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Supplementary Figures 1-5. Supplementary Figure 1. Box plots showing the distribution of the top 4 radiomic features resulting from differential analysis of Dead vs Alive patients in the Lung1 datasets. Supplementary Figure 2. Box plots showing the distribution of the top 4 radiomic features resulting from differential analysis of Dead vs Alive patients in the Lung1 datasets. Values were scaled by min-max procedure. Supplementary Figure 3. Box plot of the distribution of the feature "Maximum" between alive and dead patients in Lung1 dataset using original (left) and normalized (right) values. The p-value of the difference of feature levels between alive and dead patients was estimated by Wilcoxon-Mann-Whitney test and adjusted by Benjamini-Hochberg procedure (False Discovery Rate, FDR). Supplementary Figure 4. Box plots showing the distribution of the top 2 radiomic features resulting from differential analysis of patients in the Lung1 datasets across disease stages. Values were quantilenormalized. Supplementary Figure 5. Heat map of radiomic profiles of n=388 patients from the Lung1 dataset.

Supplementary Tables 1-2. STable 1: Table of the results of differential radiomic analysis between dead and alive patients from the Lung1 dataset (Aerts et al., 2014). STable 2: Table of the results of differential radiomic analysis across different disease stages for patients from the Lung1 dataset (Aerts et al., 2014).

Quantitative analysis of biomedical images, referred to as radiomics, is emerging as a promising approach to facilitate clinical decisions and improve patient stratification. The typical radiomic workflow includes image acquisition, segmentation, feature extraction, and analysis of high-dimensional datasets. While procedures for primary radiomic analyses have been established in recent years, processing the resulting radiomic datasets remains a challenge due to the lack of specific tools for doing so. Here we present RadAR (Radiomics Analysis with R), a new software to perform comprehensive analysis of radiomic features. RadAR allows users to process radiomic datasets in their entirety, from data import to feature processing and visualization, and implements multiple statistical methods for analysis of these data. We used RadAR to analyze the radiomic profiles of more than 850 patients with cancer from publicly available datasets and showed that it was able to recapitulate expected results. These results demonstrate RadAR as a reliable and valuable tool for the radiomics community.Significance:A new computational tool performs comprehensive analysis of high-dimensional radiomic datasets, recapitulating expected results in the analysis of radiomic profiles of >850 patients with cancer from independent datasets.

RadaR tutorial

Background Published treatment technique comparisons for postoperative left-sided whole breast irradiation (WBI) with deep-inspiration breath-hold (DIBH) are scarce, small, and inconclusive. In this study, fully automated multi-criterial plan optimization, generating a single high-quality, Pareto-optimal plan per patient and treatment technique, was used to compare for a large patient cohort 1) intensity modulated radiotherapy (IMRT) with two tangential fields and 2) volumetric modulated arc therapy (VMAT) with two small tangential subarcs. Materials and methods Forty-eight randomly selected patients recently treated with DIBH and 16 × 2.66 Gy were included. The optimizer was configured for the clinical planning protocol. Comparisons between IMRT and VMAT included dosimetric plan parameters, estimated excess relative risks (ERR) for toxicities, delivery times, MUs, and deliverability accuracy at a linac. Results The automatically generated IMRT and VMAT plans applied in this study were similar or higher in quality than the manually generated clinical plans. For equal PTVin V95% (98.4 ± 0.9%), VMAT had significant advantages compared to IMRT regarding breast dose homogeneity and doses in heart and ipsilateral lung, at the cost of some minor deteriorations for contralateral breast (few cases with larger deteriorations) and lung. Conformality improved from 1.38 to 1.18 (p Conclusion For WBI in conservative therapy of left-sided breast patients treated with DIBH, VMAT with two tangential subarcs was generally dosimetrically superior to IMRT with two tangential static fields. Results need confirmation by robustness analyses.

To investigate and report on the diffusion and clinical use of automated radiotherapy planning systems in Italy and to assess the perspectives of the community of Italian medical physicists involved in radiotherapy on the use of these tools.A survey of medical physicists (one per Institute) of 175 radiotherapy centers in Italy was conducted between February 21st and April 1st, 2021. The information collected included the institute's characteristics, plan activity, availability/use of automatic tools and related issues regarding satisfaction, criticisms, expectations, and perceived professional modifications. Responses were analysed, including the impact of a few variables such as the institute type and experience.125 of the centers (71%) answered the survey, with regional variability (range: 47%-100%); among these, 49% have a TPS with some automatic option. Clinical use of automatic planning is present in 33% of the centers, with 13% applying it in50% of their plans. Among the 125 responding centres the most used systems are Pinnacle (16%), Raystation (9%) and Eclipse (4%). The majority of participants consider the use of automated techniques to be beneficial, while only 1% do not see any advantage; 83% of respondents see the possibility of enriching their professional role as a potential benefit, while 3% see potential threats.Our survey shows that 49% of the responding centres have an automatic planning solution although clinically used in only 33% of the cases. Most physicists consider the use of automated techniques to be beneficial and show a prevalently positive attitude.

