Search

Background: This study was an open-label, 2-arms, monocentric, randomized clinical trial comparing Xonrid®, a topical medical device, versus standard of care (SOC) in preventing and treating acute radiation dermatitis (ARD) in Head and Neck Cancer (HNC) and Breast Cancer (BC) patients undergoing radiotherapy (RT)., Methods: Eligible HNC and BC patients were randomized 1:1 to receive Xonrid® + SOC or SOC during RT. Patients were instructed to apply Xonrid® on the irradiated area three times daily, starting on the first day of RT and until 2 weeks after RT completion or until the development of grade ≥ 3 skin toxicity. The primary endpoint was to evaluate the proportion of patients who developed an ARD grade < 2 at the 5th week in both groups. Secondary endpoints were median time to grade 2 (G2) skin toxicity onset; changes in skin erythema and pigmentation and trans-epidermal water loss (TEWL); patient-reported skin symptoms. All patients were evaluated at baseline, weekly during RT and 2 weeks after treatment completion. The evaluation included: clinical toxicity assessment; reflectance spectrometry (RS) and TEWL examination; measurement of patients' quality of life (QoL) through Skindex-16 questionnaire., Results: Eighty patients (40 for each cancer site) were enrolled between June 2017 and July 2018. Groups were well balanced for population characteristics. All BC patients underwent 3-Dimensional Conformal RT (3D-CRT) whereas HNC patients underwent Volumetric-Modulated Arc Therapy (VMAT). At week 5 the proportion of BC patients who did not exhibit G2 ARD was higher in Xonrid® + SOC group (p = 0.091). In the same group the onset time of G2 ARD was significantly longer than in SOC-alone group (p < 0.0491). For HNC groups there was a similar trend, but it did not reach statistical significance. For both cancer sites, patients' QoL, measured by the Skindex-16 score, was always lower in the Xonrid® + SOC group., Conclusion: Despite the failure to achieve the primary endpoint, this study suggests that Xonrid® may represent a valid medical device in the prevention and treatment of ARD at least in BC patients, delaying time to develop skin toxicity and reducing the proportion of patients who experienced G2 ARD during RT treatment and 2 weeks later., Trial Registration: The study was approved by the Ethical Committee of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT 52/14 - NCT02261181 ). Registered on ClinicalTrial.gov on 21st August 2017.

Aim: To assess the impact of age, comorbidities and endocrine therapy (ET) in older breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT)., Methods: From June 2009 to December 2017, we enrolled in this study 735 ER-positive BC patients (stage pT1-T2, pNx-1, M0 and age ≥ 65 years) receiving hypo-RT and followed them until September 2019. Baseline comorbidities included in the hypertension-augmented Charlson Comorbidity Index were retrospectively retrieved. Logistic regression model estimated adjusted-odds ratios (ORs) of ET prescription in relation to baseline patient and tumor characteristics. Competing risk analysis estimated 5-year cumulative incidence function (CIF) of ET discontinuation due to side effects (with BC progression or death as competing events), and its effect on locoregional recurrence (LRR) and distant metastasis (DM) (with death as competing event)., Results: ET has been prescribed in 89% patients. In multivariable analysis, the odds of ET prescription was significantly reduced in older patients (≥ 80 years, OR 0.08, 95% CI 0.03-0.20) and significantly increased in patients with moderate comorbidity. Patients ≥ 80 years discontinued the prescribed therapy earlier and more frequently than younger (65-69 years) patients (p = 0.060). Five-year CIF of LLR, DM and death from causes other that BC were 1.7%, 2.2% and 7.5%, respectively. Patients who discontinued ET had higher chance of LRR (p = 0.004). ET use did not impact on OS in any of the analyzed groups., Conclusions: In older patients, ET did not show a benefit in terms of overall survival. Further studies focusing on tailored treatment approaches are warranted to offer the best care in terms of adjuvant treatment to these patients.

Survival of pediatric patients with brain tumor has increased over the past 20 years, and increasing evidence of iatrogenic toxicities has been reported. In follow-ups, images are acquired at different time points where substantial changes of brain morphology occur, due to childhood physiological development and treatment effects. To address the image registration complexity, we propose two multi-metric approaches (M plus , M dot ), combining mutual information (MI) and normalized gradient field filter (NGF). The registration performance of the proposed metrics was assessed on a simulated dataset (Brainweb) and compared with those obtained by MI and NGF separately, using mean magnitude and mean angular errors. The most promising metric (M plus ) was then selected and tested on a retrospective dataset comprising 45 pediatric patients who underwent focal radiotherapy for brain cancer. The quality of the realignment was scored by a radiation oncologist using a perceived misalignment metric (PM). All patients but one were assessed as PM ≤ 2 (good alignment), but the remaining one, severely affected by hydrocephalus and pneumocephalus at the first MRI acquisition, scored PM = 5 (unacceptable). These preliminary findings suggest that M plus might improve the registration accuracy in complex applications such as pediatric oncology, when data are acquired throughout the years of follow-up, and is worth investigating. Graphical abstract Graphical abstract showing the clinical workflow of the overall registration procedure including the three rigid steps, the fourth deformable step, the reference MRI and the registered MRI as well as the contoured ROIs. The registration performance is assessed by means of the Perceived Misalignment score (PM).

