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Simple Summary: Studies comparing performances of machine learning (ML) methods in building predictive models of toxicity in RT are rare. Thanks to the availability of a large cohort (n = 1314) of breast cancer patients homogeneously treated with tangential fields, different ML approaches could be compared. This work shows how more complex models typically achieve higher performances. At the same time, for this test case, the importance is given mainly by a few variables, and toxicity can be predicted by simpler models with similar performances. The availability of more individually characterizing features (here partially missing) is expected to have a likely much higher impact than the choice of the best-performing ML/DL approach. Purpose. Different ML models were compared to predict toxicity in RT on a large cohort (n = 1314). Methods. The endpoint was RTOG G2/G3 acute toxicity, resulting in 204/1314 patients with the event. The dataset, including 25 clinical, anatomical, and dosimetric features, was split into 984 for training and 330 for internal tests. The dataset was standardized; features with a high p-value at univariate LR and with Spearman ρ > 0.8 were excluded; synthesized data of the minority were generated to compensate for class imbalance. Twelve ML methods were considered. Model optimization and sequential backward selection were run to choose the best models with a parsimonious feature number. Finally, feature importance was derived for every model. Results. The model's performance was compared on a training–test dataset over different metrics: the best performance model was LightGBM. Logistic regression with three variables (LR3) selected via bootstrapping showed performances similar to the best-performing models. The AUC of test data is slightly above 0.65 for the best models (highest value: 0.662 with LightGBM). Conclusions. No model performed the best for all metrics: more complex ML models had better performances; however, models with just three features showed performances comparable to the best models using many (n = 13–19) features. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to study the evolution of quality of life (QoL) in the first 5 years following Intensity-modulated radiation therapy (IMRT) for prostate cancer (PCa) and to determine possible associations with clinical/treatment data. Material and methods: Patients were enrolled in a prospective multicentre observational trial in 2010-2014 and treated with conventional (74–80 Gy, 1.8–2 Gy/fr) or moderately hypofractionated IMRT (65–75.2 Gy, 2.2–2.7 Gy/fr). QoL was evaluated by means of EORTC QLQ-C30 at baseline, at radiation therapy (RT) end, and every 6 months up to 5 years after IMRT end. Fourteen QoL dimensions were investigated separately. The longitudinal evaluation of QoL was analysed by means of Analysis of variances (ANOVA) for multiple measures. Results: A total of 391 patients with complete sets of questionnaires across 5 years were available. The longitudinal analysis showed a trend toward the significant worsening of QoL at RT end for global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. QoL worsening was recovered within 6 months from RT end, with the only exception being physical functioning. Based on ANOVA, the most impaired time point was RT end. QoL dimension analysis at this time indicated that acute Grade ≥ 2 gastrointestinal (GI) toxicity significantly impacted global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. Acute Grade ≥ 2 genitourinary (GU) toxicity resulted in lower role functioning and higher pain. Prophylactic lymph-nodal irradiation (WPRT) resulted in significantly lower QoL for global health, fatigue, appetite loss, and diarrhoea; lower pain with the use of neoadjuvant/concomitant hormonal therapy; and lower fatigue with the use of an anti-androgen. Conclusions: In this prospective, longitudinal, observational study, high radiation IMRT doses delivered for PCa led to a temporary worsening of QoL, which tended to be completely resolved at six months. Such transient worsening was mostly associated with acute GI/GU toxicity, WPRT, and higher prescription doses. [ABSTRACT FROM AUTHOR]

To evaluate the persistence of symptoms after radiotherapy (RT) for localised prostate cancer (PCa) and the association with quality of life (QOL). Prospective patient-reported outcome (PRO) from a multi-institutional study on PCa treated with radical RT (2010–2014) was analysed. Data was collected at baseline (BL) and follow-ups (FUPs) up to 5 years. Patients with BL and ≥3 late FUPs (≥6 months) were analysed. PRO was scored by means of the IPSS and ICIQ-SF (urinary), LENT-SOMA (gastrointestinal [GI]), and EORTC-C30 (pain, insomnia, fatigue, and QOL) questionnaires. Symptoms were defined 'persistent' if the median score over FUPs was ≥3 (urinary) or ≥2 (GI, pain, insomnia, and fatigue), and worse than BL. Different thresholds were chosen to have enough events for each symptom. QOL was linearly transformed on a continuous scale (0–100). Linear-mixed models were used to identify significant differences between groups with and without persistent symptoms including age, smoking status, previous abdominal surgery, and diabetes as confounders. Mean QOL differences between groups were evaluated longitudinally over FUPs. The analysis included 293 patients. Persistent urinary symptoms ranged from 2% (straining) to 12% (weak stream, and nocturia). Gastrointestinal symptoms ranged from 7% (rectal pain, and incontinence) to 30% (urgency). Proportions of pain, insomnia, and fatigue were 6, 13, and 18%. Significant QOL differences of small-to-medium clinical relevance were found for urinary incontinence, frequency, urgency, and nocturia. Among GI symptoms, rectal pain and incontinence showed small-to-medium differences. Fatigue was associated with the largest differences. The analysis showed that symptoms after RT for PCa occur with different persistence and their association with QOL varies in magnitude. A number of persistent urinary and GI symptoms showed differences in a comparable range. Urinary incontinence and frequency, rectal pain, and faecal incontinence more often had significant associations. Fatigue was also prevalent and associated with largely deteriorated QOL. [ABSTRACT FROM AUTHOR]

Fatigue is common in breast‐cancer survivors. Our study assessed fatigue longitudinally in breast cancer patients receiving adjuvant radiotherapy (RT) and aimed to identify risk factors associated with long‐term fatigue and underlying fatigue trajectories. Fatigue was measured in a prospective multicenter cohort (REQUITE) using the Multidimensional Fatigue Inventory (MFI‐20) and analyzed using mixed models. Multivariable logistic models identified factors associated with fatigue dimensions at 2 years post‐RT and latent class growth analysis identified individual fatigue trajectories. A total of 1443, 1302, 1203 and 1098 patients completed the MFI‐20 at baseline, end of RT, after 1 and 2 years. Overall, levels of fatigue significantly increased from baseline to end of RT for all fatigue dimensions (P <.05) and returned to baseline levels after 2 years. A quarter of patients were assigned to latent trajectory high (23.7%) and moderate (24.8%) fatigue classes, while 46.3% and 5.2% to the low and decreasing fatigue classes, respectively. Factors associated with multiple fatigue dimensions at 2 years include age, BMI, global health status, insomnia, pain, dyspnea and depression. Fatigue present at baseline was consistently associated with all five MFI‐20 fatigue dimensions (ORGeneralFatigue = 3.81, P <.001). From latent trajectory analysis, patients with a combination of factors such as pain, insomnia, depression, younger age and endocrine therapy had a particularly high risk of developing early and persistent high fatigue years after treatment. Our results confirmed the multidimensional nature of fatigue and will help clinicians identify breast cancer patients at higher risk of having persistent/late fatigue so that tailored interventions can be delivered. [ABSTRACT FROM AUTHOR]

This document is a reply to comments on a previously published paper about the risk factors for fatigue in breast cancer patients who have undergone radiotherapy. The authors explain that they focused on late fatigue because there is a lack of understanding about this aspect of fatigue in breast cancer patients. They also address concerns about missing data and attrition rates in their study, stating that mortality did not substantially influence the attrition rate. The authors express gratitude for the opportunity to discuss their research and express interest in future collaborations to further understand fatigue in breast cancer patients. [Extracted from the article]

