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Item does not contain fulltext IMPORTANCE: Currently, preoperative radiotherapy for all soft-tissue sarcomas is identical at a 50-Gy dose level, which can be associated with morbidity, particularly wound complications. The observed clinical radiosensitivity of the myxoid liposarcoma subtype might offer the possibility to reduce morbidity. OBJECTIVE: To assess whether a dose reduction of preoperative radiotherapy for myxoid liposarcoma would result in comparable oncological outcome with less morbidity. DESIGN, SETTING, AND PARTICIPANTS: The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas (DOREMY) trial is a prospective, single-group, phase 2 nonrandomized controlled trial being conducted in 9 tertiary sarcoma centers in Europe and the US. Participants include adults with nonmetastatic, biopsy-proven and translocation-confirmed myxoid liposarcoma of the extremity or trunk who were enrolled between November 24, 2010, and August 1, 2019. Data analyses, using both per-protocol and intention-to-treat approaches, were conducted from November 24, 2010, to January 31, 2020. INTERVENTIONS: The experimental preoperative radiotherapy regimen consisted of 36 Gy in once-daily 2-Gy fractions, with subsequent definitive surgical resection after an interval of 4 or more weeks. MAIN OUTCOMES AND MEASURES: As a short-term evaluable surrogate for local control, the primary end point was centrally reviewed pathologic treatment response. The experimental regimen was regarded as a success when 70% or more of the resection specimens showed extensive treatment response, defined as 50% or greater of the tumor volume containing treatment effects. Morbidity outcomes consisted of wound complications and late toxic effects. RESULTS: Among the 79 eligible patients, 44 (56%) were men and the median (interquartile range) age was 45 (39-56) years. Two patients did not undergo surgical resection because of intercurrent metastatic disease. Extensive pathological treatment response was observed in 70 of 77 patients (91%; posterior mean, 90.4%; 95% highest probability density interval, 83.8%-96.4%). The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%. CONCLUSIONS AND RELEVANCE: The findings of the DOREMY nonrandomized clinical trial suggest that deintensification of preoperative radiotherapy dose is effective and oncologically safe and is associated with less morbidity than historical controls, although differences in radiotherapy techniques and follow-up should be considered. A 36-Gy dose delivered in once-daily 2-Gy fractions is proposed as a dose-fractionation approach for myxoid liposarcoma, given that phase 3 trials are logistically impossible to execute in rare cancers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02106312.

PURPOSE: Pencil beam scanned proton therapy (PBS-PT) treatment quality might be compromised by interplay and motion effects. Via fraction-wise reconstruction of 4D dose distributions and dose accumulation, we assess the clinical relevance of motion related target dose degradation in thoracic cancer patients.METHODS AND MATERIALS: For the ten thoracic patients (Hodgkin lymphoma and non-small cell lung cancer) treated at our proton therapy facility, daily breathing pattern records, treatment delivery log-files and weekly repeated 4DCTs were collected. Patients exhibited point-max target motion of up to 20 mm. They received robustly optimized treatment plans, delivered with five-times rescanning in fractionated regimen. Treatment delivery records were used to reconstruct 4D dose distributions and the accumulated treatment course dose per patient. Fraction-wise target dose degradations were analyzed and the accumulated treatment course dose, representing an estimation of the delivered dose, was compared with the prescribed dose.RESULTS: No clinically relevant loss of target dose homogeneity was found in the fraction-wise reconstructed 4D dose distributions. Overall, in 97% of all reconstructed fraction doses, D98 remained within 5% from the prescription dose. The V95 of accumulated treatment course doses was higher than 99.7% for all ten patients.CONCLUSIONS: 4D dose reconstruction and accumulation enables the clinical estimation of actual exhibited interplay and motion effects. In the patients considered here, the loss of homogeneity caused by interplay and organ motion did not show systematic pattern and smeared out throughout the course of fractionated PBS-PT treatment. Dose degradation due to anatomical changes showed to be more severe and triggered treatment adaptations for five patients.