Background: We evaluated the prognostic role of gross tumor volumes (GTVs) of primary tumor and positive lymph nodes on overall survival (OS) and progression-free survival (PFS) in locally advanced unresectable sinonasal cancer (SNC) treated with definitive intensity-modulated radiotherapy (IMRT) with or without chemotherapy., Methods: Primary tumor GTV (GTV-T), pathologic neck nodes GTV (GTV-N), and positive retropharyngeal nodes GTV (GTV-RPN) of 34 patients with epithelial nonglandular SNC receiving IMRT with or without chemotherapy were retrospectively measured. The GTV variables were analyzed in relation with OS and PFS. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. We also estimated the crude cumulative incidence of locoregional relapses only. The optimal volume cutoff value was determined using an outcome-oriented method among the observed values., Results: GTV-T was significantly associated with decreased OS ( P =0.003) and PFS ( P =0.003). Moreover, patients with disease total volumes (GTV) smaller than 149.44 cm³ had better OS and PFS than patients with higher volumes ( P <0.0001 for both). Neck nodal metastasis impacted on OS and PFS ( P =0.030 and P =0.033, respectively), but GTV-N did not ( P =0.961; P =0.958). Retropharyngeal nodes metastasis was not associated with prognosis (OS: P =0.400; PFS: P =0.104). When GTV-RPN was added to GTV-N (GTV-TN), a relation with PFS ( P =0.041) and a trend toward significance for OS ( P =0.075) were found., Conclusions: Our results show that tumor volume is a powerful predictor of outcome in SNC. This could be useful to identify patients with worse prognosis deserving different treatment strategies.

To assess the efficacy, and the acute and late toxicity of hypofractionated radiotherapy (Hypo-RT), and the impact of age and comorbidities on disease progression and death in elderly breast cancer (BC) patients. Women aged ≥65 years who received Hypo-RT (42.4 Gy in 16 fractions, plus a boost for high-risk patients) were considered for the present analysis. Competing risk analysis was used to estimate the 5-year cumulative incidence of BC progression and BC-related death, calculating the adjusted subhazard ratios (SHR) with 95% confidence intervals (95%CI) in relation to age, hypertension-augmented Charlson Comorbidity Index (hCCI), tumor characteristics, and chemotherapy. The sample included 794 patients with a median age of 74 years (range 65-91 years). At the baseline, 70% of these patients had at least one comorbidity. With a median follow-up of 48.3 months, the 5-year cumulative incidence of BC progression and BC-related death was 6.7% (95%CI 4.8%-9.2%) and 2.3% (95%CI 1.2%-3.9%), respectively. Old age (≥80 years) and a high burden of comorbidity (hCCI ≥ 2) were independently associated with BC progression. Hypo-RT is safe in elderly BC patients, but age and comorbidities influence BC progression. Further studies are warranted., (© 2019 Wiley Periodicals, Inc.)

Purpose: Pediatric radiotherapy (RT) is a highly specialized field, requiring great experience to delineate correctly tumor targets and organs at risk. To reduce treatment failures related to planning inaccuracies and to obtain robust clinical results despite the limited numbers of enrolled pediatric patients, the SIOP PNET5MB clinical trial on medulloblastoma requires a real-time, pre-radiation review of the RT treatment (craniospinal irradiation and boost plan) under the direct responsibility of the national coordinator center. Here we describe the centralized radiotherapy quality assurance (QA) program developed in Italy for this purpose., Methods: Using the software package VODCA (MSS, Hagendorn, Switzerland, www.vodca.ch ), we developed a cloud platform able to handle computed tomography (CT) images and RT objects and to support the complete workflow required by the review process in the context of the SIOP PNET5 trial., Results: All Italian centers participating in the PNET5 trial adopted the proposed QA system. 24 patients were successfully enrolled and reviewed. For 15 patients (62.5%), one or more plan revisions were requested for the craniospinal irradiation plan and for 11 patients (45.8%) plan revisions were requested for the boost. RT was delivered after the plan was centrally approved for all enrolled patients. So far, in Italy, no patients have been excluded from PNET5 due to dosimetric incompliance to the protocol or for exceeding the RT starting time limit., Conclusion: The cloud platform successfully supported the trial workflow, producing official review documents. This efficient QA was crucial to guarantee optimized treatments and protocol compliance for all pediatric patients enrolled in the SIOP protocol.

Purpose: To examine interobserver variability between the radiation oncologist (RTO) and the radiation therapist (RTT) in delineating the tumor bed (TB) in early breast cancer (BC)., Methods: We retrospectively analyzed patients who received a radiotherapy boost to the TB. In a first group, the clinical target volume (CTV) for the boost was the surgical bed, defined by using surgical clips. In a second group, the CTV was defined by identifying a seroma cavity or a metallic find on the scar. These contours were compared in terms of volume, number of slices, and Dice similarity coefficient (DSC)., Results: Forty patients were assessed: 20 had surgical clips (group 1) while the other 20 had none (group 2). There was no difference in the number of slices contoured by the 2 operators for group 1, but a statistically significant difference emerged in the volumes: the RTT identified a TB that was a mean 45% smaller than the one identified by the RTO. Random differences were found between the 2 operators for group 2. The TBs delineated for this group were significantly larger ( P <0.05) than those identified by the RTT for group 1. The mean Dice value between the RTO's and the RTT's TBs was 0.69±0.07 (range 0.53-0.81) for group 1 and 0.37±0.18 (range 0-0.58) for group 2 ( P <0.05)., Conclusions: This study showed that the use of clips coincided with less interoperator variability. With appropriate training, the RTT may play an important part in the multidisciplinary radiotherapy team.

Purpose: To apply Failure Mode and Effects Analysis (FMEA) to optimize linac quality control (QC) protocol in order to ensure patient safety and treatment quality, taking maximum advantage of the available resources., Material and Methods: Each parameter tested by the QC was considered as a potential failure mode (FM). For each FM, likelihood of occurrence (O), severity of effect (S), and lack of detectability (D) were evaluated and corresponding Risk Priority Number (RPN) was calculated from the product of three indexes. The scores were assigned using two methods: (a) A survey submitted to the medical physicists; (b) A semi-quantitative analysis (SQA) performed through: simulation of FMs in the treatment planning system; studies reported in literature; results obtained by the QC data analysis. A weighted RPN for all FMs was calculated taking into account both the methods. For each linac, the tests were then sorted by their frequency and the RPN value., Results: A high variability was found in the scores of the survey, although in many it was reduced in RPN values, highlighting the more relevant tests as on beam output and imaging system. Integrating these results with those obtained by SQA, the RPN-based ranking of tests has been provided considering the specific use of the accelerator: for example, more accurate tests on dose modulation and multileaf collimator speed were required in linacs where intensity-modulated treatment is performed, while, more specific tests on couch and jaw position indicators were necessary where treatments with multiple isocenters and/or junctions between adjacent fields were often delivered., Conclusions: Failure Mode and Effects Analysis is a useful tool to prioritize the linac QCs, taking into account the specific equipment and clinical practice. The integration of SQA and survey results reduces subjectivity of the FMEA scoring and allows to optimize linac QCs without "losing" the expertise and experience of medical physicists and clinical staff., (© 2019 American Association of Physicists in Medicine.)

