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Background and Purpose: Stereotactic body radiation therapy (SBRT) has demonstrated safe and effective results for primary liver tumors. Magnetic Resonance guided Radiotherapy (MRgRT) is an innovative radiotherapy modality for abdominal tumors. The aim of this study is to report on acute and late toxicities and initial oncological results for primary liver tumors treated with MRgRT., Materials and Methods: We prospectively included in our cohort all patients treated by MRgRT for a primary liver tumor at the Montpellier Cancer Institute. The primary endpoint was acute and late toxicities assessed according to CTCAE v 5.0. The mean prescribed dose was 50 Gy in 5 fractions., Results: Between October 2019 and April 2022, MRgRT treated 56 patients for 72 primary liver lesions. No acute or late toxicities of CTCAE grade greater than 2 attributable to radiotherapy were noted during follow-up. No cases of radiation-induced liver disease (RILD), either classical or non-classical, occurred. After a median follow-up of 13.2 months (95% CI [8.8; 15.7]), overall survival was 85.1% (95% CI: [70.8; 92.7]) at 1 year and 74.2% at 18 months (95% CI [52.6; 87.0]). Local control was 98.1% (95% CI: [87.4; 99.7]) and 94.7% (95% CI: [79.5; 98.7]) at 12 and 18 months, respectively. Among the HCC subgroup, no local recurrences were observed., Conclusion: MRgRT for primary liver tumors is safe without severe adverse events and reach excellent local control. Numerous studies are underway to better assess the value of MRI guidance and adaptive process in these indications., 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 Elsevier B.V. All rights reserved.)

Background and Purpose: Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy., Materials and Methods: A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure., Results: Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10 -5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10 -8 ), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10 -10 ), rs75912034 (p = 1.12 × 10 -10 ), rs145328458 (p = 1.06 × 10 -9 ) and rs61966612 (p = 1.23 × 10 -9 ), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10 -8 ) and rs34063419 (p = 1.21 × 10 -8 ), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10 -8 ). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level., Conclusions: This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints., 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.)

Introduction: Previous studies showed that healthcare professionals and patients had only moderate to low agreement on their assessment of treatment-related symptoms. We aimed to determine the levels of agreement in a large cohort of prostate cancer patients., Methods: Analyses were made of data from 1,756 prostate cancer patients treated with external beam radiotherapy (RT) and/or brachytherapy in Europe and the USA and recruited into the prospective multicentre observational REQUITE study. Eleven pelvic symptoms at the end of RT were compared after translating patient-reported outcomes (PROs) into CTCAE-based healthcare professional ratings. Gwet's AC2 agreement coefficient and 95% confidence intervals were calculated for each symptom. To compare severity of grading between patients and healthcare professionals, percent agreement and deviations for each symptom were graphically depicted. Stratified and sensitivity analyses were conducted to identify potential influencing factors and to assess heterogeneity and robustness of results., Results: The agreement for the 11 pelvic symptoms varied from very good (AC2 > 0.8: haematuria, rectal bleeding, management of sphincter control) to poor agreement (AC2 ≤ 0.2: proctitis and urinary urgency). Fatigue had a negative impact on the agreement. Patients tended to grade symptoms more severely than healthcare professionals. Information on sexual dysfunction was missing more frequently in healthcare professional assessment than PROs., Conclusion: Agreement was better for observable than subjective symptoms, with patients usually grading symptoms more severely than healthcare professionals. Our findings emphasize that PROs should complement symptom assessment by healthcare professionals and be taken into consideration for clinical decision-making to incorporate the patient perspective., 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. Conflict of Interest D. Azria: none related to the current manuscript. Outside the current manuscript: involved in the creation of the start-up NovaGray in 2015. D. De Ruysscher: none related to the current manuscript. Outside the current manuscript: advisory board of Astra Zeneca, Bristol-Myers-Squibb, Roche/Genentech, Merck/Pfizer, Celgene, Noxxon, Mologen and has received investigator initiated grants from Bristol-Myers-Squibb, Boehringer Ingelheim and Astra-Zeneca. E. Sperk: none related to the current manuscript. Outside the current