Purpose To determine the targeting accuracy of brain radiosurgery when planning procedures employing different MRI and MRI + CT combinations are adopted. Materials and method A new phantom, the BrainTool, has been designed and realized to test image co-registration and targeting accuracy in a realistic anatomical situation. The phantom was created with a 3D printer and materials that mimic realistic brain MRI and CT contrast using a model extracted from a synthetic MRI study of a human brain. Eight markers distributed within the BrainTool provide for assessment of the accuracy of image registrations while two cavities that host an ionization chamber are used to perform targeting accuracy measurements with an iterative cross-scan method. Two procedures employing 1.5 T MRI-only or a combination of MRI (taken with 1.5 T or 3 T scanners) and CT to carry out Gamma Knife treatments were investigated. As distortions can impact targeting accuracy, MR images were preliminary evaluated to assess image deformation extent using GammaTool phantom. Results MR images taken with both scanners showed average and maximum distortion of 0.3 mm and 1 mm respectively. The marker distances in co-registered images resulted below 0.5 mm for both MRI scans. The targeting mismatches obtained were 0.8 mm, 1.0 mm and 1.2 mm for MRI-only and MRI + CT (1,5T and 3 T), respectively. Conclusions Procedures using a combination of MR and CT images provide targeting accuracies comparable to those of MRI-only procedures. The BrainTool proved to be a suitable tool for carrying out co-registration and targeting accuracy of Gamma Knife brain radiosurgery treatments.

PURPOSE To report the long-term results of external-beam accelerated partial-breast irradiation (APBI) intensity-modulated radiation therapy (IMRT) Florence phase III trial comparing whole-breast irradiation (WBI) to APBI in early-stage breast cancer. PATIENTS AND METHODS The primary end point was to determine the 5-year difference in ipsilateral breast tumor recurrence (IBTR) between 30 Gy in 5 once-daily fractions (APBI arm) and 50 Gy in 25 fractions with a tumor bed boost (WBI arm) after breast-conserving surgery. RESULTS Five hundred twenty patients, more than 90% of whom had characteristics associated with low recurrence risk, were randomly assigned (WBI, n = 260; APBI, n = 260) between 2005 and 2013. Median follow-up was 10.7 years. The 10-year cumulative incidence of IBTR was 2.5% (n = 6) in the WBI and 3.7% (n = 9) in the APBI arm (hazard ratio [HR], 1.56; 95% CI, 0.55 to 4.37; P = .40). Overall survival at 10 years was 91.9% in both arms (HR, 0.95; 95% CI, 0.50 to 1.79; P = .86). Breast cancer–specific survival at 10 years was 96.7% in the WBI and 97.8% in the APBI arm (HR, 0.65; 95% CI, 0.21 to 1.99; P = .45). The APBI arm showed significantly less acute toxicity ( P = .0001) and late toxicity ( P = .0001) and improved cosmetic outcome as evaluated by both physician ( P = .0001) and patient ( P = .0001). CONCLUSION The 10-year cumulative IBTR incidence in early breast cancer treated with external APBI using IMRT technique in 5 once-daily fractions is low and not different from that after WBI. Acute and late treatment-related toxicity and cosmesis outcomes were significantly in favor of APBI.

Several phase 3 trials have demonstrated partial breast irradiation noninferiority compared with whole breast irradiation in terms of local control and similar or reduced toxicity. During recent years, especially owing to the COVID-19 pandemic, a growing interest in 5-fraction regimens emerged. The APBI-IMRT-Florence trial (NCT02104895) schedule (30 Gy in 5 fractions) might represent an appealing treatment option, being both a safe and effective partial breast irradiation schedule, with long-term reported results. The aim of this report is to support planners interested in implementing this technique and to warrant equal access to postoperative radiation treatment for most early breast cancer patient candidates. We report the current delivery technique optimized from the original protocol and the updated dose constraints for plan optimization. We also report a statistical analysis of dosimetric parameters on 50 patients treated in consecutive fractions. Treatment-related toxic effects were assessed using the acute radiation morbidity scoring criteria and late radiation morbidity scoring scheme from the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer. The mean volume of ipsilateral breast was 731 cm

Purpose The aim of this work was to establish a methodological approach for creation and optimization of an atlas for auto‐contouring, using the commercial software MIM MAESTRO (MIM Software Inc. Cleveland OH). Methods A computed tomography (CT) male pelvis atlas was created and optimized to evaluate how different tools and options impact on the accuracy of automatic segmentation. Pelvic lymph nodes (PLN), rectum, bladder, and femurs of 55 subjects were reviewed for consistency by a senior consultant radiation oncologist with 15 yr of experience. Several atlas and workflow options were tuned to optimize the accuracy of auto‐contours. The deformable image registration (DIR), the finalization method, the k number of atlas best matching subjects, and several post‐processing options were studied. To test our atlas performances, automatic and reference manual contours of 20 test subjects were statistically compared based on dice similarity coefficient (DSC) and mean distance to agreement (MDA) indices. The effect of field of view (FOV) reduction on auto‐contouring time was also investigated. Results With the optimized atlas and workflow, DSC and MDA median values of bladder, rectum, PLN, and femurs were 0.91 and 1.6 mm, 0.85 and 1.6 mm, 0.85 and 1.8 mm, and 0.96 and 0.5 mm, respectively. Auto‐contouring time was more than halved by strictly cropping the FOV of the subject to be contoured to the pelvic region. Conclusion A statistically significant improvement of auto‐contours accuracy was obtained using our atlas and optimized workflow instead of the MIM Software pelvic atlas.

