 years, range 27-76 years, were included. Median TTP was 3 months (m), range 1-33+ m. Median overall survival was 7 m, range 1-44 m. Factors significantly influencing TTP were KPS (p = 0.002), intensified local treatment (p < 0.001), and palliative systemic treatment (p = 0.001). Factors significantly influencing survival were intensified local treatment (p = 0.004), metastatic sites (p = 0.008), KPS (p = 0.006), and palliative systemic treatment (p < 0.001)., Conclusion: As shown by the significant influence of metastatic sites, some patients die from their advanced systemic tumour situation before they would die from cerebral progression. In other individuals however, intensified local treatment and systemic treatment appear to influence cerebral time to progression and overall survival.

Background and Purpose: To evaluate the outcome of very young children with anaplastic ependymoma after delayed or omitted radiotherapy (RT)., Materials and Methods: Children under age of 3 years with anaplastic ependymoma were enrolled in the HIT-SKK 87 trial from 1987. After surgery, low-risk patients (R0, M0) received maintenance chemotherapy until elective RT at age of three. In high-risk patients (R+, M+) intensive induction chemotherapy was followed by maintenance chemotherapy and subsequently delayed RT. If there was, progression radiotherapy started immediately. In the HIT-SKK 92, trial MTX-based chemotherapy was applied. RT was administered in non-responders only., Results: Thirty-four children with anaplastic ependymoma were eligible (age 1.0-33.0 months). All children received chemotherapy. In 13 children, no RT was administered. Preventive RT after chemotherapy was given in nine, and salvage RT in 12 children. OS and PFS rates after 3-year were 55.9 and 27.3%, respectively. Twenty-five children relapsed. Positive impact on survival was observed in children with higher age, M0-stage, complete resection, and treatment with radiotherapy. Without RT only 3/13, children survived., Conclusion: Delaying RT jeopardizes survival even after intensive chemotherapy. Predominant site of failure is the primary tumor site. RT of the neuraxis should be omitted in localized disease.

Purpose: To study local tumor control and radiogenic side effects after fractionated LINAC based stereotactic radiotherapy for selected uveal melanoma., Patients and Methods: Between June 1997 and March 2001, 90 patients suffering from uveal melanoma were treated at a LINAC with 6 MV. The head was immobilized with a modified stereotactic frame system (BrainLAB). For stabilization of the eye position a light source was integrated into the mask system in front of the healthy or the diseased eye. A mini-video camera was used for on-line eye movement control. Tumors included in the study were either located unfavorably with respect to macula and optical disc (<3 mm distance) or presented with a thickness >7 mm. Median tumor volume was 305+/-234 mm3 (range 70-1430 mm3), and mean tumor height was 5.4+/-2.3 mm (range 2.7-15.9 mm). Total doses of 70 (single dose 14 Gy @ 80% isodose) or 60 Gy (single dose 12 Gy @ 80% isodose) were applied in five fractions within 10 days. The first fractionation results in total dose (TD) (2 Gy) of 175 Gy for tumor and 238 Gy for normal tissue, corresponding values for the second fractionation schedule are 135 and 180 Gy, respectively., Results: After a median follow-up of 20 months (range 1-48 months) local control was achieved in 98% (n=88). The mean relative tumor reductions were 24, 27, and 37% after 12, 24 and 36 months. Three patients (3.3%) developed metastases. Secondary enucleation was performed in seven patients (7.7%). Long term side effects were retinopathy (25.5%), cataract (18.9%), optic neuropathy (20%), and secondary neovascular glaucoma (8.8%)., Conclusion: Fractionated LINAC based stereotactic photon beam therapy in conjunction with a dedicated eye movement control system is a highly effective method to treat unfavorably located uveal melanoma. Total doses of 60 Gy (single dose 12 Gy) are considered to be sufficient to achieve good local tumor control.

Background and Purpose: A systematic procedure for up-front centralized data review and the set-up of individualized treatment proposals was integrated prospectively into the German-Austrian multicenter trial DAL-HD-90 for pediatric Hodgkin's disease (HD) in order to introduce local radiotherapy according to the individual patient's spread of disease within a combined-modality treatment. This paper investigates the feasibility of such a procedure and its impact on the final definition of the extent and stage of disease as well as on the choice of treatment., Patients and Methods: Between October 1990 and July 1995, 578 children and adolescents <18 years (259 girls, 319 boys, median age 12.9 years) with HD were enrolled into the HD-90 trial. After clinical and pathological staging (66.4/33.6%), patients were allocated to treatment groups (TG) 1 'early stage', TG2 'intermediate stage', or TG3 'advanced stage'. All groups underwent two cycles of OPPA (vincristine, prednisone, procarbazine, doxorubicin) (girls) or OEPA (E, etoposide) (boys) for induction chemotherapy. TG2 and TG3 continued on as two or four cycles, respectively, of COPP (C, cyclophosphamide). Low-dose local radiotherapy was given to the initially involved sites, with radiation doses of 25 Gy in TG1/TG2, and 20 Gy in TG3. All documentation forms, radiographs, and chest and abdominal computed tomography (CT) scans were centrally reviewed, addressing in particular the individual patient's extent and stage of disease. This review and the set-up of individualized treatment proposals were in the hands of the study coordinator, one additional pediatrician and two radiation oncologists and radiologists at the study center. During a time slot of at least 8 weeks (two cycles of standard chemotherapy in all three TGs) the individualized treatment proposals were to be sent to the participating hospital., Results: Complete sets of documentation from 564/578 patients (97.6%) were submitted sufficiently early to the study center. A total of 285 out of 574 chest radiographs, 468 out of 553 chest CT scans and 421 out of 548 abdominal CT scans were available from 71 hospitals. A total of 564 individualized treatment proposals were worked out by the review group and sent to the hospitals before radiotherapy began. Re-analysis of images and documentation forms, including laboratory and clinical data, resulted in a revision of stage in 115/571 patients (20.1%) and of TG in 76/571 patients (13.3%). A total of 67/76 patients were shifted into a higher TG, 60 patients on account of additionally detected extralymphatic involvement, five patients because of additionally detected lymph node involvement and two patients due to clinical data which had to be classified as B-symptoms. A total of 9/76 patients were shifted into a lower TG; in three patients extranodal disease and in six patents local lymph node involvement could not be confirmed., Conclusions: The up-front centralized review of patient data and consecutive set-up and delivery of individualized treatment proposals for almost every patient are feasible within a large multicenter trial. Sufficient time and manpower at the study center are needed for the review process and the set-up of individualized treatment proposals. Such a procedure has a significant impact on the homogeneity of stage definition, allocation to TG, and individualized treatment proposals.