manuscript: Lecture honoraria Zeiss Meditec Ag, travel support Zeiss Meditec AG., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: To investigate the association between clinician-scored toxicities and patient-reported health-related quality of life (HRQoL), in early-stage (ES-) and locally-advanced (LA-) non-small cell lung cancer (NSCLC) patients receiving loco-regional radiotherapy, included in the international real-world REQUITE study., Materials and Methods: Clinicians scored eleven radiotherapy-related toxicities (and baseline symptoms) with the Common Terminology Criteria for Adverse Events version 4. HRQoL was assessed with the European Organization for Research and Treatment of Cancer core HRQoL questionnaire (EORTC-QLQ-C30). Statistical analyses used the mixed-model method; statistical significance was set at p = 0.01. Analyses were performed for baseline and subsequent time points up to 2 years after radiotherapy and per treatment modality, radiotherapy technique and disease stage., Results: Data of 435 patients were analysed. Pre-treatment, overall symptoms, dyspnea, chest wall pain, dysphagia and cough impacted overall HRQoL and specific domains. At subsequent time points, cough and dysphagia were overtaken by pericarditis in affecting HRQoL. Toxicities during concurrent chemo-radiotherapy and 3-dimensional radiotherapy had the most impact on HRQoL. Conversely, toxicities in sequential chemo-radiotherapy and SBRT had limited impact on patients' HRQoL. Stage impacts the correlations: LA-NSCLC patients are more adversely affected by toxicity than ES-NSCLC patients, mimicking the results of radiotherapy technique and treatment modality., Conclusion: Pre-treatment symptoms and acute/late toxicities variously impact HRQoL of ES- and LA-NSCLC patients undergoing different treatment approaches and radiotherapy techniques. Throughout the disease, dyspnea seems crucial in this association, highlighting the additional effect of co-existing comorbidities. Our data call for optimized radiotherapy limiting toxicities that may affect patients' HRQoL., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Genome-wide association studies (GWAS) of late hematuria following prostate cancer radiotherapy identified single nucleotide polymorphisms (SNPs) near AGT, encoding angiotensinogen. We tested the hypothesis that patients taking angiotensin converting enzyme inhibitors (ACEi) have a reduced risk of late hematuria. We additionally tested genetically-defined hypertension., Materials and Methods: Prostate cancer patients undergoing potentially-curative radiotherapy were enrolled onto two multi-center observational studies, URWCI (N = 256) and REQUITE (N = 1,437). Patients were assessed pre-radiotherapy and followed prospectively for development of toxicity for up to four years. The cumulative probability of hematuria was estimated by the Kaplan-Meier method. Multivariable grouped relative risk models assessed the effect of ACEi on time to hematuria adjusting for clinical factors and stratified by enrollment site. A polygenic risk score (PRS) for blood pressure was tested for association with hematuria in REQUITE and our Radiogenomics Consortium GWAS., Results: Patients taking ACEi during radiotherapy had a reduced risk of hematuria (HR 0.51, 95%CI 0.28 to 0.94, p = 0.030) after adjusting for prior transurethral prostate and/or bladder resection, heart disease, pelvic node radiotherapy, and bladder volume receiving 70 Gy, which are associated with hematuria. A blood pressure PRS was associated with hypertension (odds ratio per standard deviation 1.38, 95%CI 1.31 to 1.46, n = 5,288, p < 0.001) but not hematuria (HR per standard deviation 0.96, 95%CI 0.87 to 1.06, n = 5,126, p = 0.41)., Conclusions: Our study is the first to show a radioprotective effect of ACEi on bladder in an international, multi-site study of patients receiving pelvic radiotherapy. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects the bladder., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: To describe the quality assurance (QA) program and early toxicities in the phase III randomized trial BONBIS (NCT00907868) on the role of a localized radiation boost in ductal carcinoma in situ (DCIS)., Materials and Methods: From November 2008 to July 2014, 2004 patients were randomized in arm A (only whole breast radiotherapy, WBRT) and arm B (WBRT + boost). The QA program involved 44 participant centers that performed the dummy run (DR). Compliance and uniformity of clinical target volume (CTV) delineations, and dose prescription and delivery according to the BONBIS trial radiotherapy guidelines were analyzed. Acute toxicities (during and up to 3 months after radiotherapy completion, NCI-CTCAE v3.0 classification) were evaluated in 1929 patients., Results: The differences in whole breast CTV (CTV1) and planning target volume (PTV1) were ≤10%, and the differences in boost CTV (CTV2) and PTV (PTV2) were ≥20% compared with