Purpose: Due to the rarity of vaginal intraepithelial neoplasia (VAIN), it is impossible to define the best treatment approach or to assess vaginal morbidity. However, brachytherapy (BT) could be a valuable choice for VAIN grade 3 (VAIN3). The aim of this paper was to report a single-institution study of the application of high-dose-rate BT and to evaluate clinical outcomes as well as to investigate the dose-effect relationship for vaginal stenosis., Material and Methods: We retrospectively collected hospital records and treatment plans of 14 consecutive women treated in our department from August 2010 to August 2016, with HDR-BT delivered using iridium-192 by a remote after-loading system. Doses in 3D-planned treatment based on computed tomography (CT) were prescribed in high-risk clinical target volume (HR-CTV) at the vaginal wall. Vaginal stenosis was defined as vaginal shortening/narrowing according to CTCAE4.1. The International Commission on Radiation Units & Measurements (ICRU) bladder and rectal points were used for dose report analysis. The posterior-inferior border of the symphysis points was used to derive reference points. The median age of the enrolled women was 60 years, and the median total radiation dose delivered was 35 Gy., Results: During a median period of 15 days, the treatment was well tolerated, and no interruption was necessary. Acute toxicity was minimal, whereas late toxicity appeared in 4 patients as G2 and in 3 patients as G3 vaginal stenosis. Patients with stenosis G ≥ 2 received a higher median dose to the rectal point and were mainly over 60 years old., Conclusions: Patients with VAIN3 seemed to benefit from BT. It is generally assumed that the vagina is radio-resistant, and no constraints have yet been set, but sexual dysfunction after BT is an important cause of long-term distress. Finding applicable dose limits to the vagina could improve patients' quality of life., Competing Interests: Authors report no conflict of interest.