Purpose: According to ASTRO and ESTRO guidelines, external beam Partial Breast Irradiation (PBI) is a valid option for early-stage breast cancer patients. Nevertheless, there is lack of consensus about the best treatment schedule. Methods: We retrospectively analysed data of female patients treated at our institution from 2013 to 2022 with adjuvant "one-week" partial breast irradiation. Clinical Target Volume (CTV) was an isotropic expansion of 15 mm from the tumour bed (identified as the breast tissue between surgical clips). The treatment schedule was 30 Gy delivered with Volumetric Modulated Arc Therapy in 5 daily fractions. The primary endpoint was Local Control (LC). Disease-Free Survival (DFS), Overall Survival (OS) and safety were secondary endpoints. Results: Three hundred and forty-four patients with a median age of 69 (33–87) years were included in the study. After a median follow-up of 34 (7–105) months, 7 patients (2.0%) developed a local recurrence. Three-year LC, DFS and OS actuarial rates were 97.5% (95% CI 96.2%–98.8%), 95.7% (95% CI 94.2%–97.2%), and 96.9% (95% CI 95.7%–98.1%), respectively. Ten (2.9%) patients experienced grade 2 late toxicities. Five (1.5%) patients reported late cardiac major events. Three (0.9%) late pulmonary toxicities were detected. One hundred and five (30.5%) patients reported fat necrosis. Good or excellent cosmetic evaluation following the Harvard Scale was reported in 252 (96.9%) cases by the physicians, while in 241 (89.2%) cases by the patients. Conclusion: "One-week" PBI is effective and safe, and this schedule is a valid option for highly selected early breast cancer patients. [ABSTRACT FROM AUTHOR]

Most patients receive whole breast radiotherapy in a supine position. However, two randomised trials showed lower acute toxicity in prone position. Furthermore, in most patients, prone positioning reduced doses to the organs at risk. To confirm these findings, we compared toxicity outcomes, photographic assessment, and dosimetry between both positions using REQUITE data. REQUITE is an international multi-centre prospective observational study that recruited 2069 breast cancer patients receiving radiotherapy. Data on toxicity, health-related quality of life (HRQoL), and dosimetry were collected, as well as a photographic assessment. A matched case control analysis compared patients treated prone (n = 268) versus supine (n = 493). Exact matching was performed for the use of intensity-modulated radiotherapy, boost, lymph node irradiation, chemotherapy and fractionation, and the nearest neighbour for breast volume. Primary endpoints were dermatitis at the end of radiotherapy, and atrophy and cosmetic outcome by photographic assessment at two years. At the last treatment fraction, there was no significant difference in dermatitis (p =.28) or any HRQoL domain, but prone positioning increased the risk of breast oedema (p <.001). At 2 years, patients treated in prone position had less atrophy (p =.01), and higher body image (p <.001), and social functioning (p <.001) scores. The photographic assessment showed no difference in cosmesis at 2 years (p =.22). In prone position, mean heart dose (MHD) was significantly lower for left-sided patients (1.29 Gy vs 2.10 Gy, p <.001) and ipsilateral mean lung dose (MLD) was significantly lower for all patients (2.77 Gy vs 5.89 Gy, p <.001). Prone radiotherapy showed lower MLD and MHD compared to supine position, although the risk of developing breast oedema during radiotherapy was higher. At 2 years the photographic assessment showed no difference in the cosmetic outcome, but less atrophy was seen in prone-treated patients and this seems to have a positive influence on the HRQoL domain of body image. [ABSTRACT FROM AUTHOR]

Three‐dimensional (3D) imaging techniques (e.g., confocal microscopy) are commonly used to visualize in vitro models, especially microvasculature on‐a‐chip. Conversely, 3D analysis is not the standard method to extract quantitative information from those models. We developed the μVES algorithm to analyze vascularized in vitro models leveraging 3D data. It computes morphological parameters (geometry, diameter, length, tortuosity, eccentricity) and intravascular flow velocity. μVES application to microfluidic vascularized in vitro models shows that they successfully replicate functional features of the microvasculature in vivo in terms of intravascular fluid flow velocity. However, wall shear stress is lower compared to in vivo references. The morphological analysis also highlights the model's physiological similarities (vessel length and tortuosity) and shortcomings (vessel radius and surface‐over‐volume ratio). The addition of the third dimension in our analysis produced significant differences in the metrics assessed compared to 2D estimations. It enabled the computation of new indices, such as vessel eccentricity. These μVES capabilities can find application in analyses of different in vitro vascular models, as well as in vivo and ex vivo microvasculature. [ABSTRACT FROM AUTHOR]

Stability analysis remains a fundamental step in developing a successful imaging biomarker to personalize oncological strategies. This study proposes an in silico contour generation method for simulating segmentation variations to identify stable radiomic features. Ground-truth annotation provided for the whole prostate gland on the multi-parametric MRI sequences (T2w, ADC, and SUB-DCE) were perturbed to mimic segmentation differences observed among human annotators. In total, we generated 15 synthetic contours for a given image-segmentation pair. One thousand two hundred twenty-four unfiltered/filtered radiomic features were extracted applying Pyradiomics, followed by stability assessment using ICC(1,1). Stable features identified in the internal population were then compared with an external population to discover and report robust features. Finally, we also investigated the impact of a wide range of filtering strategies on the stability of features. The percentage of unfiltered (filtered) features that remained robust subjected to segmentation variations were T2w—36% (81%), ADC—36% (94%), and SUB—43% (93%). Our findings suggest that segmentation variations can significantly impact radiomic feature stability but can be mitigated by including pre-filtering strategies as part of the feature extraction pipeline. [ABSTRACT FROM AUTHOR]

Purpose: Aim of this study is to assess the repeatability of radiomic features on magnetic resonance images (MRI) and their stability to variations in time of repetition (TR), time of echo (TE), slice thickness (ST), and pixel spacing (PS) using vegetable phantoms. Methods: The organic phantom was realized using two cucumbers placed inside a cylindrical container, and the analysis was performed using T1-weighted (T1w), T2-weighted (T2w), and diffusion-weighted images. One dataset was used to test the repeatability of the radiomic features, whereas other four datasets were used to test the sensitivity of the different MRI sequences to image acquisition parameters (TR, TE, ST, and PS). Four regions of interest (ROIs) were segmented: two for the central part of each cucumber and two for the external parts. Radiomic features were extracted from each ROI using Pyradiomics. To assess the effect of preprocessing on the reduction of variability, features were extracted both before and after the preprocessing. The coefficient of variation (CV) and intra-class correlation coefficient (ICC) were used to evaluate variability. Results: The use of intensity standardization increased the stability for the first-order statistics features. Shape and size features were always stable for all the analyses. Textural features were particularly sensitive to changes in ST and PS, although some increase in stability could be obtained by voxel size resampling. When images underwent image preprocessing, the number of stable features (ICC > 0.75 and mean absolute CV < 0.3) was 33 for apparent diffusion coefficient (ADC), 52 for T1w, and 73 for T2w. Conclusions: The most critical source of variability is related to changes in voxel size (either caused by changes in ST or PS). Preprocessing increases features stability to both test-retest and variation of the image acquisition parameters for all the types of analyzed MRI (T1w, T2w, and ADC), except for ST. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the implementation of specific dose constraints on healthy tissues to maintain the theoretical risk of late toxicity below 5% five years after radiotherapy (RT), many patients experience "unusual" toxicity during their oncological follow-up. This narrative review describes the methods of individual radiation sensitivity (iRS) diagnosis, their impact on the RT workflow as well as initiatives to support clinical decision-making initiatives. (1) Background: radiotherapy is a cornerstone of cancer treatment. When delivering a tumoricidal dose, the risk of severe late toxicities is usually kept below 5% using dose-volume constraints. However, individual radiation sensitivity (iRS) is responsible (with other technical factors) for unexpected toxicities after exposure to a dose that induces no toxicity in the general population. Diagnosing iRS before radiotherapy could avoid unnecessary toxicities in patients with a grossly normal phenotype. Thus, we reviewed iRS diagnostic data and their impact on decision-making processes and the RT workflow; (2) Methods: following a description of radiation toxicities, we conducted a critical review of the current state of the knowledge on individual determinants of cellular/tissue radiation; (3) Results: tremendous advances in technology now allow minimally-invasive genomic, epigenetic and functional testing and a better understanding of iRS. Ongoing large translational studies implement various tests and enriched NTCP models designed to improve the prediction of toxicities. iRS testing could better support informed radiotherapy decisions for individuals with a normal phenotype who experience unusual toxicities. Ethics of medical decisions with an accurate prediction of personalized radiotherapy's risk/benefits and its health economics impact are at stake; (4) Conclusions: iRS testing represents a critical unmet need to design personalized radiotherapy protocols relying on extended NTCP models integrating iRS. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) ranges from indolent to aggressive tumors that may rapidly progress and metastasize. The switch to aggressive PCa is fostered by reactive stroma infiltrating tumor foci. Therefore, reactive stroma-based biomarkers may potentially improve the early detection of aggressive PCa, ameliorating disease classification. Gene expression profiles of PCa reactive fibroblasts highlighted the up-regulation of genes related to stroma deposition, including periostin and sparc. Here, the potential of periostin as a stromal biomarker has been investigated on PCa prostatectomies by immunohistochemistry. Moreover, circulating levels of periostin and sparc have been assessed in a low-risk PCa patient cohort enrolled in active surveillance (AS) by ELISA. We found that periostin is mainly expressed in the peritumoral stroma of prostatectomies, and its stromal expression correlates with PCa grade and aggressive disease features, such as the cribriform growth. Moreover, stromal periostin staining is associated with a shorter biochemical recurrence-free survival of PCa patients. Interestingly, the integration of periostin and sparc circulating levels into a model based on standard clinico-pathological variables improves its performance in predicting disease reclassification of AS patients. In this study, we provide the first evidence that circulating molecular biomarkers of PCa stroma may refine risk assessment and predict the reclassification of AS patients. [ABSTRACT FROM AUTHOR]