the reference DR values; 95% of the prescribed dose encompassed 98.7% and 100% of the median CTV1 and CTV2. Grade ≥2 breast erythema (38.3% vs. 22.4% of grade 2 and 5.4% vs. 2.1% of grade 3, p < 0.001), grade ≥2 dermatitis (2.8% vs. 0.7%, p < 0.001), and grade 2 hyperpigmentation (6.9% vs. 3.6%, p = 0.005) were more frequent in arm B than arm A. No acute lung or cardiac toxicity was observed. Smoking history, large breast size, and large breast CTV were strong predictive factors of grade ≥2 acute skin toxicities., Conclusions: The QA program showed deviations in breast and tumor bed delineation. The boost significantly increased acute skin toxicities., Competing Interests: Conflict of interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Curative radio-chemotherapy is recognized as a standard treatment option for muscle-invasive bladder cancer (MIBC). Nevertheless, the technical aspects for MIBC radiotherapy are heterogeneous with a lack of practical recommendations., Methods and Materials: In 2018, a workshop identified the need for two cooperative groups to develop consistent, evidence-based guidelines for irradiation technique in the delivery of curative radiotherapy. Two radiation oncologists performed a review of the literature addressing several topics relative to radical bladder radiotherapy: planning computed tomography acquisition, target volume delineation, radiation schedules (total dose and fractionation) and dose delivery (including radiotherapy techniques, image-guided radiotherapy (IGRT) and adaptive treatment modalities). Searches for original and review articles in the PubMed and Google Scholar databases were conducted from January 1990 until March 2020. During a meeting conducted in October 2020, results on 32 topics were presented and discussed with a working group involving 15 radiation oncologists, 3 urologists and one medical oncologist. We applied the American Urological Association guideline development's method to define a consensus strategy., Results: A consensus was obtained for all 34 except 4 items. The group did not obtain an agreement on CT enhancement added value for planning, PTV margins definition for empty bladder and full bladder protocols, and for pelvic lymph-nodes irradiation. High quality evidence was shown in 6 items; 8 items were considered as low quality of evidence., Conclusion: The current recommendations propose a homogenized modality of treatment both for routine clinical practice and for future clinical trials, following the best evidence to date, analyzed with a robust methodology. The XXX group formulates practical guidelines for the implementation of innovative techniques such as adaptive radiotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: To identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi)., Materials and Methods: Analysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream. Among 43 literature-identified SNPs, the 30% most strongly associated with each toxicity were tested. SNP-SNP combinations (named SNP-allele sets) seen in ≥10% of the cohort were condensed into risk (RS) and protection (PS) scores, respectively indicating increased or decreased toxicity risk. Performance of RS and PS was evaluated by logistic regression. RS and PS were then combined into a single PRSi evaluated by area under the receiver operating characteristic curve (AUC)., Results: Among 1,387 analysed patients, toxicity rates were 11.7% (rectal bleeding), 4.0% (urinary frequency), 5.5% (haematuria), 7.8% (nocturia) and 17.1% (decreased urinary stream). RS and PS combined 8 to 15 different SNP-allele sets, depending on the toxicity endpoint. Distributions of PRSi differed significantly in patients with/without toxicity with AUCs ranging from 0.61 to 0.78. PRSi was better than the classical summed PRS, particularly for the urinary frequency, haematuria and decreased urinary stream endpoints., Conclusions: Our method incorporates SNP-SNP interactions when calculating PRS for radiotherapy toxicity. Our approach is better than classical summation in discriminating patients with toxicity and should enable incorporating genetic information to improve normal tissue complication probability models., 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 © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Online magnetic resonance-guided radiotherapy (oMRgRT) represents one of the most innovative applications of current image-guided radiation therapy (IGRT). The revolutionary concept of oMRgRT systems is the ability to acquire MR images for adaptive treatment planning and also online imaging during treatment delivery. The daily adaptive planning strategies allow to improve targeting accuracy while avoiding critical structures. This ESTRO-ACROP recommendation aims to provide an overview of available systems and guidance for best practice in the implementation phase of hybrid MR-linac systems. Unlike the implementation of other radiotherapy