This retrospective work aims to evaluate the possible impact on intra- and inter-observer variability, contouring time, and contour accuracy of introducing a pelvis computed tomography (CT) auto-segmentation tool in radiotherapy planning workflow.Tests were carried out on five structures (bladder, rectum, pelvic lymph-nodes, and femoral heads) of six previously treated subjects, enrolling five radiation oncologists (ROs) to manually re-contour and edit auto-contours generated with a male pelvis CT atlas created with the commercial software MIM MAESTRO. The ROs first delineated manual contours (M). Then they modified the auto-contours, producing automatic-modified (AM) contours. The procedure was repeated to evaluate intra-observer variability, producing M1, M2, AM1, and AM2 contour sets (each comprising 5 structures × 6 test patients × 5 ROs = 150 contours), for a total of 600 contours. Potential time savings was evaluated by comparing contouring and editing times. Structure contours were compared to a reference standard by means of Dice similarity coefficient (DSC) and mean distance to agreement (MDA), to assess intra- and inter-observer variability. To exclude any automation bias, ROs evaluated both M and AM sets as "clinically acceptable" or "to be corrected" in a blind test.Comparing AM to M sets, a significant reduction of both inter-observer variability (p 0.001) and contouring time (-45% whole pelvis, p 0.001) was obtained. Intra-observer variability reduction was significant only for bladder and femoral heads (p 0.001). The statistical test showed no significant bias.Our atlas-based workflow proved to be effective for clinical practice as it can improve contour reproducibility and generate time savings. Based on these findings, institutions are encouraged to implement their auto-segmentation method.

Background. Partial breast irradiation (PBI) is a reasonable alternative for a whole breast irradiation (WBI) in selected early stage breast cancer patients. The 5-year analysis of the APBI IMRT Florence phase 3 trial showed no significant difference in terms of ipsilateral tumor recurrence (IBTR) and survival rates between the two arms. We present the 10-year follow up data. Methods. From March 2005 to June 2013, women aged more than 40 years affected by early BC, with a maximum pathological tumor size of 25 mm, were randomly assigned in a 1:1 ratio to receive either WBI using three-dimensional conformal radiotherapy (3DCRT) or accelerated PBI (APBI) using intensity-modulated radiotherapy (IMRT) technique. Patients in the APBI arm received a total dose of 30 Gy to the tumor bed in five daily fractions. The WBI arm received 50 Gy in 25 fractions, followed by a boost on the tumor bed of 10 Gy in five fractions. The primary end-point, IBTR rate is now assessed at 10 years in the ITT population, as well as secondary endpoints: overall survival (OS), breast cancer specific survival (BCSS), distant metastasis free survival (DMFS), contralateral breast cancer (CBC), and locoregional recurrences (LRR). This trial is registered with ClinicalTrials.gov, number NCT02104895. Results. Of the 520 patients, 260 were enrolled in the APBI-arm and 260 in the WBI-arm; median age was 62.8 years (63.6 in the APBI and 61.6 in the WBI arm, p=0.20). Both treatment-arms achieved a median 10-year follow-up (10.1 in APBI-arm and 10.4 in WBI-arm, p=0.39) and were comparable regarding age, tumor size, grade, tumor type, and adjuvant endocrine treatment. No significant difference in terms of IBTR rates between treatment arms was shown (log rank test p=0.58). In the group who received APBI, the 5-year IBTR was 1.96% (5 events; 95% CI: 0.3;3.7) and the 10-year IBTR was 3.74% (9 events; 95% CI: 1.5;6.3). In the group who received WBI, the 5-year IBTR rate was 1.2% (3 events; 95% CI: 0;2.5) and the 10-year IBTR was 2.5% (6 events; 95% CI: 0.7;4.5). HR for APBI patients compared with WBI patients was 1.33 (p=0.58; 95% CI: 0.49;3.56). There were no significant differences between treatment arms regarding survival outcomes. OS (log rank test p=0.33): APBI 95.4% (95% CI: 93.6;97.2) versus WBI 94.3% (95% CI: 92.3;96.3); HR for APBI patients 0.66 (p=0.33; 95% CI: 0.29;1.53). BCSS (log rank test p=0.55): APBI 98% (95% CI: 96.8;99.2) versus WBI 97.5% (95% CI: 96.2;98.8); HR for APBI patients 0.68 (P=0.55; 95% CI: 0.19;2.42). DMFS (log rank test p=0.45): APBI 97.4% (95% CI: 96.0;98.8) versus WBI 96.1% (95% CI: 94.4;97.8); HR for APBI patients 0.67 (p=0.45; 95% CI: 0.24;1.89). Cumulative incidence estimates of 10-year LRR were 3.9% (95% CI: 2.24;5.56) for APBI versus 3.0% (95% CI: 1.53;4.47) for WBI (log rank test p=0.59). CBC observed after APBI were 5 (1.9%) as compared to 9 (3.5%) after WBI (p=0.42). Conclusion. IBTR rate after 10 years in patients with early breast cancer who were treated with APBI using IMRT technique in 5 fractions is rare and not significantly different from patients treated with WBI. OS, BCSS, DMFS, and LRR control are also comparable. Thus, APBI should be considered a reasonable alternative for a WBI in early breast cancer patients. Citation Format: Icro Meattini, Calogero Saieva, Sara Lucidi, Monica lo Russo, Vieri Scotti, Isacco Desideri, Livia Marrazzo, Gabriele Simontacchi, Monica Mangoni, Carlotta Becherini, Luca Visani, Lisa Paoletti, Erica Moretti, Luca Triggiani, Marco Bernini, Lorenzo Orzalesi, Luis Sanchez, Jacopo Nori, Stefania Pallotta, Simonetta Bianchi, Lorenzo Livi. Accelerated partial breast or whole breast irradiation after breast conservation surgery for patients with early breast cancer: 10-year follow up results of the APBI IMRT Florence randomized phase 3 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS4-06.