The multichannel vaginal cylinder (MVC) applicator employed for gynecological high dose rate (HDR) brachytherapy increases dose delivery complexity, and thus makes the treatment more prone to errors. A quality assurance (QA) procedure tracking the source throughout dose delivery can detect dwell position and time errors in the multiple channels of the applicator. A new MVC system with integrated real time in vivo treatment delivery QA has been developed based on diodes embedded on the outer surface of the MVC. It has been pre-calibrated and verified using a non-clinical treatment plan with consecutive test positions and dwell times within each catheter, followed by the delivery of ten clinical plans of adjuvant vaginal cuff brachytherapy following hysterectomy for endometrial cancer. The non-clinical verification showed overall mean dwell position and time discrepancies between the nominal and measured treatment of -0.2 ± 0.5 mm and -0.1 ± 0.1 s (k = 1), respectively. The clinical plans showed mean positional discrepancies of 0.2 ± 0.4 and 0.0 ± 0.8 mm, for the central and peripheral catheters, respectively, and mean dwell time discrepancies of -0.1 ± 0.2 and -0.0 ± 0.1 s for central and peripheral catheters, respectively. The innovative prototype of the MVC system has shown the ability to track the source with sub-mm and sub-second accuracy, and demonstrated potential for its incorporation into the clinical routine., (Copyright © 2019 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: This study was designed to apply artificial neural network (ANN) classification methods for the prediction of late fecal incontinence (LFI) after high-dose prostate cancer radiation therapy and to develop a ready-to-use graphical tool., Materials and Methods: In this study, 598 men recruited in 2 national multicenter trials were analyzed. Information was recorded on comorbidity, previous abdominal surgery, use of drugs, and dose distribution. Fecal incontinence was prospectively evaluated through self-reported questionnaires. To develop the ANN, the study population was randomly split into training (n = 300), validation (n = 149), and test (n = 149) sets. Mean grade of longitudinal LFI (ie, expressed as the average incontinence grade over the first 3 years after radiation therapy) ≥1 was considered the endpoint. A suitable subset of variables able to better predict LFI was selected by simulating 100,000 ANN configurations. The search for the definitive ANN was then performed by varying the number of inputs and hidden neurons from 4 to 5 and from 1 to 9, respectively. A final classification model was established as the average of the best 5 among 500 ANNs with the same architecture. An ANN-based graphical method to compute LFI prediction was developed to include one continuous and n dichotomous variables., Results: An ANN architecture was selected, with 5 input variables (mean dose, previous abdominal surgery, use of anticoagulants, use of antihypertensive drugs, and use of neoadjuvant and adjuvant hormone therapy) and 4 hidden neurons. The developed classification model correctly identified patients with LFI with 80.8% sensitivity and 63.7% ± 1.0% specificity and an area under the curve of 0.78. The developed graphical tool may efficiently classify patients in low, intermediate, and high LFI risk classes., Conclusions: An ANN-based model was developed to predict LFI. The model was translated in a ready-to-use graphical tool for LFI risk classification, with direct interpretation of the role of the predictors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction/objective: Oral and oropharyngeal mucositis (OM) represents amultifactorialand complexinterplayof patient-, tumor-, and treatment-related factors. We aimed to build a predictive model for acute OM for locally advanced nasopharyngeal carcinoma (NPC) patients by combining clinical and dosimetric factors., Materials/methods: A series of consecutive NPC patients treated curatively with IMRT/VMAT + chemotherapy at 70 Gy (2-2.12 Gy/fr) was considered. For each patient, clinical- tumor- and treatment-related data were retrospectively collected. oral cavity (OC) and parotid glands (PG, considered as a single organ) were selected as organs-at-risk (OARs). Acute OM was assessed according to CTCAE v4.0 at baseline and weekly during RT. Two endpoints were considered: grade ≥3 and mean grade ≥1.5. DVHs were reduced to Equivalent Uniform Dose (EUD). Dosimetric and clinical/treatment features selected via LASSO were inserted into a multivariable logistic model. Goodness of fit was evaluated through Hosmer-Lemeshow test and calibration plot., Results: Data were collected for 132 patients. G ≥ 3 and mean G ≥ 1.5 OM were reported in 40 patients (30%). Analyses resulted in a 3-variables model for G ≥ 3 OM, including OC EUD with n = 0.05 (OR = 1.02), PG EUD with n = 1 (OR = 1.06), BMI ≥ 30 (OR = 3.8, for obese patients), and a single variable model for mean G ≥ 1.5 OM, i.e. OC EUD with n = 1 (mean dose) (OR = 1.07). Calibration was good in both cases., Conclusion: OC mean dose was found to impact most on OM duration (mean G ≥ 1.5), while G ≥ 3 OM was associated to a synergic effect between PG mean dose and high dose received by small OC volumes, with BMI acting as a dose-modifying factor., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To examine local control, disease-free survival (DFS), and toxicity in elderly (≥ 65 years) breast cancer patients treated with hypofractionated radiotherapy (hypo-RT) with or without a boost to the tumor bed., Patients and Methods: The study was conducted on 752 patients treated from April 2009 to February 2017. Patients received 42.4 Gy in 16 daily fractions (2.65 Gy per fraction). A boost was only administered in cases of grade 3 primary tumor and close or positive margins. Acute and late toxicity was prospectively assessed during and after hypo-RT, based on the Radiation Therapy Oncology Group scale. DFS and local recurrence-free survival were estimated by the Kaplan-Meier method for cumulative probability. Log-rank tests were used to identify differences by subtype. Cox proportional hazard models were used to investigate the impact of various factors on the risk of disease progression., Results: Among the 752 patients treated, 41 (5.5%) experienced disease progression, including 7 (17.1%) exclusively local recurrences; 1 (2.4%) local and nodal recurrence; 1 (2.4%) local and nodal recurrence plus metastasis; 7 (17.1%) nodal recurrences plus metastases; and 25 (61%) exclusively distant metastases. The 5-year DFS, local recurrence-free survival, breast cancer-specific survival, and overall survival rates were 91.8% (95% confidence interval [CI], 88.6-94.2), 98.0% (95% CI, 96.1-99.1), 98.2% (95% CI, 96.5-99.1), and 87.5% (95% CI, 83.8-90.5), respectively. On univariate analysis, the administration of a boost, disease grade (grades 1 and 2 vs. 3), and molecular subtype (triple negative or human epidermal growth factor receptor 2 [HER2] positive, or luminal B vs. luminal A) significantly affected disease progression (P < .01). These findings were confirmed by multivariate analysis., Conclusion: Hypo-RT is effective and well tolerated in the elderly population, and the routine use of a boost for patients over 65 years is not justified. Further studies on the boost issue are strongly advocated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: An increase in naturally-occurring porphyrins has been described in the blood of subjects bearing different kinds of tumors, including colorectal, and this is probably related to a systemic alteration of heme metabolism induced by tumor cells. The aim of our study was to develop an artificial neural network (ANN) classifier for early detection of colorectal adenocarcinoma based on plasma porphyrin accumulation and risk factors., Methods: We measured the endogenous fluorescence of blood plasma in 100 colorectal adenocarcinoma patients and 112 controls using a conventional spectrofluorometer. Height, weight, personal and family medical history, use of alcohol, red meat, vegetables and tobacco were all recorded. An ANN model was built up from demographic data and from the integral of the fluorescence emission peak in the range 610-650 nm. We used the Receiver Operating Characteristic (ROC) curve to assess performance in distinguishing colorectal adenocarcinoma patients and controls. A liquid chromatography-high resolution mass spectrometry (LC-HRMS) analytical method was employed to identify the agents responsible for native fluorescence., Results: The fluorescence analysis indicated that the integral of the fluorescence emission peak in the range 610-650 nm was significantly higher in colorectal adenocarcinoma patients than controls (p < 0.0001) and was weakly correlated with the TNM staging (Spearman's rho = 0.224, p = 0.011). LC-HRMS measurements showed that the agents responsible for the fluorescence emission were mainly protoporphyrin-IX (PpIX) and coproporphyrin-I (CpI). The overall accuracy of our ANN model was 88% (87% sensitivity and 90% specificity) with an area under the ROC curve of 0.83., Conclusions: These results confirm that tumor cells accumulate a diagnostic level of endogenous porphyrin compounds and suggest that plasma porphyrin concentrations, indirectly measured through fluorescence analysis, may be useful, together with risk factors, as a clinical decision support tool for the early detection of colorectal adenocarcinoma. Our future efforts will be aimed at examining how plasma porphyrin accumulation correlates with survival and response to therapy.