techniques, oMRgRT adds the MR environment to the daily practice of radiotherapy, which might be a new experience for many centers. New issues and challenges that need to be thoroughly explored before starting clinical treatments will be highlighted., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: To assess the long-term outcomes of patients with squamous cell carcinoma of the anal canal (SCCAC) treated with Intensity-Modulated Radiation Therapy (IMRT)., Material and Methods: From 2007 to 2015, 193 patients were treated by IMRT for SCCAC. Radiotherapy delivered 45 Gy in 1.8 Gy daily-fractions to the primary tumor and elective nodal areas, immediately followed by a boost of 14.4-20 Gy to the primary tumor and involved nodes. Concurrent chemotherapy with 5-FU-mitomycin (MMC) or cisplatin was added for locally advanced tumors. Survivals were estimated by Kaplan-Meier method. Locoregional (LR) relapses were precisely assessed. Prognostic factors were evaluated by uni- and multivariate analyses. Late toxicity was scored according to the Common Toxicity Criteria for Adverse Events v4.0., Results: Median follow-up was 70 months (range, 1-131). Forty-nine men (25%) and 144 women (75%) were analyzed. Median age was 62 years. Tumor stages were I, II, III and IV in 7%, 24%, 63% and 6% of cases, respectively. Chemotherapy was delivered in 167 patients (87%), mainly MMC (80%). Five-year OS, DFS, CFS and LR control rates were 74%, 68%, 66% and 85%, respectively. Forty-one patients (21%) had a relapse: 22 were LR, mostly in-field (68%). Predictors for LR failure were exclusive radiotherapy, chemotherapy lacking MMC and treatment breaks >3 days. Overall late toxicity ≥grade 2 occurred in 43% of patients, with 24% grade 3 and one case of grade 4 (hematuria)., Conclusion: CRT with IMRT assures excellent local control in locally advanced SCCAC with manageable long-term toxicity. Multicentric prospective trials are required to reinforce those results., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data., Methods: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated., Results: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ≥2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung)., Conclusion: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers., Patient Summary: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: To evaluate the benefit of independent component analysis (ICA)-based models for predicting rectal bleeding (RB) following prostate cancer radiotherapy., Materials and Methods: A total of 593 irradiated prostate cancer patients were prospectively analyzed for Grade ≥2 RB. ICA was used to extract two informative subspaces (presenting RB or not) from the rectal DVHs, enabling a set of new pICA parameters to be estimated. These DVH-based parameters, along with others from the principal component analysis (PCA) and functional PCA, were compared to "standard" features (patient/treatment characteristics and DVH bins) using the Cox proportional hazards model for RB prediction. The whole cohort was divided into: (i) training (N = 339) for ICA-based subspace identification and Cox regression model identification and (ii) validation (N = 254) for RB prediction capability evaluation using the C-index and the area under the receiving operating curve (AUC), by comparing predicted and observed toxicity probabilities., Results: In the training cohort, multivariate Cox analysis retained pICA and PC as significant parameters of RB with 0.65 C-index. For the validation cohort, the C-index increased from 0.64 when pICA was not included in the Cox model to 0.78 when including pICA parameters. When pICA was not included, the AUC for 3-, 5-, and 8-year RB prediction were 0.68, 0.66, and 0.64, respectively. When included, the AUC increased to 0.83, 0.80, and 0.78, respectively., Conclusion: Among the many various extracted or calculated features, ICA parameters improved RB prediction following prostate cancer radiotherapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The optimal design and patient selection for interventional trials in radiogenomics seem trivial at first sight. However, radiogenomics do not give binary information like in e.g. targetable mutation biomarkers. Here, the risk to develop severe side effects is continuous, with increasing incidences of side effects with higher doses and/or volumes. In addition, a multi-SNP assay will produce a predicted probability of developing side effects and will require one or more cut-off thresholds for classifying risk into discrete categories. A classical biomarker trial design is therefore not optimal, whereas a risk factor stratification approach is more appropriate. Patient selection is crucial and this should be based on the dose-response relations for a specific endpoint. Alternatives to standard treatment should be available and this should take into account the preferences of patients. This will be discussed in