Background We investigated whether the pattern of intensity-modulated radiotherapy (IMRT) dose distribution to the skin can be correlated with the development of G3/G4 radiation dermatitis (RD). Methods A frequency-matched cohort analysis was perfomed on patients treated with IMRT and concurrent cisplatin or cetuximab. Risk ratios were obtained by fitting Poisson regression models. Results The incidence of G3/G4 RD was 41.1% in 90 patients included (50% vs 36.6% in the cetuximab and cisplatin cohorts, respectively). In multivariate analysis, PS ≥ 1 and weight loss at RT completion >10 kg were the only factors that retained significance. The best dosimetric predictive accuracy was provided by 19.9 cc and 5.8 cc of skin ring 2 mm V50 and V60, respectively (AUC: 0.61 for both). Conclusion Along with clinical factors, the pattern of dose distribution to a ring structure localized 2 mm below the patient's surface may help predict the development of severe RD.

Purpose The complexity of the modern Stereotactic Body Radiation Therapy (SBRT) techniques requires comprehensive quality assurance programs, to ensure the right treatment to the patient. Dosimetry of small radiation fields is a challenge especially for radiotherapy centres starting to work on this issue. The matter to be discussed here concerns the need of detailed measurement procedures and cross checks to be paired to the usual recommendations on detectors and correction factors. Materials and Methods The presented work involved 24 Italian radiotheraphy centres, with the specific purpose to minimize systematic errors in output factor measurements over different radiotherapy centres. Using the unshielded silicon diode IBA Razor, reference curves for the relative signal ratio (RSR) as a function of beam size were created for each Linac family. Results With this study we have demonstrated consistency of small field dosimetry on all the centres involved, moreover all radiotherapy centres using Razor are allowed to compare measurements amongst each other and centres with values deviating more than 5% from the reference curve are advised to repeat their measurements. With this procedure, some critical issues were detected from two centres in RSR measurements, that, if implemented into the own treatment planning system, would induce an unwanted overdosage larger than 5%. Conclusions The proposed approach could allow one to envision high-skilled therapy centres providing support to those featuring minor experience and could represent an important strategy for the clinical implementation of emerging technologies at high quality levels. The methodology adopted exploits crowd knowledge methods which could be applied in others areas of radiation dosimetry.

Purpose The present work aims to guide the physicist in order to start automated planning for the VMAT treatment of glioblastoma multiforme (GBM) by giving a recipe that was set up and tested during a long-term (two years) evaluation. Methods An automatic technique in AutoPlanning module of the Pinnacle3 (Philips Medical Systems, Fitchburg, WI) treatment planning system was created and validated by comparing dose distributions of automatic plans (APs) and manual plans (MPs) and by performing a blind AP-MP comparison on a cohort of 20 patients. Automatic technique was then applied to 145 patients and failures were recorded i.e. the number of times for which dose distributions produced by the automatic module were not suitable for treatment. Results Each of the 20 APs considered in the validation step was clinically acceptable and proved to be better (15 cases) or equal (5 cases) respect to MPs. A statistically significant improvement in brain stem, optic pathways, cochleae, pituitary gland and scalp sparing was observed for APs, while no statistically significant differences were recorded in target coverage or plan parameters. For only 5 cases out of the 145 plans the operator intervention was needed in order to obtain a clinical acceptable plan, while for the remaining 140 plans the automatic created solution was suitable. Conclusions A straightforward automatic procedure has been created and tested in our clinic. The AutoPlanning technique proposed represents a reliable tool to improve treatment planning efficiency and the recipe, here presented, could be simply imported to every radiotherapy center.