We address a mathematical model for oxygen transfer in the microcirculation. The model includes blood flow and hematocrit transport coupled with the interstitial flow, oxygen transport in the blood and the tissue, including capillary-tissue exchange effects. Moreover, the model is suited to handle arbitrarily complex vascular geometries. The purpose of this study is the validation of the model with respect to classical solutions and the further demonstration of its adequacy to describe the heterogeneity of oxygenation in the tissue microenvironment. Finally, we discuss the importance of these effects in the treatment of cancer using radiotherapy. [ABSTRACT FROM AUTHOR]

Aim: To explore breast cancer patient's perspective on future genetic testing for prediction of toxicity after breast radiotherapy (RT). Materials and methods: The study involved patient enrolled in the Italian branch of the REQUITE project conducted at the National Cancer Institute in Milan. Semi-structured interviews were conducted within one month from the end of radiotherapy treatment by two radiation oncologists and a radiotherapy technician previously trained by a clinical psychologist with experience in the oncology field. Semi-structured interviews are characterized by a set of pre-defined questions and developed ad hoc by researchers in Leicester within the REQUITE project. The interview questions investigated interest in undergoing the genetic test and expectations on its usefulness and disadvantages. Results: Eighteen interviews were conducted and analysed. Forty-five initial codes were combined into nine themes which were then clustered in two main macro-areas (i) Opportunities and (ii) Challenges. Overall, all patients understand the aim of the genetic test and considered its intrinsic opportunity to make the physician more confident with the treatment. Regarding side effects, most of patients felt prepared to RT but not without fear. Many women considered important to have the largest and reliable information, also about negative experiences. Prevailing emotions were anxiety and fear but not connected to genetic test's result. Conclusions: A genetic test could be an opportunity because generate knowledge and give patients a dynamic role in the decision-making approach. Prediction of single patient radiosensitivity before RT could prompt suggestion to entail a more and more tailored radiation treatment in the era of personalized approach. [ABSTRACT FROM AUTHOR]

For decades, dose-volume information for segmented anatomy has provided the essential data for correlating radiotherapy dosimetry with treatment-induced complications. Dose-volume information has formed the basis for modelling those associations via normal tissue complication probability (NTCP) models and for driving treatment planning. Limitations to this approach have been identified. Many studies have emerged demonstrating that the incorporation of information describing the spatial nature of the dose distribution, and potentially its correlation with anatomy, can provide more robust associations with toxicity and seed more general NTCP models. Such approaches are culminating in the application of computationally intensive processes such as machine learning and the application of neural networks. The opportunities these approaches have for individualising treatment, predicting toxicity and expanding the solution space for radiation therapy are substantial and have clearly widespread and disruptive potential. Impediments to reaching that potential include issues associated with data collection, model generalisation and validation. This review examines the role of spatial models of complication and summarises relevant published studies. Sources of data for these studies, appropriate statistical methodology frameworks for processing spatial dose information and extracting relevant features are described. Spatial complication modelling is consolidated as a pathway to guiding future developments towards effective, complication-free radiotherapy treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether prostate cancer (PCa) patients' coping strategies (i.e., fighting spirit, anxious preoccupation, fatalism, helplessness/hopelessness, and avoidance) significantly change during the first 3-year follow-up period of active surveillance (AS). Materials and methods: Altogether, 104 patients on AS completed the Mini-Mental Adjustment to Cancer (Mini-MAC) at baseline (T0), at 10 and 12 months after diagnostic biopsy (T1 and T2, respectively) and then at 24- (T3) and 36-month (T4) follow-up. Paired samples T test was used to detect statistically significant changes over time. Changes ≥ 1 point (or ≤ − 1) were hypothesized to be clinically relevant. Results: During the first 3 years on AS, men experienced decreased anxiety, avoidance thoughts/behaviors, and fight-against-cancer attitudes, and these changes were found to be statistically significant. When considering clinically significant changes between inclusion in AS (T0) and 3-year follow-up (T4), avoidance decreased in 19% of patients. Conclusions: Most patients were observed to have adopted functional coping strategies at baseline, which were maintained through the first 3 years on AS. Overall, men on AS may perceive increasing control over their cancer and comfort with the AS protocol over time and experience slight decreases in anxious preoccupation, cancer-related avoidance thoughts and behaviors, and fight-against-cancer reactions. For those men who find it difficult to cope with AS, psychological monitoring and interventions could be helpful throughout the monitoring journey. [ABSTRACT FROM AUTHOR]

Background: The psychological burden possibly deriving from not immediately undergoing radical treatment for prostate cancer (PCa) could be a potential disadvantage of active surveillance (AS), especially in the eve of some relevant clinical exams [i.e., re-biopsy, prostate-specific antigen (PSA) test, and medical examination]. Even if it is known from the literature that the majority of PCa men in AS do not report heightened anxiety, there is a minority of patients who show clinically significant levels of anxiety after diagnosis. The present study aimed to investigate if demographic, clinical, and psychological variables at the entrance in AS (T0) were associated with the risk of developing clinically significant PCa-related anxiety 2 months before the first re-biopsy (T1) and to offer psychological support to improve quality of life (QoL). Materials and Methods: A total of 236 patients participated in the PCa Research International: AS (PRIAS) protocol and in PRIAS-QoL study. Demographic/clinical features, health-related QoL domains, coping with cancer, PCa-related anxiety [Memorial Anxiety Scale for PCa (MAX-PC)], personality traits, and decision-making-related factors were assessed at T0. MAX-PC was also administered at T1. PCa-related anxiety at T1 was considered to be of clinical significance if the MAX-PC score was ≥1.5. Multivariable logistic regression coupled to bootstrap was used to detect factors associated with high levels of anxiety. Results: The median age was 64.4 years. Fifty-six patients (24%) reported MAX-PC total score above the cutoff. Three factors were associated with a high level of PCa anxiety at T1: anxious preoccupation [odds ratio (OR) = 4.36], extraversion (OR = 1.9), and prostate-related symptoms (median OR = 0.46). Physical well-being was associated with a low PCa anxiety subscale (median OR = 0.15); neuroticism and functional well-being were associated with PSA anxiety (median OR = 7.05 and 0.73, respectively). Neuroticism and helplessness/hopelessness were associated with fear of progression (median OR = 18.1 and 5.8, respectively). Conclusion: Only a partial portion of the sample experienced significant levels of anxiety after 10 months. Psychological assessment should be routinely conducted to detect risk factors (i.e., anxious preoccupation, extraversion) for increased anxiety, offering tailored psychological interventions aimed at promoting interpersonal awareness and emotional well-being. [ABSTRACT FROM AUTHOR]