detail., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Several small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium., Materials and Methods: The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity., Results: For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance., Conclusion: This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Although radical cystectomy is still considered the standard of care for most localized muscle-invasive bladder cancer (MIBC) patients, bladder-sparing strategies with chemoradiotherapy have demonstrated comparable local control and survival rates when adjusting for tumor stage. We present a pooled analysis of individual patient data out of published trials with gemcitabine-based chemoradiotherapy for MIBC., Methods and Materials: Individual patient data were collected from Institutions that enrolled patients into trials that evaluated gemcitabine-based chemoradiotherapy for MIBC., Results: We identified eight studies published on gemcitabine-based radiochemotherapy and 190 patients were included in this analysis. A complete response (CR) was observed in 166 patients (93%). After a median follow up of 44.5months, 36 patients (18.9%) presented a bladder recurrence and 14 subsequently underwent cystectomy. The 5-year overall survival (OS), disease-specific survival (DSS), and cystectomy-free survival (CFS) rates were 59%, 80.9%, and 93.3%, respectively. The achievement of CR after chemoradiotherapy was the main prognostic variable which was associated with improved OS, DSS, and CFS. The treatment was well tolerated., Conclusion: This pooled analysis strengthens the evidence that chemoradiotherapy regimens with concurrent gemcitabine are feasible and well tolerated. Prospective randomized controlled trials are on-going to definitively assess the efficacy of gemcitabine-based chemoradiotherapy for MIBC., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: In planning to meet evidence based needs for radiotherapy, guidelines for the provision of capital and human resources are central if access, quality and safety are not to be compromised. A component of the ESTRO-HERO (Health Economics in Radiation Oncology) project is to document the current availability and content of guidelines for radiotherapy in Europe., Materials and Methods: An 84 part questionnaire was distributed to the European countries through their national scientific and professional radiotherapy societies with 30 items relating to the availability of guidelines for equipment and staffing and selected operational issues. Twenty-nine countries provided full or partial evaluable responses., Results: The availability of guidelines across Europe is far from uniform. The metrics used for capital and human resources are variable. There seem to have been no major changes in the availability or specifics of guidelines over the ten-year period since the QUARTS study with the exception of the recent expansion of RTT staffing models. Where comparison is possible it appears that staffing for radiation oncologists, medical physicists and particularly RTTs tend to exceed guidelines suggesting developments in clinical radiotherapy are moving faster than guideline updating., Conclusion: The efficient provision of safe, high quality radiotherapy services would benefit from the availability of well-structured guidelines for capital and human resources, based on agreed upon metrics, which could be linked to detailed estimates of need., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target., Methods: The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes., Results: In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals., Conclusion: Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Despite publication of numerous radiogenomics studies to date, positive single nucleotide polymorphism (SNP) associations have rarely been reproduced in independent validation studies. A major reason for these inconsistencies is a high number of false positive findings because no adjustments were made for multiple comparisons. It is also possible that some validation studies were false negatives due to methodological shortcomings or a failure to reproduce relevant details of the original study. Transparent reporting is needed to ensure these flaws do not hamper progress in radiogenomics. In response to the need for improving the quality of research in the area, the Radiogenomics Consortium produced an 18-item checklist for reporting radiogenomics studies. It is recognised that not all studies will have recorded all of the information included in the checklist. However, authors should report on all checklist items and acknowledge any missing information. Use of STROGAR guidelines will advance the field of radiogenomics by increasing the transparency and completeness of reporting., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Rectal cancer predominantly affects the elderly. Unfortunately, this age category is