Purpose Patient-specific quality assurance (QA) is very important in radiotherapy, especially for patients with highly conformed treatment plans like VMAT plans. Traditional QA protocols for these plans are time-consuming reducing considerably the time available for patient treatments. In this work, a new MC-based secondary dose check software (SciMoCa) is evaluated and benchmarked against well-established TPS (Monaco and Pinnacle3 ) by means of treatment plans and dose measurements. Methods Fifty VMAT plans have been computed using same calculation parameters with SciMoCa and the two primary TPSs. Plans were validated with measurements performed with a 3D diode detector (ArcCHECK) by translating patient plans to phantom geometry. Calculation accuracy was assessed by measuring point dose differences and gamma passing rates (GPR) from a 3D gamma analysis with 3%-2 mm criteria. Comparison between SciMoCa and primary TPS calculations was made using the same estimators and using both patient and phantom geometry plans. Results TPS and SciMoCa calculations were found to be in very good agreement with validation measurements with average point dose differences of 0.7 ± 1.7% and -0.2 ± 1.6% for SciMoCa and two TPSs, respectively. Comparison between SciMoCa calculations and the two primary TPS plans did not show any statistically significant difference with average point dose differences compatible with zero within error for both patient and phantom geometry plans and GPR (98.0 ± 3.0% and 99.0 ± 3.0% respectively) well in excess of the typical 95 % clinical tolerance threshold. Conclusion This work presents results obtained with a significantly larger sample than other similar analyses and, to the authors' knowledge, compares SciMoCa with a MC-based TPS for the first time. Results show that a MC-based secondary patient-specific QA is a clinically viable, reliable, and promising technique, that potentially allows significant time saving that can be used for patient treatment and a per-plan basis QA that effectively complements traditional commissioning and calibration protocols.

We evaluate the combined usage of two systems, the Integral Quality Monitor (IQM) transmission detector and SoftDiso software, for in vivo dose monitoring by simultaneous detection of delivery and patient setup errors in whole breast irradiation. An Alderson RANDO phantom was adapted with silicon breast prostheses to mimic the female anatomy. Plans with simulated delivery errors were created from a reference left breast plan, and patient setup errors were simulated by moving the phantom. Deviations from reference values recorded by both monitoring systems were measured for all plans and phantom positions. A 2D global gamma analysis was performed in SoftDiso for all phantom displacements. Both IQM signals and SoftDiso R-values are sensitive to small MU variations. However, only IQM is sensitive to jaw position variations. Conversely, IQM is unable to detect patient positioning errors, and the R-value has good sensitivity to phantom displacements. A gamma comparison analysis allows one to determine alert thresholds to detect phantom shifts or relatively large rotations. The combined use of the IQM and SoftDiso allows for fast identification of both delivery and setup errors and substantially reduces the impact of error identification and correction on the treatment workflow.

Purpose: The use of optical surface systems (OSSs) for patient setup verification in external radiation therapy is increasing. To manage potential deformations in a patient’s anatomy, a novel deformable image registration (DIR) tool has been applied in a commercial OSS. In this study we investigate the accuracy of the DIR as compared to rigid image registration (RR). Methods and Materials: The positioning accuracy of the DIR and RR implemented in the OSS was investigated using an ad hoc-developed anthropomorphic deformable phantom, named Mary. The phantom consists of 33 slices of expanded polystyrene slabs shaped thus to simulate part of a female body. Anatomical details, simulating the ribs and spinal cord, together with 10 inner targets at different depths are included in thorax and abdominal parts. Mary is capable of realistic body movements and deformations, such as head and arm rotations, body torsion and moderate breast/abdomen swelling. The accuracy of DIR and RR was investigated for four internal targets after deliberately deforming the phantom nine times. Breast and abdomen enlargements and torsions around x, y, and z axes were applied. For reference purposes, rigid displacements (where Mary’s anatomy was kept intact) were included. The phantom was positioned on the linac couch under the OSS guidance and for each target and displacement a CBCT was acquired. The accuracy of DIR and RR was assessed evaluating the difference in means of absolute values between CBCT and the OSS registration parameters (lateral, longitudinal, vertical, rot, pitch, and roll), using both a reference surface extracted from CT (CTr) or acquired with the OSS (OSSr). A comparison of the four different combinations, DIR + OSSr, DIR + CTr, RR + OSSr, and RR + CTr, was carried out to evaluate the position accuracy for the various combinations. Finally, the positioning accuracy of the different target positions using only OSSr was investigated for the DIR. A paired sample Wilcoxon signed-rank test (P < 0.05) and a two-tailed Mann–Whitney test (P < 0.05) were carried out. Results: The DIR in combination with OSSr showed significantly (P < 0.05) improved positioning accuracy in the lateral and longitudinal directions and in pitch, compared to RR, when deformations were applied to Mary. The positioning accuracy improved from 1.9 ± 1.5 mm, 1.1 ± 0.8 mm to 1.1 ± 1.2 mm, 0.6 ± 0.5 mm in lateral and longitudinal directions, respectively, and from 0.8 ± 0.6° to 0.4 ± 0.4° in pitch, using DIR compared to RR. Both the DIR and RR showed a similar positioning accuracy when rigid displacements of Mary were applied. For DIR, the OSSr generally showed improved calculation accuracy compared to CTr. Independent of the reference image used, the target position influenced the registration accuracy, and hence, one target could not be evaluated using RR due to its inability to calculate the correct position. Conclusions: Improved positioning accuracy was observed for DIR with respect to RR when deformations of Mary’s anatomy were applied. For both DIR and RR, improved positioning accuracy was observed using OSSr as compared to CTr. The position of the target inside the phantom influenced the positioning accuracy for DIR. (Less)