Background: Acute skin toxicity is a common and usually transient side-effect of breast radiotherapy although, if sufficiently severe, it can affect breast cosmesis, aftercare costs and the patient's quality-of-life. The aim of this study was to develop predictive models for acute skin toxicity using published risk factors and externally validate the models in patients recruited into the prospective multi-center REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve QUalITy of lifE in cancer survivors) study. Methods: Patient and treatment-related risk factors significantly associated with acute breast radiation toxicity on multivariate analysis were identified in the literature. These predictors were used to develop risk models for acute erythema and acute desquamation (skin loss) in three Radiogenomics Consortium cohorts of patients treated by breast-conserving surgery and whole breast external beam radiotherapy (n = 2,031). The models were externally validated in the REQUITE breast cancer cohort (n = 2,057). Results: The final risk model for acute erythema included BMI, breast size, hypo-fractionation, boost, tamoxifen use and smoking status. This model was validated in REQUITE with moderate discrimination (AUC 0.65), calibration and agreement between predicted and observed toxicity (Brier score 0.17). The risk model for acute desquamation, excluding the predictor tamoxifen use, failed to validate in the REQUITE cohort. Conclusions: While most published prediction research in the field has focused on model development, this study reports successful external validation of a predictive model using clinical risk factors for acute erythema following radiotherapy after breast-conserving surgery. This model retained discriminatory power but will benefit from further re-calibration. A similar model to predict acute desquamation failed to validate in the REQUITE cohort. Future improvements and more accurate predictions are expected through the addition of genetic markers and application of other modeling and machine learning techniques. [ABSTRACT FROM AUTHOR]

Objective: To investigate predictors of patient-reported urinary incontinence (PRUI) in the first 2 years after post-prostatectomy radiotherapy (PORT) with particular emphasis on possible dose-effect relationships. Patients and Methods: Two-hundred-thirteen patients, whose clinical and dosimetric data were prospectively collected within a registered multi-institutional cohort study, underwent PORT with adjuvant (n = 106) or salvage (n = 107) intent with conventional (n = 123, prescribed dose to the prostatic bed: 66.6–79.8Gy in 1.8–2.0Gy/fr) or moderately hypo- (n = 90, 65.8–76.8Gy in 2.1–2.7Gy/fr) fractionation during the period 2011–2017. PRUI was evaluated through the ICIQ-SF questionnaire filled in at baseline and every 6 months thereafter. The analysis focused on three ICIQ-based clinically relevant endpoints: (a) very frequent leakage (FREQUENCY, ICIQ3 score >3), (b) moderate to severe amount of urine loss (AMOUNT, ICIQ4>2) (c) objective severe symptoms (OBJECTIVE, ICIQ3+4>5). Predictors of the incidence within 2 years for the three endpoints were investigated focusing only on patients without endpoint symptoms at baseline. A uni-variable logistic regression analysis was performed in order to determine the best dose metrics describing PRUI risk in terms of 2-Gy equivalent dose (EQD2) calculated with different α/β values reported in the literature (0.8, 3, 5Gy), and to identify the most significant clinical variables. Variables showing p < 0.20 at uni-variable analysis were entered into a backward stepwise multi-variable logistic regression analysis. Lastly, the goodness of fit and model calibration were evaluated and internally validated. Results: Patients without symptoms at baseline experienced (a), (b), and/or (c) within 2 years in 41/130 (32%), 40/192 (21%), and 41/129 (32%) of the cases, respectively. EQD2 for α/β = 0.8Gy was the best dose metric associated with PRUI. Multi-variable analysis identified baseline incontinence levels as the strongest predictor for all endpoints (p < 0.006). Both FREQUENCY and OBJECTIVE were significantly influenced also by EQD2(α/β = 0.8Gy). The goodness of fit was excellent, as was the calibration; internal calibration confirmed apparent performance. Conclusion: Baseline mild urinary incontinence symptoms strongly modulate the 2-year risk of PRUI. In addition, FREQUENCY is characterized by a marked dose-effect relationship also influencing the trend of OBJECTIVE, with results more reliable than AMOUNT as an objective index. A strong impact of fractionation on severe PRUI after post-prostatectomy radiotherapy also emerged. [ABSTRACT FROM AUTHOR]

Purpose: For prostate cancer treatment, comparable or superior biochemical control was reported when using External-Beam-Radiotherapy (EBRT) with High-Dose-Rate-Brachytherapy (HDRB)-boost, compared to dose-escalation with EBRT alone. The conformal doses produced by HDRB could allow further beneficial prostate dose-escalation, but increase in dose is limited by normal tissue toxicity. Previous works showed correlation between urethral dose and incidence of urinary toxicity, but there is a lack of established guidelines on the dose constraints to this organ. This work aimed at fitting a Normal-Tissue-Complication-Probability model to urethral stricture data collected at one institution and validating it with an external cohort, looking at neo-adjuvant androgen deprivation as dose-modifying factor. Materials and Methods: Clinical and dosimetric data of 258 patients, with a toxicity rate of 12.8%, treated at a single institution with a variety of prescription doses, were collected to fit the Lyman–Kutcher–Burman (LKB) model using the maximum likelihood method. Due to the different fractionations, doses were converted into 2 Gy-equivalent doses (α/β = 5 Gy), and urethral stricture was used as an end-point. For validation, an external cohort of 187 patients treated as part of the TROG (Trans Tasman Radiation Oncology Group) 03.04 RADAR trial with a toxicity rate of 8.7%, was used. The goodness of fit was assessed using calibration plots. The effect of neo-adjuvant androgen deprivation (AD) was analyzed separating patients who had received it prior to treatment from those who did not receive it. Results: The obtained LKB parameters were TD50 = 116.7 Gy and m = 0.23; n was fixed to 0.3, based on numerical optimization of the likelihood. The calibration plot showed a good agreement between the observed toxicity and the probability predicted by the model, confirmed by bootstrapping. For the external validation, the calibration plot showed that the observed toxicity obtained with the RADAR patients was well-represented by the fitted LKB model parameters. When patients were stratified by the use of AD TD50 decreased when AD was not present. Conclusions: Lyman–Kutcher–Burman model parameters were fitted to the risk of urethral stricture and externally validated with an independent cohort, to provide guidance on urethral tolerance doses for patients treated with a HDRB boost. For patients that did not receive AD, model fitting provided a lower TD50 suggesting a protective effect on urethra toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Despite its increasing application, radiomics has not yet demonstrated a solid reliability, due to the difficulty in replicating analyses. The extraction of radiomic features from clinical MRI (T1w/T2w) presents even more challenges because of the absence of well‐defined units (e.g. HU). Some preprocessing steps are required before the estimation of radiomic features and one of this is the intensity normalization, that can be performed using different methods. The aim of this work was to evaluate the effect of three different normalization techniques, applied on T2w‐MRI images of the pelvic region, on radiomic features reproducibility. Methods: T2w‐MRI acquired before (MRI1) and 12 months after radiotherapy (MRI2) from 14 patients treated for prostate cancer were considered. Four different conditions were analyzed: (a) the original MRI (No_Norm); (b) MRI normalized by the mean image value (Norm_Mean); (c) MRI normalized by the mean value of the urine in the bladder (Norm_ROI); (d) MRI normalized by the histogram‐matching method (Norm_HM). Ninety‐one radiomic features were extracted from three organs of interest (prostate, internal obturator muscles and bulb) at both time‐points and on each image discretized using a fixed bin‐width approach and the difference between the two time‐points was calculated (Δfeature). To estimate the effect of normalization methods on the reproducibility of radiomic features, ICC was calculated in three analyses: (a) considering the features extracted on MRI2 in the four conditions together and considering the influence of each method separately, with respect to No_Norm; (b) considering the features extracted on MRI2 in the four conditions with respect to the inter‐observer variability in region of interest (ROI) contouring, considering also the effect of the discretization approach; (c) considering Δfeature to evaluate if some indices can recover some consistency when differences are calculated. Results: Nearly 60% of the features have shown poor reproducibility (ICC < 0.5) on MRI2 and the method that most affected features reliability was Norm_ROI (average ICC of 0.45). The other two methods were similar, except for first‐order features, where Norm_HM outperformed Norm_Mean (average ICC = 0.33 and 0.76 for Norm_Mean and Norm_HM, respectively). In the inter‐observer setting, the number of reproducible features varied in the three structures, being higher in the prostate than in the penile bulb and in the obturators. The analysis on Δfeature highlighted that more than 60% of the features were not consistent with respect to the normalization method and confirmed the high reproducibility of the features between Norm_Mean and Norm_HM, whereas Norm_ROI was the less reproducible method. Conclusions: The normalization process impacts the reproducibility of radiomic features, both in terms of changes in the image information content and in the inter‐observer setting. Among the considered methods, Norm_Mean and Norm_HM seem to provide the most reproducible features with respect to the original image and also between themselves, whereas Norm_ROI generates less reproducible features. Only a very small subset of feature remained reproducible and independent in any tested condition, regardless the ROI and the adopted algorithm: skewness or kurtosis, correlation and one among Imc2, Idmn and Idn from GLCM group. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this work was to determine how the spatial pattern of dose in the ano-rectal wall is related to late gastro-intestinal toxicity for prostate cancer patients treated with mainly IMRT. Patients and methods: Patients from the DUE-01 multicentre study with patient-reported (prospective) follow-up and available dosimetric data were included. Conventionally fractionated patients received 74–80 Gy and hypofractionated patients received 65–75.2 Gy. A large majority of the patients were treated with intensity-modulated radiotherapy (IMRT). Dose-surface maps (DSMs) for the anal canal and rectum as a single structure, and for the anal canal and the rectum separately, were co-registered rigidly in two dimensions and, for the patients with and without toxicity, respectively, the mean value of the dose in each pixel was calculated. A pixel-wise t-test was used to highlight the anatomical areas where there was a significant difference between the 'mean dose maps' of each group. Univariate models were also fitted to a range of spatial parameters. The endpoints considered were a mean grade ≥1 late fecal incontinence and a maximum grade ≥2 late rectal bleeding. Results: Twenty-six out of 213 patients had fecal incontinence, while 21/225 patients had rectal bleeding. Incontinence was associated with a higher dose in the caudal region of the anal canal; the most relevant spatial parameter was the lateral extent of the low and medium isodoses (5–49 Gy in EQD2). Bleeding was associated with high isodoses reaching the posterior rectal wall. The spatial dose parameters with the highest AUC value (.69) were the lateral extent of the 60–70 Gy isodoses. Conclusions: To avoid fecal incontinence it is important to limit the portion of the anal canal irradiated. Our analysis confirms that rectal bleeding is a function of similar spatial dose parameters for patients treated with IMRT, compared to previous studies on patients treated with three-dimensional conformal radiotherapy. [ABSTRACT FROM AUTHOR]