Aim: To evaluate the effects of display pixel pitch and maximum luminance on intra- and inter-observer reproducibility and observer performance when evaluating chest lesions and bone fractures., Materials and Methods: This was a multi-institutional study for a retrospective interpretation of selected digital radiography images. Overall, 82 images were selected by senior radiologists, including 50 cases of chest lesions and 32 cases of bone fractures. These images were displayed at two pixel pitches (0.212 and 0.165 mm size pixels) and two maximum luminance values (250 and 500 cd/m 2 ) and reviewed twice by senior and junior radiologists. All the observers had to indicate the likelihood of the presence of the lesions and to rate the relative confidence of their assessment. Cohen Kappa statistic was computed to estimate the reproducibility in correctly identifying lesions; for multi-reader-multi-case (MRMC) analysis, weighted Jackknife Alternative Free-response Receiver Operating Characteristic (wJAFROC) statistical tools was applied., Results: The intra-radiologist and inter-observer reproducibility values were the highest for the 0.165 mm size pixel at 500 cd/m 2 display, for both chest lesions and bone fractures evaluations. As regards chest lesions, observer performances were significantly greater with 0.165 mm size pixel display at 500 cd/m 2 than with lower maximum luminance and/or larger pixel pitch displays. Concerning bone fractures, the performance obtained with 0.212 mm size pixel display at 250 cd/m 2 was statistically lower than that obtained with 0.165 mm sixe pixel display at 500 cd/m 2 ., Conclusion: Our results indicate that an increased maximum luminance level and a decreased pixel pitch of medical-grade display improve the accuracy of detecting both chest lesions and bone fractures.

The purpose of the study was to examine adherence to hormone therapy (HT) in elderly breast cancer patients (≥ 65 years old) treated with hypofractionated radiotherapy. We analyzed data on 550 ER-positive breast cancer patients given hypofractionated whole-breast radiotherapy from June 2009 to September 2016. Baseline comorbidities considered in the hypertension-augmented Charlson Comorbidity Index (hCCI) were retrospectively retrieved. Total hCCI scores were classified as no comorbidity (hCCI = 0), low burden of comorbidity (hCCI = 1), and high burden of comorbidity (hCCI ≥ 2). Competing risk analysis was used to estimate the 5-year cumulative incidence of HT discontinuation. Fine and Gray models were used to estimate the adjusted subhazard ratio (SHR) of HT discontinuation by hCCI score. HT was initially prescribed for 85.6% of patients and almost all of them (468/471) took it for at least one month. It was subsequently discontinued by 45 patients (9.6%), for an overall 5-year cumulative incidence of 11.7%. The 5-year cumulative incidence of HT discontinuation rose from 3.9% in the youngest age group (65-69 years) to 23.3% in the oldest (≥ 80 years) (p = 0.005). Baseline comorbidity had some effect on the likelihood of discontinuing HT, but only among patients with a low burden of comorbidity (hCCI = 1, SHR 2.00, 95%CI 0.95-4.20). Adherence to HT was better in our sample than in the literature, probably because patients were selected and motivated to continue HT. This confirms the importance of communication with patients to improve adherence to HT. We confirmed the association between HT discontinuation and older age, while comorbidity had a limited influence.

Introduction: The purpose of this study was to examine the impact of trastuzumab on acute skin and cardiac toxicity in patients with breast cancer treated with chemotherapy with or without trastuzumab and adjuvant whole breast hypofractionated radiotherapy (hypo-RT)., Materials and Methods: The study was conducted on 727 patients treated from April 2009 to October 2016. Patients received 42.4 Gy in 16 daily fractions (2.65 Gy per fraction). A boost was only administered in cases with grade (G) 3 primary tumor and close or positive margins. Acute and late toxicity was assessed prospectively during and after hypo-RT, based on the Radiation Therapy Oncology Group scale. Multivariable logistic regression models were used to examine the onset of acute skin toxicity (≥ G2) in the whole study population, and the impact of trastuzumab on the onset of acute skin (≥ G2) or cardiac toxicity in the subgroup of 176 patients given chemotherapy., Results: A total of 176 patients received chemotherapy with anthracycline and taxane, and 51 (29%) of them were also treated with trastuzumab. Acute G1, G2, and G3 skin toxicity occurred, respectively, in 56.8%, 27.3%, and 1.1% of the patients given chemotherapy alone, and in 64.7%, 19.6%, and 0% of those given trastuzumab as well. Among the patients given chemotherapy, left ventricular ejection fraction (LVEF) toxicity developed with a severity of G1 (LVEF < 60%-50%) in 12 (6.8%) patients, G2 (LVEF < 50%-40%) in 2 (1.1%) patients, and G3 (LVEF < 40%) in 1 (0.6%) patient. Among the patients also given trastuzumab, 7 (13.7%) patients had G1 LVEF toxicity, and 1 (2%) patient had G2 LVEF toxicity. We found that patients given trastuzumab were at higher risk of cardiac toxicity ≥ G1 (odds ratio, 4.3; P = .01), and at lower risk of acute skin toxicity ≥ G2 (odds ratio, 0.4; P = .03) than patients given chemotherapy alone., Conclusions: This analysis showed that trastuzumab with adjuvant hypo-RT for patients with breast cancer was generally well-tolerated in routine clinical practice. A longer follow-up will be necessary to assess late cardiac toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Local recurrences after breast conserving treatment are mainly close to the original tumor site, and as such shorter fractionation strategies focused on and nearest mammary gland, i.e. accelerated partial breast irradiation (APBI), have been developed. Stereotactic APBI has been attempted, although there is little experience using CyberKnife (CK) for early breast cancer., Methods: This pilot study was designed to assess the feasibility of CK-APBI on 20 evaluable patients of 29 eligible, followed for 2 years. The primary endpoint was acute/sub-acute toxicity; secondary endpoints were late toxicity and the cosmetic result., Results: Mean pathological tumor size was 10.5 mm (±4.3, range 3-18), 8 of these patients were classified as LumA-like, 11 as LumB-like, and 1 as LumB-HER2-enriched. Using CK-APBI with Iris, the treatment time was approximately 60 min (range~ 35 to ~ 120). All patients received 30 Gy in five fractions delivered to the PTV. The median number of beams was 180 (IQR 107-213; range:56-325) with a median PTV isodose prescription of 86.0% (IQR 85.0-88.5; range:82-94). The median PTV was 88.1 cm3 (IQR 63.8-108.6; range:32.3-238.8). The median breast V100 and V50 was 0.6 (IQR 0.1-1.5; range:0-13) and 18.6 (IQR 13.1-21.7; range:7.5-37), respectively. The median PTV minimum dose was 26.2 Gy (IQR 24.7-27.6; range 22.3-29.3). Mild side effects were recorded during the period of observation. Cosmetic evaluations were performed by three observers from the start of radiotherapy up to 2 years. Patients' evaluation progressively increase from 60% to 85% of excellent rating; this trend was similar to that of external observer., Conclusions: These preliminary results showed the safe feasibility of CK-APBI in early breast cancer, with mild acute and late toxicity and very good cosmetic results., Trial Registration: The present study is registered at Clinicaltrial.gov ( NCT02896322 ). Retrospectively egistered August 4, 2016.