Purpose: To determine dose constraints that correlate with alopecia in patients treated with photon-based Volumetric Modulated Arc Therapy (VMAT) for primary brain tumors. Methods: During the treatment planning process, the scalp was drawn as a region of interest. Dose received by 0.1 cc (D0.1cc), mean dose (Dmean), absolute volumes receiving different doses (V16Gy, V20Gy, V25Gy, V30Gy, V35Gy, V40Gy, and V43Gy) were registered for the scalp. Alopecia was assessed according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Receiver operating characteristics (ROC) curve analysis was used to identify parameters associated with hair-loss. Results: One-hundred and one patients were included in this observational study. At the end of radiotherapy (RT), 5 patients did not develop alopecia (Dmean scalp 3.1 Gy). The scalp of the patients with G1 (n = 11) and G2 (n = 85) alopecia received Dmean of 10.6 Gy and 11.8 Gy, respectively. At ROC analysis, V16Gy20Gy ≥ 5.2 cc were the strongest predictors of acute alopecia risk. Chronic hair-loss assessment was available for 74 patients: median time to recovery from G2 alopecia was 5, 9 months. The actuarial rate of hair regrowth was 98.1% at 18 months after the end of RT. At ROC analysis, V40Gy43Gy ≥2.2 cc were the strongest predictors of chronic G2-alopecia risk. V20Gy, V40Gy, and D0,1cc were shown to be independent variables according to correlation coefficient r. Conclusions: V20Gy and V40Gy were the strongest predictors for acute and chronic G2 hair-loss, respectively. The low-dose bath typical of VMAT corresponds to large areas of acute but transient alopecia. However, the steep dose gradient of VMAT allows to reduce the areas of the scalp that receive higher doses, minimizing the risk of permanent alopecia. The application of our dosimetric findings for the scalp may help in reducing the alopecia risk and also in estimating the probability of hair-loss during patient counseling before starting radiotherapy.

Quantitative analysis of biomedical images, referred to as radiomics, is emerging as a promising approach to facilitate clinical decisions and improve patient stratification. The typical radiomic workflow includes image acquisition, segmentation, feature extraction, and analysis of high-dimensional datasets. While procedures for primary radiomic analyses have been established in recent years, processing the resulting radiomic datasets remains a challenge due to the lack of specific tools for doing so. Here we present RadAR (Radiomics Analysis with R), a new software to perform comprehensive analysis of radiomic features. RadAR allows users to process radiomic datasets in their entirety, from data import to feature processing and visualization, and implements multiple statistical methods for analysis of these data. We used RadAR to analyze the radiomic profiles of more than 850 patients with cancer from publicly available datasets and showed that it was able to recapitulate expected results. These results demonstrate RadAR as a reliable and valuable tool for the radiomics community. Significance: A new computational tool performs comprehensive analysis of high-dimensional radiomic datasets, recapitulating expected results in the analysis of radiomic profiles of >850 patients with cancer from independent datasets.

In case of circumscribed recurrent glioblastoma (rec-GBM), a second surgery (Re-S) and reirradiation (Re-RT) are local strategies to consider. The aim is to provide an algorithm to use in the daily clinical practice. The first step is to consider the life expectancy in order to establish whether the patient should be a candidate for active treatment. In case of a relatively good life expectancy (>3 months) and a confirmed circumscribed disease(i.e. without multiple lesions that are in different lobes/hemispheres), the next step is the assessment of the prognostic factors for local treatments. Based on the existing prognostic score systems, patients who should be excluded from local treatments may be identified; based on the validated prognostic factors, one or the other local treatment may be preferred. The last point is the estimation of expected toxicity, considering patient-related, tumor-related and treatment-related factors impacting on side effects. Lastly, patients with very good prognostic factors may be considered for receiving a combined treatment.

Introduction: For a long time, accelerated partial breast irradiation (APBI) effectiveness for ductal carcinoma in situ (DCIS) has been debated, due to conflicting published results. Recent encouraging data from phase 3 trials reopened new perspectives for this radiation approach. The aim of the present study was to analyze the long-term efficacy and safety results of the series of patients with DCIS enrolled in the APBI arm of the APBI-IMRT-Florence phase 3 trial (NCT02104895). Methods: Patients were treated in a phase 3 randomized trial comparing whole breast irradiation (50 Gy in 25 fractions to the whole breast, plus 10 Gy in 5 fractions to the tumor bed) to APBI (30 Gy in 5 nonconsecutive fractions) using the intensity-modulated radiotherapy technique. Results: Overall, 22 patients were treated in the APBI arm. Median age was 62 years (mean 59; range 42–75 years). At a median follow-up of 9.2 years (mean 8.8; range 3.8–12.1 years), no contralateral invasive/DCIS occurrence, distant metastasis, or breast cancer–related death were recorded. The 5- and 10-year local recurrence, distant metastasis–free survival, and breast cancer–specific survival were 100%. The 10-year overall survival rate was 90.9%. No late toxicity at 5 and 10 years was recorded. Conclusions: Waiting for pending studies and mature follow-up, we confirmed the efficacy and safety of APBI for low-risk DCIS.