Keywords: radiotherapy; toxicity; modeling; normal tissue complication probability; dose-response EN radiotherapy toxicity modeling normal tissue complication probability dose-response 1 3 3 05/29/21 20210526 NES 210526 Introduction Radiation therapy (RT) represents a mainstay of treatment for many cancer types, either as a single modality or within a multidisciplinary approach, including surgery and systemic therapy. Radiotherapy, toxicity, modeling, normal tissue complication probability, dose-response. [Extracted from the article]

Purpose: To investigate the potential of texture analysis applied on T2‐w and postcontrast T1‐w images acquired before radiotherapy for prostate cancer (PCa) and 12 months after its completion in quantitatively characterizing local radiation effect on the muscular component of internal obturators, as organs potentially involved in urinary toxicity. Methods: T2‐w and postcontrast T1‐w MR images were acquired at 1.5 T before treatment (MRI1) and at 12 months of follow‐up (MRI2) in 13 patients treated with radiotherapy for PCa. Right and left internal obturator muscle contours were manually delineated upon MRI1 and then automatically propagated on MRI2 by an elastic registration method. Planning CT images were coregistered to both MRIs and dose maps were deformed accordingly. A high‐dose region receiving >55 Gy and a low‐dose region receiving <55 Gy were identified in each muscle volume. Eighteen textural features were extracted from each region of interest and differences between MRI1 and MRI2 were evaluated. Results: A signal increase was highlighted in both T2‐w and T1‐w images in the portion of the obturators near the prostate, i.e., in the region receiving medium‐high doses. A change in the spatial organization was identified, as an increase in homogeneity and a decrease in contrast and complexity, compatible with an inflammatory status. In particular, the region receiving medium‐high doses presented more significant or, at least, stronger differences. Conclusions: Texture analysis applied on T1‐w and T2‐w MR images has demonstrated its ability in quantitative evaluating radiation‐induced changes in obturator muscles after PCa radiotherapy. [ABSTRACT FROM AUTHOR]

A recent “hot topic” in prostate cancer radiotherapy is the observed association between acute/late rectal toxicity and the presence of abdominal surgery before radiotherapy. The exact mechanism is unclear. Our working hypothesis was that a previous surgery may influence plasma level of inflammatory molecules and this might result in enhanced radiosensitivity. We here present results on the feasibility of monitoring the expression of inflammatory molecules during radiotherapy. Plasma levels of a panel of soluble mediators associated with the inflammatory response were measured in prostate cancer patients undergoing radical radiotherapy. We measured 3 cytokines (IL-1b, IL-6, and TNF alpha), 2 chemokines (CCL2 and CXCL8), and the long pentraxin PTX3. 20 patients were enrolled in this feasibility evaluation. All patients were treated with IMRT at 78 Gy. 3/20 patients reported grade 2 acute rectal toxicity, while 4/20 were scored as grade 2 late toxicity. CCL2 was the most interesting marker showing significant increase during and after radiotherapy. CCL2 levels at radiotherapy end could be modelled using linear regression including basal CCL2, age, surgery, hypertension, and use of anticoagulants. The 4 patients with late toxicity had CCL2 values at radiotherapy end above the median value. This trial is registered with ISRCTN64979094. [ABSTRACT FROM AUTHOR]

The ability to stratify patients using a set of biomarkers, which predict that toxicity risk would allow for radiotherapy (RT) modulation and serve as a valuable tool for precision medicine and personalized RT. For patients presenting with tumors with a low risk of recurrence, modifying RT schedules to avoid toxicity would be clinically advantageous. Indeed, for the patient at low risk of developing radiation-associated toxicity, use of a hypofractionated protocol could be proposed leading to treatment time reduction and a cost-utility advantage. Conversely, for patients predicted to be at high risk for toxicity, either a more conformal form or a new technique of RT, or a multidisciplinary approach employing surgery could be included in the trial design to avoid or mitigate RT when the potential toxicity risk may be higher than the risk of disease recurrence. In addition, for patients at high risk of recurrence and low risk of toxicity, dose escalation, such as a greater boost dose, or irradiation field extensions could be considered to improve local control without severe toxicities, providing enhanced clinical benefit. In cases of high risk of toxicity, tumor control should be prioritized. In this review, toxicity biomarkers with sufficient evidence for clinical testing are presented. In addition, clinical trial designs and predictive models are described for different clinical situations. [ABSTRACT FROM AUTHOR]