Purpose: A direct planning approach with multi-channel vaginal cylinders (MVCs) used for HDR brachytherapy of vaginal cancers is particularly challenging. Purpose of this study was to compare the dosimetric performances of different forward and inverse methods used for the optimization of MVC-based vaginal treatments for endometrial cancer, with a particular attention to the definition of strategies useful to limit the high doses to the vaginal mucosa., Methods: Twelve postoperative vaginal HDR brachytherapy treatments performed with MVCs were considered. Plans were retrospectively optimized with three different methods: Dose Point Optimization followed by Graphical Optimization (DPO + GrO), Inverse Planning Simulated Annealing with two different class solutions as starting conditions (surflPSA and homogIPSA) and Hybrid Inverse Planning Optimization (HIPO). Several dosimetric parameters related to target coverage, hot spot extensions and sparing of organs at risk were analyzed to evaluate the quality of the achieved treatment plans. Dose homogeneity index (DHI), conformal index (COIN) and a further parameter quantifying the proportion of the central catheter loading with respect to the overall loading (i.e., the central catheter loading index: CCLI) were also quantified., Results: The achieved PTV coverage parameters were highly correlated with each other but uncorrelated with the hot spot quantifiers. HomogIPSA and HIPO achieved higher DHIs and CCLIs and lower volumes of high doses than DPO + GrO and surflPSA., Conclusions: Within the investigated optimization methods, HIPO and homoglPSA showed the highest dose homogeneity to the target. In particular, homogIPSA resulted also the most effective in reducing hot spots to the vaginal mucosa., (Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: This study was based on a survey to investigate perceptions of hadrontherapy of the members of the Italian Association of Medical Physics (AIFM). The survey was digitally submitted to the 991 members between the end of January and the beginning of April 2016., Methods: A 19-item questionnaire was designed focusing on advantages and disadvantages of hadrontherapy, current status and possible future improvements, and need and opportunities for future investments in Italy and abroad. Information about professional qualifications, main fields of clinical involvement and specific competencies of the respondents was also collected., Results: The survey was completed by 121 AIFM members (response rate 12.2%). In the answers collected, it was shown that medical physicists expressed interest in hadrontherapy mainly for reasons of personal interest rather than for professional needs (90% ± 2.5% vs. 52% ± 4.3% of the respondents, respectively), with a good knowledge of the related basic aspects as well as of the pros and cons of its application. However, poor knowledge of the current status of hadrontherapy was observed among the medical physicists not directly involved at a professional level, who were less than 3% of the physicists working in radiotherapy., Conclusions: In light of these results, the implementation of new training and education initiatives should be devised to promote a deeper and global knowledge of hadrontherapy-related issues, not only from a theoretical point of view but also in practical terms. Moreover, a close collaboration between highly specialized medical physicists employed in hadrontherapy centers and others in oncology hospitals should be -encouraged.

Purpose: Three MOSkins dosimeters were assembled over a rectal probe and used to perform in vivo dosimetry during HDR brachytherapy treatments of vaginal cancer. The purpose of this study was to verify the applicability of the developed tool to evaluate discrepancies between planned and measured doses to the rectal wall., Materials and Methods: MOSkin dosimeters from the Centre for Medical Radiation Physics are particularly suitable for brachytherapy procedures for their ability to be easily incorporated into treatment instrumentation. In this study, 26 treatment sessions of HDR vaginal brachytherapy were monitored using three MOSkin mounted on a rectal probe. A total of 78 measurements were collected and compared to doses determined by the treatment planning system., Results: Mean dose discrepancy was determined as 2.2±6.9%, with 44.6% of the measurements within ±5%, 89.2% within ±10% and 10.8% higher than ±10%. When dose discrepancies were grouped according to the time elapsed between imaging and treatment (i.e., group 1: ≤90min; group 2: >90min), mean discrepancies resulted in 4.7±3.6% and 7.1±5.0% for groups 1 and 2, respectively. Furthermore, the position of the dosimeter on the rectal catheter was found to affect uncertainty, where highest uncertainties were observed for the dosimeter furthest inside the rectum., Conclusions: This study has verified MOSkin applicability to in-patient dose monitoring in gynecological brachytherapy procedures, demonstrating the dosimetric rectal probe setup as an accurate and convenient IVD instrument for rectal wall dose verification. Furthermore, the study demonstrates that the delivered dose discrepancy may be affected by the duration of treatment planning., (Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Rationale and Objectives: This study evaluates the influence of the calibrated luminance level of medical displays in the detectability of microcalcifications and spiculated lesions in digital breast tomosynthesis images., Materials and Methods: Four models of medical displays with calibrated maximum and minimum luminance, respectively, ranging from 500 to 1000 cd/m 2 and from 0.5 to 1.0 cd/m 2 , were investigated. Forty-eight studies were selected by a senior radiologist: 16 with microcalcifications, 16 with spiculated lesions, and 16 without lesions. All images were anonymized and blindly evaluated by one senior and two junior radiologists. For each study, lesion presence or absence and localization statements, interpretative difficulty level, and overall quality were reported. Cohen's kappa statistic was computed between monitors and within or between radiologists to estimate the reproducibility in correctly identifying lesions; for multireader-multicase analysis, the weighted jackknife alternative free-response receiver operating characteristic statistical tool was applied., Results: Intraradiologist reproducibility ranged from 0.75 to 1.00. Interreader as well as reader-truth agreement values were >0.80 and higher with the two 1000 cd/m 2 luminance displays than with the lower luminance displays for each radiologist. Performances in the detectability of breast lesions were significantly greater with the 1000 cd/m 2 luminance displays when compared to the display with the lowest luminance value (P value <0.001)., Conclusions: Our findings highlight the role of display luminance level on the accuracy of detecting breast lesions., (Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate efficacy, safety and tolerability of Xonrid®, a new medical device, in preventing radiation dermatitis associated with head and neck cancer (HNC) radiotherapy (RT)., Methods: In this monocentric, prospective pilot study, adult consecutive HNC patients who were planned to receive curative RT with or without chemotherapy were enrolled. Patients were instructed to apply Xonrid® on the irradiated area during treatment continuing until 2 weeks after the completion of RT or the development of severe skin toxicity. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 scale. The patient reported outcome measures included the Skindex-16 questionnaire and patient satisfaction. Skin reflectance spectra were analyzed to objectively evaluate dermatitis., Results: In total, 41 subjects were enrolled (30 males, median age 60 years). No skin adverse events were recorded either in the skin area where the product was applied or in the nearby skin over the entire period of administration. At the end of RT, nine patients (22%) presented G1, 31 (76%) G2, and one patient (2%) G3 skin toxicity (after 5 weeks). Seven and 20 patients reached skin maximum toxicity at the fourth week and after the seventh week, respectively. An increasing trend of median spectrophotometry scores along with skin toxicity grades was observed. A correlation between Skindex-16 scores and skin toxicity grade during treatment was found., Conclusions: Our study results suggest that Xonrid® is well tolerated, safe, and effective in minimizing and delaying high-grade radiation dermatitis in HNC patients.