Local treatment for pulmonary oligometastases (one to five lesions) using metastasectomy or stereotactic ablative radiotherapy (SABR) was investigated in a cohort that received multidisciplinary tumor board-based treatment decisions. The first choice of treatment was surgery; SABR was recommended in cases of adverse clinical factors. Propensity score-adjusted and unadjusted overall survival was the primary end point; local control and time to failure of a local-only treatment strategy were also analyzed. With a minimum follow-up time of 5.8 years, the 5-year overall survival rate was 41% for surgery (n = 68) and 45% for SABR (n = 42). Again not different for the two modalities, 40% of patients were free from failure of a local-only treatment strategy, and 20% were free from any progression at 5 years. The 5-year local control rate was 83% for SABR and 81% for surgery. Despite treatment selection clearly disadvantaging SABR against surgery, even unadjusted outcome was not better when pulmonary oligometastases were surgically removed rather than irradiated. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Purpose: To compare neurocognitive functioning in Small Cell Lung Cancer patients(SCLC) who received prophylactic cranial irradiation(PCI) with or without hippocampus avoidance (HA). Material and Methods: In a multicenter randomized phase III trial (NCT01780675) patients with SCLC were randomized to standard PCI (25 Gy /10 fractions) or HA-PCI. Neuropsychological tests were performed at baseline and 4, 8, 12, 18 and 24 months after PCI. The primary endpoint was total recall on the Hopkins Verbal Learning Test- Revised(HVLT-R) at 4 months; a decline of at least 5 points from baseline was considered a failure. Secondary endpoints included other cognitive outcomes, evaluation of the incidence and location of brain metastases and overall survival(OS). Results: From April 2013 until March 2018 a total of 168 patients were randomized. The median follow-up time was 26 .6 months. In both treatment arms 70% of patients had limited disease and baseline characteristics were well balanced. Decline on the HVLT-R total recall score at 4 months was not significantly different between the arms: 29% of PCI patients dropped ≥5 points and 28% of HA-PCI patients (p=1.000). Performance on other cognitive tests measuring memory, executive function, attention, motor function and processing speed did not change significantly different over time between the groups. The OS was not significantly different. The cumulative incidence of brain metastases at 2 years was 20% (95% CI: 12% - 29%) for the PCI arm and 16% (95% CI: 7% - 24%) for the HA-PCI arm. Conclusion: This randomized phase III trial did not show lower probability of cognitive decline in SCLC patients receiving hippocampus avoidance PCI compared to conventional PCI. No increase in brain metastases at 2 years was observed in the HA- PCI arm. Trial Registration: NCT01780675 Funding Statement: Maarten Lambrecht Speaker’s fee AstraZeneca, all others No Funding. Declaration of Interests: YL reports personal fees from Astra-Zeneca and RaySearch outside the context of the submitted work. All other authors have nothing to declare. Ethics Approval Statement: This trial (NCT01780675) was conducted according to the Declaration of Helsinki and approved by the Medical Ethics Committee of the Netherlands Cancer Institute.

Objective: Multicenter randomized phase III trial (NCT01780675) to investigate memory functioning and safety after PCI with or without hippocampus sparing in Small Cell Lung Cancer (SCLC) (25 Gy/ 10 fractions) using the Hopkins Verbal Learning Test-Revised (HVLT-R). We here report on the differences between localized (stage I-III) vs. metastatic (stage IV) patients. Methods: Primary endpoint: decline in HVLT-R total recall at 4 months. Decline of 5 or more out of a possible 36 points was considered a failure. Results: 168 patients were randomized. Median follow-up: 24.6 months. Median age: 64 years, 51% female, performance score WHO 0-1: 93%. Stage distribution: 70% localized, 30% metastatic. Localized disease: at 4 months, 27 % in both treatment arms had a decline of ≥ 5 points of HVLT-R total recall (p=1.00); at 8 months: 34 % and 22 % in PCI and HA-PCI (p=0.40). Metastatic disease: at 4 months, 33 % in both treatment arms had a decline of ≥ 5 points (p=1.00); at 8 months: 33 % and 50 % in PCI and HA-PCI (p=1.00). No difference in the incidence of brain metastases between PCI and HA-PCI in localized or metastatic SCLC were observed. No patients developed isolated brain metastases in the hippocampal avoidance region. There were no statistically significant differences in the overall survival (OS) between PCI and HA-PCI, neither in localized, nor in metastatic disease. Conclusion: HA-PCI did not affect neuro-cognitive decline compared to standard PCI, both in localized and in metastatic SCLC. No increase in brain metastases was observed. Regular PCI remains the standard of care.

Background and purpose: Stereotactic ablative radiotherapy (SABR; or stereotactic body radiotherapy, SBRT) emerges as treatment option for pulmonary oligometastatic disease (OMD), but there are no studies comparing SABR with pulmonary metastasectomy (PME). We analysed consecutive patients referred via a university-hospital based multidisciplinary team.Material and methods: Patients were offered PME as first choice and SABR in case they were considered to be less suitable surgical candidates. Overall survival was the primary endpoint. Secondary endpoints were progression-free-survival, local control of treated metastases, and freedom-from-failure of a local-only treatment strategy without systemic therapy.Results: From 2007 until 2010, 110 patients were treated and analysed (PME, n = 68; SABR, n = 42). Median follow-up time was 43 months (minimally, 25). Estimated overall survival rates at one, three, and five years were 87%, 62%, and 41% for PME, and 98%, 60%, and 49% for SABR, respectively (logrank-test, p = 0.43). Local control at two years was 94% for SABR and 90% for PME. Progression-free survival was 17% at three years, but 43% of the patients still had not failed a local-only treatment strategy.Conclusions: Although SABR was second choice after PME, survival after PME was not better than after SABR. Prospective comparative studies are clearly required to define the role of both, SABR and PME in OMD. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