under-represented in clinical trials because clinicians are loath to include patients with a high risk of comorbidity., Patients and Methods: An exploratory analysis of the ACCORD12/PRODIGE 2 phase III trial was carried out to retrospectively compare the benefit of neoadjuvant chemotherapy between the elderly (≥70 years; n=142) and younger patients (<70 years; n=442), this analysis was not preplanned in the study protocol. Patients with histologically confirmed resectable stage T3 or T4 rectal adenocarcinoma were eligible with an age limit of 80 years., Results: Overall, the two age categories did not statistically differ in terms of patient's clinical and tumor baseline characteristics. Preoperative chemoradiotherapy leads to more severe grade 3/4 toxicities (25.6% vs. 15.8%, p=0.01) and more permanent stomas (33.3% vs. 22.8%, p=0.014) in elderly patients who were less often operated on than younger patients (95.8% vs. 99.0%, p=0.008). The relative number of interventions per surgery type (p=0.18), treatment efficacy in terms of R0 resection rate (88.6% vs. 90.6%; p=0.54) and complete pathological response (14.7% vs. 16.9%; p=0.55) were nearly identical between the two categories., Conclusion: Altogether these results warrant the development of specific optimal therapeutic strategies for the elderly., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To compare the dose coverage of planning and clinical target volume (PTV, CTV), and organs-at-risk (OAR) between intensity-modulated (3D-IMRT) and conventional conformal radiotherapy (3D-CRT) before and after internal organ variation in prostate cancer., Methods and Materials: We selected 10 patients with clinically significant interfraction volume changes. Patients were treated with 3D-IMRT to 80 Gy (minimum PTV dose of 76 Gy, excluding rectum). Fictitious, equivalent 3D-CRT plans (80 Gy at isocenter, with 95% isodose (76 Gy) coverage of PTV, with rectal blocking above 76 Gy) were generated using the same planning CT data set ("CT planning"). The plans were then also applied to a verification CT scan ("CT verify") obtained at a different moment. PTV, CTV, and OAR dose coverage were compared using non-parametric tests statistics for V95, V90 (% of the volume receiving 95 or 90% of the dose) and D50 (dose to 50% of the volume)., Results: Mean V95 of the PTV for "CT planning" was 94.3% (range, 88-99) vs 89.1% (range, 84-94.5) for 3D-IMRT and 3D-CRT (p=0.005), respectively. Mean V95 of the CTV for "CT verify" was 97% for both 3D-IMRT and 3D-CRT. Mean D50 of the rectum for "CT planning" was 26.8 Gy (range, 22-35) vs 43.5 Gy (range, 33.5-50.5) for 3D-IMRT and 3D-CRT (p=0.0002), respectively. For "CT verify", this D50 was 31.1 Gy (range, 16.5-44) vs 44.2 Gy (range, 34-55) for 3D-IMRT and 3D-CRT (p=0.006), respectively. V95 of the rectum was 0% for both plans for "CT planning", and 2.3% (3D-IMRT) vs 2.1% (3D-CRT) for "CT verify" (p=non-sig.)., Conclusion: Dose coverage of the PTV and OAR was better with 3D-IMRT for each patient and remained so after internal volume changes.

Background and Purpose: To assess the feasibility and efficacy of accelerated 66-Gy postoperative radiotherapy (PORT) using a single-fraction regimen from Mondays to Thursdays and a concomitant boost on Friday afternoon sessions in patients with locally advanced head and neck cancer (LAHNC)., Patients and Methods: Between December 1997 and June 2002, 89 consecutive patients with pT1-pT4 and/or pN0-pN3 LAHNC were included. PORT was indicated in patients with positive surgical margins, T4 tumors, or extracapsular nodal infiltration. RT consisted of 66 Gy (2 Gy/fr) in 5 weeks and 3 days. Median follow-up was 21 months (range 2-59)., Results: Acute morbidity was acceptable: grade 3 mucositis in 20 (22%) patients, grade 3 dysphagia in 22 (25%) patients, and grade 3 skin erythema in 18 (20%) patients. Median weight loss was 2 kg (range 0-14.5). No grade 4 toxicity was observed. Late effects included grade 3 xerostomia in 6 (7%) patients, and grade 3 edema in 2 (2%) patients. Median time to locoregional relapse was 10 months (range 2-21). Two-year overall, cause-specific, and disease-free survival rates were 70% (95% confidence interval (CI) 59-81), 75% (95% CI 64-86), and 63% (95% CI 52-74), respectively. The 2-year actuarial locoregional control rate was 80% (95% CI 70-90). Distant metastasis probability at 4 years was 38% (95% CI 20-56). Multivariate analysis revealed that pT-classification (pT1-2 vs. pT3-4) and extranodal extension (0, 1 vs. 2 or more) were the two factors independently influencing the outcome., Conclusions: We conclude that reducing the overall treatment time using an accelerated PORT schedule including a once-weekly concomitant boost (six fractions per week) is easily feasible with excellent local control. Acute and late RT-related morbidity is acceptable. Given the disease progression pattern (distant metastases), adjuvant chemotherapy should be considered.