Purpose: Definition of the optimal treatment schedule for high-risk prostate cancer is under debate. A combination of photon intensity modulated radiotherapy (IMRT) on pelvis with a carbon ion boost might be the optimal treatment scheme to escalate the dose on prostate and deliver curative dose with respect to normal tissue and quality of dose distributions. In fact, carbon ion beams offer the advantage to deliver hypofractionated radiotherapy (RT) using a significantly smaller number of fractions compared to conventional RT without increasing risks of late effects., Methods: This study is a prospective phase II clinical trial exploring safety and feasibility of a mixed beam scheme of carbon ion prostate boost followed by photon IMRT on pelvis. The study is designed to enroll 65 patients with localized high-risk prostate cancer at 3 different oncologic hospitals: Istituto Europeo di Oncologia, Fondazione IRCCS Istituto Nazionale dei Tumori, and Centro Nazionale di Adroterapia Oncologica. The primary endpoint is the evaluation of safety and feasibility with acute toxicity scored up to 1 month after the end of RT. Secondary endpoints are treatment early (3 months after the end of RT) and long-term tolerability, quality of life, and efficacy., Results: The study is not yet recruiting; in silico studies are ongoing and we expect to start recruitment by 2017., Conclusions: The present clinical trial aims at improving the current treatment for high-risk prostate cancer, evaluating safety and feasibility of a new RT mixed-beam scheme including photons and carbon ions. Encouraging results are coming from carbon ion facilities worldwide on the treatment of different tumors including prostate cancers. Carbon ions combine physical properties allowing for high dose conformity and advantageous radiobiological characteristics. The proposed mixed beam treatment has the advantage to combine a photon high conformity standard of care IMRT phase with a hypofractionated carbon ion RT boost delivered in a short overall treatment time.

Production of photonuclear particles in a tissue-equivalent medium has been calculated for linacs at 6, 10 and 15 MV from Varian TrueBeam. Based on the knowledge of bremsstrahlung fluence spectra and linac photon beam parameters, numerical integration was performed on the cross sections for photoparticle production of the constituent elements of tissue (2H,12C,13C,16O,17O,18O,14N,15N). At 15 MV, at the depth of photon maximum dose, the total absorbed dose due to neutrons, protons, alphas and residual nuclei from photon reactions in tissue (5.5E-05 Gy per Gy of photons) is comparable to that due to neutrons from accelerator head. Results reasonably agree with data reported in the literature using Monte Carlo models simulating linac head components. This work suggests a simple method to estimate the dose contributed by the photon-induced nuclear particles for high-energy photon beams produced by linacs in use, as it might be relevant for late stochastic effects., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To validate and apply a method for the quantification of breathing-induced prostate motion (BIPM) for patients treated with radiotherapy and implanted with electromagnetic transponders for prostate localization and tracking., Methods: For the analysis of electromagnetic transponder signal, dedicated software was developed and validated with a programmable breathing simulator phantom. The software was then applied to 1,132 radiotherapy fractions of 30 patients treated in supine position, and to a further 61 fractions of 2 patients treated in prone position., Results: Application of the software in phantom demonstrated reliability of the developed method in determining simulated breathing frequencies and amplitudes. For supine patients, the in vivo analysis of BIPM resulted in median (maximum) amplitudes of 0.10 mm (0.35 mm), 0.24 mm (0.66 mm), and 0.17 mm (0.61 mm) in the left-right (LR), cranio-caudal (CC), and anterior-posterior (AP) directions, respectively. Breathing frequency ranged between 7.73 and 29.43 breaths per minute. For prone patients, the ranges of the BIPM amplitudes were 0.1-0.5 mm, 0.5-1.3 mm, and 0.7-1.7 mm in the LR, CC, and AP directions, respectively., Conclusions: The developed method was able to detect the BIPM with sub-millimeter accuracy. While for patients treated in supine position the BIPM represents a reduced source of treatment uncertainty, for patients treated in prone position, it can be higher than 3 mm.