Purpose: To describe a stereotactic irradiation technique for uveal melanomas performed at a linac, based on a non-invasive eye fixation and eye monitoring system., Methods: For eye immobilization a light source system is integrated in a standard stereotactic mask system in front of the healthy eye: During treatment preparation (computed tomography/magnetic resonance imaging) as well as for treatment delivery, patients are instructed to gaze at the fixation light source. A mini-video camera monitors the pupil center position of the diseased eye. For treatment planning and beam delivery standard stereotactic radiotherapy equipment is used. If the pupil center deviation from a predefined 'zero-position' exceeds 1 mm (for more than 2 s), treatment delivery is interrupted. Between 1996 and 1999 60 patients with uveal melanomas, where (i) tumor height exceeded 7 mm, or (ii) tumor height was more than 3 mm, and the central tumor distance to the optic disc and/or the macula was less than 3 mm, have been treated. A total dose of 60 or 70 Gy has been given in 5 fractions within 10 days., Results: The repositioning accuracy in the mask system is 0.47+/-0.36 mm in rostral-occipital direction, 0.75+/-0.52 mm laterally, and 1.12+/-0.96 mm in vertical direction. An eye movement analysis performed for 23 patients shows a pupil center deviation from the 'zero' position<1 mm in 91% of all cases investigated. In a theoretical analysis, pupil center deviations are correlated with GTV 'movements'. For a pupil center deviation of 1 mm (rotation of the globe of 5 degrees ) the GTV is still encompassed by the 80% isodose in 94%., Conclusion: For treatments of uveal melanomas, linac-based stereotactic radiotherapy combined with a non-invasive eye immobilization and monitoring system represents a feasible, accurate and reproducible method. Besides considerable technical requirements, the complexity of the treatment technique demands an interdisciplinary team continuously dedicated to this task.

Background and Purpose: To evaluate prospectively local tumor control and morbidity after 1-3 fractions of stereotactic external beam irradiation (SEBI) in patients with uveal melanoma, unsuitable for ruthenium-106 brachytherapy or local resection., Material and Methods: This phase I/II study includes 62 selected patients with uveal melanoma. The mean initial tumor height was 7.8+/-2.8 mm. With the Leskell gamma knife SEBI, 41 patients (66%) were irradiated with two equal fractions of 35, 30 or 25 Gy/fraction, 14 patients (22%) were treated with three fractions of 15 Gy each, and seven patients (11%) with small tumor volumes below 400 mm(3) were treated with one fraction of 45 Gy. The mean total dose was 54+/-8 Gy. The minimal follow-up period was 12 months, and the median follow-up was 28.3 months. Data on radiation-induced side-effects were analyzed with the Cox proportional hazards model for possible risk factors., Results: Local tumor control was achieved in 98% and tumor height reduction in 97%. The mean relative tumor volume reductions were 44, 60 and 72% after 12, 24 and 36 months, respectively. Seven patients developed metastases (11%). Secondary enucleation was performed in eight eyes (13%). Morbidity was significant in tumors exceeding 8 mm in initial height; it was comparable and acceptable in those smaller. In the stepwise multiple Cox model, tumor localization, height and volume, planning target volume (PTV), total dose and patient age were identified as the strongest risk factors for radiation-induced lens opacities, secondary glaucoma, uveitis, eyelash loss and exudative retinal detachment. In this model, the high-dose volume irradiated with more than 10 Gy/fraction was the strongest risk factor for radiation-induced uveitis., Conclusions: Stereotactic external photon beam irradiation and a total dose of 45-70 Gy delivered in one to three fractions are highly effective at achieving local tumor control in uveal melanoma. Further clinical studies using smaller fraction doses, and consequent smaller high-dose volumes, are justified to optimize dose and fractionation. Fractionated stereotactic irradiation has a challenging potential as an eye-preserving treatment in uveal melanoma.