Highlights • Head and neck squamous cell carcinoma is an immune suppressive malignancy. • Conventional intensification strategies didn’t provide any incremental benefit. • Inhibiting the PD-1/PD-L1 checkpoint may synergize with cetuximab and radiotherapy., Introduction and background Head and neck squamous cell carcinoma (HNSCC) has been increasingly recognized as an immune suppressive malignancy. The efficacy of immune checkpoint inhibitors (ICI’s) in the context of recurrent/metastatic (R/M) setting anticipates the possible integration of immunotherapy into the therapeutic armamentarium of locally advanced disease. Durvalumab (DUR) is a humanized monoclonal IgG1, anti-PD-L1 antibody with promising data in R/M HNSCC. The aim of our study is to test the antitumor activity of a combined regimen incorporating an immune checkpoint inhibitor into a conventional bio-radiation strategy for the cure of unfavorable locally advanced HNSCC. Methods/design In this open label, multi-center, single-arm, phase I/II study, enrolled patients will receive Radiotherapy (RT) (69.9 Gy/2.12 Gy in 33 fractions) with concurrent Cetuximab (CTX) (400 mg/m2 1 week before RT start followed by 250 mg/m2 weekly) and DUR (fixed dose of 1500 mg every 4 weeks starting from RT-CTX week 1) followed by adjuvant DUR (to a maximum of 6 months after completion of RT-CTX). Primary endpoint of the study is 2-year progression-free survival (PFS). A safety run-in is planned after the enrollment of first 12, 24 and 36 patients. Patients affected by high-risk (≥N2a or ≥T3, any N) larynx, hypopharynx and HPV negative oropharynx or HPV-positive oropharynx (≥T2, ≥N2b, ≥10 pack/years) will be eligible. Discussion Conventional intensification strategies failed to provide any benefit for the cure of locally advanced HNSCC. For the still prevalent HPV-negative population and the high risk-HPV positive disease, there is an unmet need for alternative treatment paradigms. Potentially, the inhibition of the PD-1/PD-L1 checkpoint may synergize with both CTX and RT through immunologic interplay, ultimately aiming to reverse the HNSCC-induced immune suppression. The DUCRO study will seek to demonstrate if such a strategy may be safe and active. Trial registration NCT number: NCT03051906 Eudract number: 2016-004668-20

Background and purpose: Reported plan quality improvements with autoplanning of radiotherapy of the prostate and seminal vesicles are poor. A system for automated multi-criterial planning has been validated for this treatment in a large international multi-center study. The system is configured with training plans using a mechanism that strives for quality improvements relative to those plans. Material and methods: Each of the four participating centers included thirty manually generated clinical Volumetric Modulated Arc Therapy prostate plans (manVMAT). Ten plans were used for autoplanning training. The other twenty were compared with an automatically generated plan (autoVMAT). Plan evaluations considered dosimetric plan parameters and blinded side-by-side plan comparisons by clinicians. Results: With equivalent Planning Target Volume (PTV) V95%, D2%, D98%, and dose homogeneity autoVMAT was overall superior for rectum with median differences of 3.4 Gy (p

The aim of this study was to develop and apply an evaluation method for assessing the accuracy of a novel 3D EPID back-projection algorithm for in vivo dosimetry. The novel algorithm of Dosimetry Check (DC) 5.8 was evaluated. A slab phantom homogeneously filled, or with air and bone inserts, was used for fluence reconstruction of different squared fields. VMAT plans in different anatomical sites were delivered on an anthropomorphic phantom. Dose distributions were measured with radiochromic films. The 2D Gamma Agreement Index (GAI) between the DC and the film dose distributions (3%, 3 mm) was computed for assessing the accuracy of the algorithm. GAIs between films and TPS and between DC and TPS were also computed. The fluence reconstruction accuracy was within 2% for all squared fields in the three slabs’ configurations. The GAI between the DC and the film was 92.7% in the prostate, 92.9% in the lung, 96.6% in the head and the neck, and 94.6% in the brain. An evaluation method for assessing the accuracy of a novel EPID algorithm was developed. The DC algorithm was shown to be able to accurately reconstruct doses in all anatomic sites, including the lung. The methodology described in the present study can be applied to any EPID back-projection in vivo algorithm.

The 4D GRAPH-X (Dynamic GRAting-based PHase contrast x-ray imaging) project aims at developing a prototype of an x-ray grating-based phase-contrast imaging scanner in a laboratory setting, which is based on the Moirè single-shot acquisition method in order to be optimized for analysing moving objects (in the specific case, a dynamic thorax phantom), that could evolve into a suitable tool for biomedical applications although it can be extended to other application fields. When designing an x-ray Talbot-Lau interferometer, high visibility and sensitivity are two important figures of merit, strictly related to the performance of the system in obtaining high quality phase contrast and dark-field images. Wave field simulations are performed to optimize the setup specifications and construct a high-resolution and high-sensitivity imaging system. In this work, the design of a dynamic imaging setup using a conventional milli-focus x-ray source is presented. Optimization by wave front simulations leads to a symmetric configuration with 5.25 μm pitch at third Talbot order and 45 keV design energy. The simulated visibility is about 22%. Results from GATE based Monte Carlo simulations show a 19% transmission percentage of the incoming beam into the detector after passing through all the gratings and the sample. Such results are promising in view of building a system optimized for dynamic imaging.