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Simple Summary: Radiotherapy is the cornerstone of treatment of nasopharyngeal cancer, in different settings with or without chemotherapy. This role has been recently strengthened by the introduction of proton therapy, as a radiation treatment option for head and neck cancer, obtaining improved plans with a reduced dose to organs-at-risk. Definition of strategies to identify patients who would benefit the most from proton therapy in terms of reduced toxicity is highly desirable, due to limited availability and higher costs of this treatment option. Two parallel working pipelines were depicted in this study for nasopharyngeal cancer patients. The introduction of a synthetic index describing the overall expected reduction in toxicities in the head and neck region with proton therapy was supported by the application of the well-established model-based selection methodology, relative to the same patient cohort. Based on this analysis, the fraction of nasopharyngeal cancer patients expected to receive a benefit with proton therapy was in line with the Dutch experience for the head and neck cancer population. (1) Background: we proposed an integrated strategy to support clinical allocation of nasopharyngeal patients between proton and photon radiotherapy. (2) Methods: intensity-modulated proton therapy (IMPT) plans were optimized for 50 consecutive nasopharyngeal carcinoma (NPC) patients treated with volumetric modulated arc therapy (VMAT), and differences in dose and normal tissue complication probability (ΔNTCPx-p) for 16 models were calculated. Patient eligibility for IMPT was assessed using a model-based selection (MBS) strategy following the results for 7/16 models describing the most clinically relevant endpoints, applying a model-specific ΔNTCPx-p threshold (15% to 5% depending on the severity of the complication) and a composite threshold (35%). In addition, a comprehensive toxicity score (CTS) was defined as the weighted sum of all 16 ΔNTCPx-p, where weights follow a clinical rationale. (3) Results: Dose deviations were in favor of IMPT (ΔDmean ≥ 14% for cord, esophagus, brainstem, and glottic larynx). The risk of toxicity significantly decreased for xerostomia (−12.5%), brain necrosis (−2.3%), mucositis (−3.2%), tinnitus (−8.6%), hypothyroidism (−9.3%), and trismus (−5.4%). There were 40% of the patients that resulted as eligible for IMPT, with a greater advantage for T3–T4 staging. Significantly different CTS were observed in patients qualifying for IMPT. (4) Conclusions: The MBS strategy successfully drives the clinical identification of NPC patients, who are most likely to benefit from IMPT. CTS summarizes well the expected global gain. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the correlation between the 'true' absolute and relative dose-volume histograms (DVHs) of the bladder wall, dose-wall histogram (DWH) defined on MRI imaging and other surrogates of bladder dosimetry in prostate cancer patients, planned both with 3D-conformal and intensity-modulated radiation therapy (IMRT) techniques. For 17 prostate cancer patients, previously treated with radical intent, CT and MRI scans were acquired and matched. The contours of bladder walls were drawn by using MRI images. External bladder surfaces were then used to generate artificial bladder walls by performing automatic contractions of 5, 7 and 10 mm. For each patient a 3D conformal radiotherapy (3DCRT) and an IMRT treatment plan was generated with a prescription dose of 77.4 Gy (1.8 Gy/fr) and DVH of the whole bladder of the artificial walls (DVH-5/10) and dose-surface histograms (DSHs) were calculated and compared against the DWH in absolute and relative value, for both treatment planning techniques. A specific software (VODCA v. 4.4.0, MSS Inc.) was used for calculating the dose-volume/surface histogram. Correlation was quantified for selected dose-volume/surface parameters by the Spearman correlation coefficient. The agreement between %DWH and DVH5, DVH7 and DVH10 was found to be very good (maximum average deviations below 2%, SD < 5%): DVH5 showed the best agreement. The correlation was slightly better for absolute (R = 0.80-0.94) compared to relative (R = 0.66-0.92) histograms. The DSH was also found to be highly correlated with the DWH, although slightly higher deviations were generally found. The DVH was not a good surrogate of the DWH (R < 0.7 for most of parameters). When comparing the two treatment techniques, more pronounced differences between relative histograms were seen for IMRT with respect to 3DCRT (p < 0.0001). [ABSTRACT FROM AUTHOR]

Study Type - Therapy (decision analysis) Level of Evidence 2b What's known on the subject? and What does the study add? The benefits of the multidisciplinary approach in oncology are widely recognised. In particular, managing patients with prostate cancer within a multidisciplinarity and multiprofessional context is of paramount importance, to address the complexity of a disease where patients may be offered multiple therapeutic and observational options handled by different specialists and having severe therapy-induced side-effects. The present study describes the establishing of a multidisciplinary clinic at the Prostate Cancer Programme of Milan Istituto Nazionale dei Tumori, its effects on the quality of care provided, and strategies implemented to meet upcoming needs and improve quality standards. Having analysed the data of the 2260 multidisciplinary clinics held from March 2005 to March 2011, our dynamic and modifiable organisational model was evaluated for ways to optimise the human resources, offer high-quality standards, meet new needs and ultimately reduce costs. The study is focused on the organisational aspects and adds a perspective from one of the major oncological centres of reference in Italy and in Europe. OBJECTIVES To describe the establishing of a multidisciplinary clinic for men with prostate cancer at the Istituto Nazionale Tumori, Milan., To evaluate the quality of care provided and to describe the management changes implemented to improve standards and meet new needs., MATERIALS AND METHODS In March 2005, we established a multidisciplinary clinic comprising weekly clinics and case-discussion sessions., We have altered the organisational model periodically to meet new needs and improve quality., RESULTS We held 2260 multidisciplinary clinics up to March 2011., For stage distribution, patients with low-risk prostate cancer increased to a peak of 61% in 2009, probably because of the anticipation of diagnosis and the active surveillance expertise of the Prostate Cancer Programme at Istituto Nazionale Tumori, Milan. The slight decrease in 2010 might be due to the availability of robot-assisted prostatectomy in several hospitals in Milan, and the start of a multicentre active surveillance protocol in December 2009., In terms of the efficacy of our multidisciplinary strategy, 11% of drug therapies (mostly hormones) prescribed outside our institute were terminated in the multidisciplinary clinic, and 6% of indications formulated in the multidisciplinary clinics were altered during the case-discussion sessions., CONCLUSIONS The multidisciplinary approach needs to be adaptable to meet new needs and improve quality., Our experience has proved successful for both physicians and patients. The team agrees on strategies; complex cases are managed by a multidisciplinary team; dedicated psychologists contribute their knowledge and perspectives; and patients report the feeling of being cared for. [ABSTRACT FROM AUTHOR]

Purpose. To verify the possibility of using Helical Tomotherapy to safely escalate dose to single or multiple highly radioresistant dominant intra-prostatic lesions (DILs) as assessed by functional magnetic resonance imaging (MRI). Material. In seven intermediate/high risk patients, T2WI, T1WI and DWI MRI imaging showed evidence of one DIL in four patients and two DILs in three patients in the peripheral zone of the prostate. The planning strategy was to deliver median doses of 80, 90, 100 and 120 Gy to PTVDIL while delivering 71.4 Gy/28 fractions (EQD2=75 Gy) to the remaining portion of PTV. A higher priority was assigned to rectal constraints relative to DIL coverage. Rectal NTCP calculations were performed using the most recently available model data. Results. The median dose to DIL could safely be escalated to at least 100 Gy (EQD2,α/β=10=113 Gy) without violating safe constraints for the organs at risk. Typical rectal NTCP values were around or below 1-3% for G3 toxicity and 5-7% for G2-G3 toxicity. For the 100 Gy DIL dose boost strategy, mean D95% of DIL and PTVDIL were 98.8 Gy and 86.7 Gy, respectively. The constraints for bladder, urethra and femoral heads were always respected. Conclusions. IGRT by Helical Tomotherapy may permit the safe escalation of EQD2,α/β=10 to at least 113 Gy to DILs without significantly increasing rectal NTCP compared to plans without dose escalation. A Phase I-II clinical study is warranted. [ABSTRACT FROM AUTHOR]

The article reports on the multivariate correlation between late genitourinary and gastrointestinal toxicities and clinical/dosimetric risk factors. It cites that predicting a high probability of toxicity could avoid unnecessary daily costs to single patient in terms of quality of life modification during and after treatment. It reveals that the integrated evaluation of clinical and dosimetric parameters in single patient can help to offer tailored probability of the specific outcome considered.

The article examines the dose-volume modeling of late and acute toxicity in radiotherapy for prostate cancer. According to the authors, the largest studies on dose-volume modeling of rectal toxicity has produced very consistent results, recommending that the rectum is prevalently serial organ when bleeding is considered as the endpoint. However, it suggests that further investigation on large groups of patients will be important to reliably evaluate quantitative models of dose-volume effects.