Purpose: To investigate survival and local recurrence after stereotactic ablative radiotherapy (SABR) or threedimensional conformal radiotherapy (3D-CRT) administered for early-stage primary lung cancer and to investigate longitudinal changes of health-related quality of life (HRQOL) parameters after either treatment.Methods and Materials: Two prospective cohorts of inoperable patients with T1-2N0M0 primary lung tumors were analyzed. Patients received 70 Gy in 35 fractions with 3D-CRT or 60 Gy in three to eight fractions with SABR. Global quality of life (GQOL), physical functioning (PF), and patient-rated dyspnea were assessed using the respective dimensions of European Organization for Research and Treatment of Cancer Core Questionnaire-C30 and LC13. HRQOL was analyzed using multivariate linear mixed-effects modeling, survival and local control (LC) using the Kaplan-Meier method, Cox proportional hazards analysis, and Fine and Gray multivariate competing risk analysis as appropriate.Results: Overall survival (OS) was better after SABR compared with 3D-CRT with a HR of 2.6 (95% confidence interval [CI]: 1.5-4.8; p Conclusion: In this nonrandomized comparison of two prospective cohorts of medically inoperable patients with Stage I lung cancer, OS and LC were better after SABR. GQOL, PF, and patient-rated dyspnea were stable after SABR, whereas PF decreased after 3D-CRTapproaching clinical significance already at 1 year. (C) 2011 Elsevier Inc.

(18)F-Fluorodeoxyglucose positron emission tomography (FDG PET) has been used to assess metabolic response several months after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer. However, whether a metabolic response can be observed already during treatment and thus can be used to predict treatment outcome is undetermined.Ten medically inoperable patients with FDG PET-positive lung tumours were included. SBRT consisted of three fractions of 20 Gy delivered at the 80% isodose at days 1, 6 and 11. FDG PET was performed before, on day 6 immediately prior to administration of the second fraction of SBRT and 12 weeks after completion of SBRT. Tumour metabolism was assessed semi-quantitatively using the maximum standardized uptake value (SUV(max)) and SUV(70%).After the first fraction, median SUV(max) increased from 6.7 to 8.1 (p = 0.07) and median SUV(70%) increased from 5.7 to 7.1 (p = 0.05). At 12 weeks, both median SUV(max) and median SUV(70%) decreased by 63% to 3.1 (p = 0.008) and to 2.5 (p = 0.008), respectively.SUV increased during treatment, possibly due to radiation-induced inflammation. Therefore, it is unlikely that (18)F-FDG PET during SBRT will predict treatment success.

Background and purpose: Radiotherapy plays a pivotal role in lung cancer treatment. Selection of patients for new (radio)therapeutic options aiming at improving outcomes requires reliable and validated prediction models. We present the implementation of a prospective platform for evaluation and development of lung radiotherapy (proPED-LUNG) as an instrument enabling multidimensional predictive modelling.Materials and methods: ProPED-LUNG was designed to comprise relevant baseline and follow up data of patients receiving pulmonary radiotherapy with curative intent. Patient characteristics, diagnostic and staging information, treatment parameters including full dose-volume-histograms, tumour control, survival, and toxicity are scored. Besides physician-rated data, a range of patient-rated data regarding symptoms and health-related quality-of-life are collected.Results: After 18 months of accrual, 315 patients have been included (accrual rate, 18 per month). Of the first hundred patients included, 70 received conformal (chemo)radiotherapy and 30 underwent stereotactic radiotherapy. Compliance at 3 and 6 months follow-up was 96-100% for patient-rated, and 8194% for physician-rated assessments. For data collection, 0.4 FTE were allocated in a 183 FTE department (0.2%).Conclusions: ProPED-LUNG is feasible with high compliance rates and yields a large amount of high quality prospective disease-related, treatment-related, patient- and physician-rated data which can be used to evaluate new developments in pulmonary radiotherapy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Purpose: To define a method of dose prescription employing Monte Carlo (MC) dose calculation in stereotactic body radiotherapy (SBRT) for lung tumours aiming at a dose as low as possible outside of the PTV.Methods and materials: Six typical T1 lung tumours - three small, three large - were constructed centrally, peripherally in the lung, and nearby the thoracic wall, respectively. For each of these, five treatment plans employing dynamic conformal arc technique were made in which the dose was prescribed to encompass the PTV with the prescription isodose level (PIL) set in a range between 50% and 80% of the isocenter dose. Three shells of respectively 10 mm thickness around the PTV were constructed to assess the dose in the tissues directly adjacent to the PTV.Results: The PTV was nicely covered (mean 98.8% +/- 0.9%) With favourable conformity indices (mean 1.09 +/- 0.1). Mean doses around the PTVs were 73% (+/-1.3%), 76% (+/-3.5%), and 85% (+/-5.1%) of the prescribed dose in shell I for PIL50%, PIL65%, and PIL80%, respectively: 40% (+/-2.6%), 44% (+/-5.1%), 54% (+/-9.3%) in shell 2; and 24% (+/-1.9%), 26% (+/-3.6%), 33% (+/-6.8%) in shell 3. All normal tissue doses including the integral dose were also consistently worst for PIL80%. Monitor units were 30% higher for PIL65%, and 70% higher for PIL50%, compared with PIL80%.Conclusions: To improve normal tissue sparing the dose should be prescribed at an isodose lower than 80% of the isocenter dose in SBRT when using conformal arc technique with MC dose calculation. (C) 2009 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 94 (2010) 42-46