Purpose We present the γTools, a new phantom designed to assess geometric and dosimetric accuracy in Gamma Knife treatments, together with first tests and results of applications. Methods The phantom is composed of two modules: the imaging module, a regular grid of 1660 control points to evaluate image distortions and image registration result and the dosimetry module for delivered dose distribution measurements. The phantom is accompanied by a MatLab routine for image distortions quantification. Dose measurement are performed with Gafchromic films fixed between two inserts and placed in various positions and orientations inside the dosimetry module thus covering a volume comparable to the full volume of a head. Results Tests performed to assess the accuracy and precision of the imaging module demonstrated sub-millimetric values. As an example of possible applications, the phantom was employed to measure image distortions of two MRI scanners and to perform dosimetric studies of single shots delivered to homogeneous and heterogeneous materials. Due to the phantom material, the measured absolute dose do not correspond to the planned dose; doses comparisons are thus carried out between normalized dose distributions. Finally, an end-to-end test was carried out in the treatment of a neuroma-like target which resulted in a 100% gamma passing rate (2% local, 2 mm) and a distance between the real target perimeter and the prescription isodose centroids of about 1 mm. Conclusions The tests demonstrate that the proposed phantom is suitable to assess both the geometrical and relative dosimetric accuracy of Gamma Knife radiosurgery treatments.

Because of its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-neoplastic properties, the PPAR-γ agonist rosiglitazone is an interesting drug for investigating for use in the prevention and treatment of radiation-induced intestinal damage. We aimed to evaluate the radioprotective effect of rosiglitazone in a murine model of acute intestinal damage, assessing whether radioprotection is selective for normal tissues or also occurs in tumour cells.Mice were total-body irradiated (12 Gy), with or without rosiglitazone (5 mg/kg/day). After 24 and 72 hours, mice were sacrificed and the jejunum was collected. HT-29 human colon cancer cells were irradiated with a single dose of 2 (1000 cells), 4 (1500 cells) or 6 (2000 cells) Gy, with or without adding rosiglitazone (20 µM) 1 hour before irradiation. HT-29-xenografted CD1 mice were irradiated (16 Gy) with or without rosiglitazone; tumour volumes were measured for 33 days.Rosiglitazone markedly reduced histological signs of altered bowel structures, that is, villi shortening, submucosal thickening, necrotic changes in crypts, oedema, apoptosis, and inflammatory infiltrate induced by irradiation. Rosiglitazone significantly decreased p-NF-kB p65 phosphorylation and TGFβ protein expression at 24 and 72 hours post-irradiation and significantly decreased gene expression ofRosiglitazone exerts a protective effect on normal tissues and reduces alterations in bowel structures and inflammation in a radiation-induced bowel toxicity model, without interfering with the radiation effect on HT-29 cancer cells. PPAR-γ agonists should be further investigated for their application in abdominal and pelvic irradiation.

Background. Accelerated partial breast irradiation (APBI) represents a valid option for selected early breast cancer (BC); potential advantages of APBI include shorter treatment time, improved safety profile, and a cost reduction compared with standard fractionation. We reported the final analysis of quality of life (QOL) results from a phase 3 randomized trial comparing standard adjuvant radiotherapy (50 Gy in 25 fractions, plus 10 Gy boost) to APBI using IMRT technique (30 Gy in 5 daily fractions). The 5-year results have been recently published showing equivalence in terms of local control (ClinicalTrials.gov, NCT02104895). Methods. Overall 205 patients (105 APBI and 100 WBI) fully completed the given questionnaires at time 0 (RT start), time 1 (RT end), and time 2 (2-year follow up). Patients were asked to compile two specific questionnaires on QOL, the EORTC QLQ-C30 as a reliable and valid measure of the QOL of cancer patients in multicultural clinical research settings, and the BR23 module as a supplementary questionnaire for assessing QOL issues relevant to patients with BC. The statistical software SPSS (SPSS Inc, Chicago, IL, USA) for Windows (version 22), and STATA (StataCorp LP, College Station TX77845, USA) for Windows (version 12) were used. Chi-squared test or Mann Whitney U test were used to compare the individual characteristics of the patients between two arms. Mean and standard deviations (SD) were calculated for all QOL domains, and all scores were compared between APBI and WBI arms using the Mann Whitney test due to non-parametric distribution of data. The Kruskal-Wallis test was used to compare the scores between age groups. Results. Mean values (and SD) of QLQ-C30 scores according to arm in the series of 205 BC patients at time 2 (time 0 vs time 2), showed significant improvement in favor of APBI in terms of global health status (mean 75.5 vs 59.5, SD range 13.3-22.0; p Conclusions. Women treated with APBI reported a significantly better QOL outcome as compared with women treated using WBI. QOL improvement was evidenced in terms of functional, symptoms, and global health status/QOL scales, both at the end of radiation and at a 2-year follow-up time. Citation Format: Meattini I, Saieva C, Desideri I, Miccinesi G, Francolini G, Meacci F, Muntoni C, Scotti V, De Luca Cardillo C, Marrazzo L, Simontacchi G, Pallotta S, Sanchez L, Casella D, Bernini M, Orzalesi L, Nori J, Bianchi S, Livi L. Accelerated partial breast irradiation versus whole breast irradiation: Health-related quality of life analysis from a phase 3 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-04.