Since 2001, 50 breast cancer patients, for whom extensive lung/heart involvement was expected from the use of conventional tangential 2-field technique (2F) owing to complex anatomies, were irradiated using a 3-field conformal technique (3F). Dose plans were designed for both 3F and 2F and a dose volume histogram analysis on ipsilateral lung, heart, and target was conducted. The 3F technique allowed a significant reduction in ipsilateral lung irradiation: mean dose dropped from 16.0±3.8 (2F) to 12.0±2.7 Gy (3F) and V 45Gy from 20.7±6.8 (2F) to 3.2±2.9% (3F). Similarly, in patients irradiated to the left breast, heart mean dose was reduced from 8.1 Gy (2F) to 6.8 Gy (3F) and D 15% from 19.0 Gy to 14.0 Gy. All differences reached a high degree of significance. The target coverage was not clinically compromised since the slight reduction using 3F compared with 2F is limited to V 95% while V 90% difference, even if statistically significant, is small: 98.2±1.8% (3F) and 98.8±1.6 (2F). A preliminary report on clinical follow up is also included; with a mean follow up of 15.8 months, no pulmonary or cardiac complications were observed. [ABSTRACT FROM AUTHOR]

Simple Summary: We built a predictive model for acute salivary dysfunction for nasopharyngeal cancer patients receiving combined treatment. The final aim was to provide a nomogram (with dosimetric and clinical risk factors) to help physicians in the streamline prevention and management of this acute side effect. No research has focused on predicting acute xerostomia so far. We do not know if models predicting late xerostomia can also be applied to acute xerostomia, since different pathogenesis is suggested for acute and late events. The model was tested in two independent external cohorts. Validation results highlighted that the dosimetric part of the predictive model was highly generalisable, with the clinical risk part still being a weak component. The good validation of the model's discriminative power and of the effect of the size of dosimetric factors created confidence for considering these factors while optimising radiotherapy. Background: Radiation-induced xerostomia is one of the most prevalent adverse effects of head and neck cancer treatment, and it could seriously affect patients' qualities of life. It results primarily from damage to the salivary glands, but its onset and severity may also be influenced by other patient-, tumour-, and treatment-related factors. We aimed to build and validate a predictive model for acute salivary dysfunction (aSD) for locally advanced nasopharyngeal carcinoma (NPC) patients by combining clinical and dosimetric factors. Methods: A cohort of consecutive NPC patients treated curatively with IMRT and chemotherapy at 70 Gy (2–2.12 Gy/fraction) were utilised. Parotid glands (cPG, considered as a single organ) and the oral cavity (OC) were selected as organs-at-risk. The aSD was assessed at baseline and weekly during RT, grade ≥ 2 aSD chosen as the endpoint. Dose-volume histograms were reduced to the Equivalent Uniform Dose (EUD). Dosimetric and clinical/treatment features selected via LASSO were inserted into a multivariable logistic model. Model validation was performed on two cohorts of patients with prospective aSD, and scored using the same schedule/scale: a cohort (NPC_V) of NPC patients (as in model training), and a cohort of mixed non-NPC head and neck cancer patients (HNC_V). Results: The model training cohort included 132 patients. Grade ≥ 2 aSD was reported in 90 patients (68.2%). Analyses resulted in a 4-variables model, including doses of up to 98% of cPG (cPG_D98%, OR = 1.04), EUD to OC with n = 0.05 (OR = 1.11), age (OR = 1.08, 5-year interval) and smoking history (OR = 1.37, yes vs. no). Calibration was good. The NPC_V cohort included 38 patients, with aSD scored in 34 patients (89.5%); the HNC_V cohort included 93 patients, 77 with aSD (92.8%). As a general observation, the incidence of aSD was significantly different in the training and validation populations (p = 0.01), thus impairing calibration-in-the-large. At the same time, the effect size for the two dosimetric factors was confirmed. Discrimination was also satisfactory in both cohorts: AUC was 0.73, and 0.68 in NPC_V and HNC_V cohorts, respectively. Conclusion: cPG D98% and the high doses received by small OC volumes were found to have the most impact on grade ≥ 2 acute xerostomia, with age and smoking history acting as a dose-modifying factor. Findings on the development population were confirmed in two prospectively collected validation populations. [ABSTRACT FROM AUTHOR]

Simple Summary: Dosiomics is born directly as an extension of radiomics: it entails extracting features from the patients' three-dimensional (3D) radiotherapy dose distribution rather than from conventional medical images to obtain specific spatial and statistical information. Dosiomic studies, in a multicentre setting, require assessing the features' stability to dose calculation settings and the features' capability in distinguishing different dose distributions. This study provides the first multicentre evaluation of the dosiomic features in terms of reproducibility, stability and sensitivity across various dose distributions obtained from multiple technologies and techniques and considering different dose calculation algorithms of TPS and two different resolutions of the dose grid. Harmonisation strategies to account for a possible variation in the dose distribution due to these confounding factors should be adopted when investigating a correlation between dosiomic features and clinical outcomes in multicentre studies. Dosiomics is a texture analysis method to produce dose features that encode the spatial 3D distribution of radiotherapy dose. Dosiomic studies, in a multicentre setting, require assessing the features' stability to dose calculation settings and the features' capability in distinguishing different dose distributions. Dose distributions were generated by eight Italian centres on a shared image dataset acquired on a dedicated phantom. Treatment planning protocols, in terms of planning target volume coverage and dose–volume constraints to the organs at risk, were shared among the centres to produce comparable dose distributions for measuring reproducibility/stability and sensitivity of dosiomic features. In addition, coefficient of variation (CV) was employed to evaluate the dosiomic features' variation. We extracted 38,160 features from 30 different dose distributions from six regions of interest, grouped by four features' families. A selected group of features (CV < 3 for the reproducibility/stability studies, CV > 1 for the sensitivity studies) were identified to support future multicentre studies, assuring both stable features when dose distributions variation is minimal and sensitive features when dose distribution variations need to be clearly identified. Dosiomic is a promising tool that could support multicentre studies, especially for predictive models, and encode the spatial and statistical characteristics of the 3D dose distribution. [ABSTRACT FROM AUTHOR]

Simple Summary: The levels of urinary incontinence (UI) at adjuvant/salvage radiotherapy (ART/SRT) start strongly influence long-term UI recovery, possibly inducing clinicians to postpone radiotherapy "as much as possible" in order to maximize UI recovery, but possibly reducing radiotherapy efficacy. Our study analyzed UI recovery from prostatectomy to ART/SRT by means of the International Consultation on Incontinence Questionnaire-Short Form filled-in by patients at ART/SRT start. Three endpoints were investigated: frequency and amount of urine loss and the "subjective" patient-perceived detrimental impact on quality of life, as well as the possible influence of clinical and personality variables. The time elapsed from prostatectomy to radiotherapy start was the strongest predictor for each UI endpoint, all improving between four and eight months after prostatectomy, but without any additional long-term recovery. Background: Baseline urinary incontinence (UI) strongly modulates UI recovery after adjuvant/salvage radiotherapy (ART/SRT), inducing clinicians to postpone it "as much as possible", maximizing UI recovery but possibly reducing efficacy. This series aims to analyze the trend of UI recovery and its predictors at radiotherapy start. Methods: A population of 408 patients treated with ART/SRT enrolled in a cohort study (ClinicalTrials.gov #NCT02803086) aimed at developing predictive models of radiation-induced toxicities. Self-reported UI and personality traits, evaluated by means of the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-SF) and Eysenck Personality Questionnaire - Revised (EPQ-R) questionnaires, were assessed at ART/SRT start. Several endpoints based on baseline ICIQ-SF were investigated: frequency and amount of urine loss (ICIQ3 and ICIQ4, respectively), "objective" UI (ICIQ3 + 4), "subjective" UI (ICIQ5), and "TOTAL" UI (ICIQ3 +4 + 5). The relationship between each endpoint and time from prostatectomy to radiotherapy (TTRT) was investigated. The association between clinical and personality variables and each endpoint was tested by uni- and multivariable logistic regression. Results: TTRT was the strongest predictor for all endpoints (p-values ≤ 0.001); all scores improved between 4 and 8 months after prostatectomy, without any additional long-term recovery. Neuroticism independently predicted subjective UI, TOTAL UI, and daily frequency. Conclusions: Early UI recovery mostly depends on TTRT with no further improvement after 8 months from prostatectomy. Higher levels of neuroticism may overestimate UI. [ABSTRACT FROM AUTHOR]

Simple Summary: Active surveillance (AS) has evolved as an alternative to radical treatment for potentially indolent prostate cancer. However, current selection criteria for entering AS are suboptimal, and a significant percentage of patients discontinue AS because of disease reclassification. Hence, there is an unmet need for novel biomarkers for the accurate identification of high-risk PCa and the unequivocal classification of indolent disease. Circulating biomarkers, including microRNAs identified through liquid biopsies, represent a valuable approach to improve on currently available clinicopathological risk-stratification tools. In an attempt to identify specific microRNA signatures as potential circulating biomarkers, the authors performed an unprecedented analysis of the global microRNA profile in plasma samples from AS patients and identified and validated a three-microRNA signature able to predict patient reclassification. The addition of the three-microRNA signature was able to improve the performance of currently available clinicopathological variables, thus showing potential for the refinement of AS patients' selection. Active surveillance (AS) has evolved as a strategy alternative to radical treatments for very low risk and low-risk prostate cancer (PCa). However, current criteria for selecting AS patients are still suboptimal. Here, we performed an unprecedented analysis of the circulating miRNome to investigate whether specific miRNAs associated with disease reclassification can provide risk refinement to standard clinicopathological features for improving patient selection. The global miRNA expression profiles were assessed in plasma samples prospectively collected at baseline from 386 patients on AS included in three independent mono-institutional cohorts (training, testing and validation sets). A three-miRNA signature (miR-511-5p, miR-598-3p and miR-199a-5p) was found to predict reclassification in all patient cohorts (training set: AUC 0.74, 95% CI 0.60–0.87, testing set: AUC 0.65, 95% CI 0.51–0.80, validation set: AUC 0.68, 95% CI 0.56–0.80). Importantly, the addition of the three-miRNA signature improved the performance of the clinical model including clinicopathological variables only (AUC 0.70, 95% CI 0.61–0.78 vs. 0.76, 95% CI 0.68–0.84). Overall, we trained, tested and validated a three-miRNA signature which, combined with selected clinicopathological variables, may represent a promising biomarker to improve on currently available clinicopathological risk stratification tools for a better selection of truly indolent PCa patients suitable for AS. [ABSTRACT FROM AUTHOR]

Simple Summary: Ionizing radiation is used as a treatment for cancer, but it also affects the endothelial cells that make up the microvasculature. In-vitro models can be used to study the detrimental effect of irradiation on those cells. This systematic review analyzed the literature models, highlighting the critical components of the production, irradiation, and analysis of radiobiological in-vitro models for microvascular endothelial cell damage. Based on those data, we suggest future directions, including advanced in-vitro models to recapitulate microenvironment features. We pinpoint essential information to be included for the good characterization of the experiments, especially in terms of the dose delivered by ionizing radiation. Ionizing radiation (IR) is used in radiotherapy as a treatment to destroy cancer. Such treatment also affects other tissues, resulting in the so-called normal tissue complications. Endothelial cells (ECs) composing the microvasculature have essential roles in the microenvironment's homeostasis (ME). Thus, detrimental effects induced by irradiation on ECs can influence both the tumor and healthy tissue. In-vitro models can be advantageous to study these phenomena. In this systematic review, we analyzed in-vitro models of ECs subjected to IR. We highlighted the critical issues involved in the production, irradiation, and analysis of such radiobiological in-vitro models to study microvascular endothelial cells damage. For each step, we analyzed common methodologies and critical points required to obtain a reliable model. We identified the generation of a 3D environment for model production and the inclusion of heterogeneous cell populations for a reliable ME recapitulation. Additionally, we highlighted how essential information on the irradiation scheme, crucial to correlate better observed in vitro effects to the clinical scenario, are often neglected in the analyzed studies, limiting the translation of achieved results. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognostic performance of traditional methodologies in advanced nasopharyngeal carcinoma does not allow to successfully stratify patients. Previous studies showed that MRI-radiomics has been used to give additional information to improve the prognosis for this type of pathology in patients from endemic areas (Asia). The purpose of this study was to use MRI-radiomics to develop prognostic models for overall survival in patients from non-endemic areas (Europe or United States). In particular, T1-weighted and T2-weighted MRI were used for the purpose. Radiomic features from those images allowed to successfully train a prognostic signature that improved the prognostic performance of models based on clinical variables alone for different clinical endpoints (overall survival, disease-free survival and loco-regional recurrence-free survival). These results suggest how MRI-radiomics is a useful additional tool for prognosis in nasopharyngeal cancer. Advanced stage nasopharyngeal cancer (NPC) shows highly variable treatment outcomes, suggesting the need for independent prognostic factors. This study aims at developing a magnetic resonance imaging (MRI)-based radiomic signature as a prognostic marker for different clinical endpoints in NPC patients from non-endemic areas. A total 136 patients with advanced NPC and available MRI imaging (T1-weighted and T2-weighted) were selected. For each patient, 2144 radiomic features were extracted from the main tumor and largest lymph node. A multivariate Cox regression model was trained on a subset of features to obtain a radiomic signature for overall survival (OS), which was also applied for the prognosis of other clinical endpoints. Validation was performed using 10-fold cross-validation. The added prognostic value of the radiomic features to clinical features and volume was also evaluated. The radiomics-based signature had good prognostic power for OS and loco-regional recurrence-free survival (LRFS), with C-index of 0.68 and 0.72, respectively. In all the cases, the addition of radiomics to clinical features improved the prognostic performance. Radiomic features can provide independent prognostic information in NPC patients from non-endemic areas. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy is one of the main treatment options for non-metastatic prostate cancer (PCa). Although treatment technical optimization has greatly improved local tumor control, a considerable fraction of patients still experience relapse due to the development of resistance. Radioresistance is a complex and still poorly understood phenomenon involving the deregulation of a variety of signaling pathways as a consequence of several genetic and epigenetic abnormalities. In this context, cumulative evidence supports a functional role of microRNAs in affecting radioresistance, suggesting the modulation of their expression as a novel radiosensitizing approach. Here, we investigated for the first time the ability of miR-205 to enhance the radiation response of PCa models. Methods: miR-205 reconstitution by a miRNA mimic in PCa cell lines (DU145 and PC-3) was used to elucidate miR-205 biological role. Radiation response in miRNA-reconstituted and control cells was assessed by clonogenic assay, immunofluorescence-based detection of nuclear γ-H2AX foci and comet assay. RNAi was used to silence the miRNA targets PKCε or ZEB1. In addition, target-protection experiments were carried out using a custom oligonucleotide designed to physically disrupt the pairing between the miR-205 and PKCε. For in vivo experiments, xenografts generated in SCID mice by implanting DU145 cells stably expressing miR-205 were exposed to 5-Gy single dose irradiation using an image-guided animal micro-irradiator. Results: miR-205 reconstitution was able to significantly enhance the radiation response of prostate cancer cell lines and xenografts through the impairment of radiation-induced DNA damage repair, as a consequence of PKCε and ZEB1 inhibition. Indeed, phenocopy experiments based on knock-down of either PKCε or ZEB1 reproduced miR-205 radiosensitizing effect, hence confirming a functional role of both targets in the process. At the molecular level, miR-205-induced suppression of PKCε counteracted radioresistance through the impairment of EGFR nuclear translocation and the consequent DNA-PK activation. Consistently, disruption of miR-205-PKCε 3'UTR pairing almost completely abrogated the radiosensitizing effect. Conclusions: Our results uncovered the molecular and cellular mechanisms underlying the radiosensitizing effect of miR-205. These findings support the clinical interest in developing a novel therapeutic approach based on miR-205 reconstitution to increase PCa response to radiotherapy. [ABSTRACT FROM AUTHOR]

The authors discuss the concept of health-related quality of life (HRQoL) which is considered a fundamental health outcome. The authors mention the significance of collecting longitudinal HRQoL data from patients with prostate cancer (PCa) who underwent carbon-ion radiotherapy. Also discussed is the need to provide the basis for the design of targeted counseling interventions in evaluating HRQoL.