Purpose: To evaluate toxicity in breast cancer patients treated with anthracycline and taxane based chemotherapy and whole breast hypofractionated radiotherapy, and to identify the risk factors for toxicity., Methods and Materials: 537 early breast cancer patients receiving hypofractionated radiotherapy after conservative surgery were enrolled from April 2009 to December 2014, in an Italian cancer institute. The dose was 42.4 Gy in 16 daily fractions, 2.65 Gy per fraction. The boost to the tumor bed was administered only in grade III breast cancer patients and in patients with close or positive margins. Acute and late toxicity were prospectively assessed during and after radiotherapy according to RTOG scale. The impact of patients clinical characteristics, performed treatments and dose inhomogeneities on the occurrence of an higher level of acute skin toxicity and late fibrosis has been evaluated by univariate and multivariate analysis., Results: The mean age was 74 (range 46-91 yrs). 27% of patients received boost. 22% of cases (n = 119) received also chemotherapy. The median follow-up was 32 months. G1 and G2/G3 acute skin toxicity were 61.3% and 20.5% and G1 and G2/G3 late fibrosis 12.6% and 4.3% respectively. Chemotherapy (p = 0.04), diabetes (p = 0.04) and boost administration (p < 0.01) were found to be statistically significant on the occurrence of late fibrosis, but a multivariate analysis did not show any factors connected. The boost administration (p < 0.01), the breast volume (p = 0.05), dose inhomogeneities (p < 0.01) and boost volume (p = 0.04) were found to be statistically significant as concerns the occurrence of acute skin reaction at the univariate analysis, but only the boost administration (p = 0.02), at multivariate analysis., Conclusions: The results of our study, according to the large randomized trials, confirmed that hypofractionated whole breast irradiation is safe, and only the boost administration seems to be an important predictor for toxicity. Chemotherapy does not impact on acute and late skin toxicity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the dosimetric coverage of axillary levels I, II, and III obtained with standard whole breast irradiation in 1 to 2 positive sentinel lymph nodes (SLNs) patients not submitted to axillary lymph nodes dissection (ALND), and to compare the lymph nodes areas coverage obtained with 3D conformal radiation therapy, intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT)., Methods: Patients with 1 to 2 positive SLNs undergoing breast-conserving therapy, without ALND, were included in the analysis. For each patient, 3 treatment plans were performed: a 3D conventional tangential plan, a static IMRT plan, and a volumetric IMRT, designed to encompass the entire breast parenchyma. The volumes of axillary levels I, II, and III receiving 90% and 95% (V90, V95) of the whole breast prescribed dose were evaluated. Dose-volume histograms were compared by means of the Friedman test., Results: Ten patients were enrolled. All defined breast volumes received &gt;95% of the prescribed dose with the 3 techniques. Median V95 for axillary level I was 26.4% (range 4.7%-61.3%) for 3D plans, 8.6% (range 0.64%-19.1%) for static IMRT plans, and 2.6% (range 0.4%-4.7%) for volumetric IMRT plans (p&lt;0.001). Median V95 for axillary level II was 5.4% (range 0%-14.6%), 1.9% (range 0%-15%), and 2.6% (range 0.4%-4.7%) for 3D, static IMRT, and volumetric IMRT, respectively (p&lt;0.001)., Conclusions: Results of our analysis showed that standard 3D tangential whole breast irradiation failed to deliver a therapeutic dose to axillary levels I and II. The coverage was even lower using static and volumetric IMRT techniques.

The evaluation of incoherent artificial optical radiation (AOR) exposure in hospital environments is a complex task due to the variety of sources available. This study has been designed to provide a proposal for the precautionary assessment of the related risk. This survey suggested that, in our Institution, at least three kinds of AOR sources required specific investigations: ambient lighting, theatre operating lighting and ultraviolet radiation (UVR) sources. For each kind of evaluated sources a specific measurement approach was developed. All irradiance measurements were made using a commercial spectroradiometer. The obtained results were compared with the appropriate exposure limit values (ELVs) defined in the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines and adopted by the European Directive 2006/25/EC. The risk related to the evaluated AOR exposure was finally assessed according to our risk matrix. According to our results, the emission of ambient lighting in the actual exposure conditions was always in accordance with the ELVs and the related risk was classifiable as not relevant. The risk related to the exposure to theatre operating lighting resulted not negligible, especially when two or more sources were used with focal spots overlapping on reflective objects. UVR sources emission may represent a health hazard depending, in particular, on the set up of the device containing the source. In case of laminar flow cabinets and closed transilluminators, if the UVR source is well contained within an enclosure with interlock, it presents no risk of exposure. Otherwise, the emission arising from UVR lamps, open transilluminators or sources not provided with interlock, may represent a risk classifiable as high even in the actual working conditions. The personal protective equipment used by workers were also assessed and their suitability was discussed.

Background and Purpose: To study if MOSkin detectors coupled to a trans-rectal ultrasound (TRUS) probe may be used for in vivo dosimetry on the rectal wall surface during US-based HDR prostate brachytherapy and to quantify possible discrepancies between planned and delivered doses., Materials and Methods: MOSkins are a specific type of MOSFET dosimeter optimized to measure dose in steep dose gradients on interfaces. Two MOSkins were assembled on a TRUS probe used for on-line treatment planning. Measurements of the dose to the rectal wall were performed over 18 treatment sessions and compared to the doses calculated on the pre-treatment plan (DPRE) and reconstructed on post-treatment images (DPOST)., Results: Averages of the absolute differences between MOSkin readings and DPRE, MOSkin readings and DPOST and DPRE and DPOST were 6.7 ± 5.1%, 3.6 ± 1.9% and 6.3 ± 4.7%, respectively. Agreement between measurements and DPOST was significantly better than between measurements and DPRE (p=0.002) and DPRE and DPOST (p=0.004). Discrepancy between DPOST and DPRE correlated with the time required for treatment planning., Conclusion: MOSkin dosimeters integrated to the TRUS probe proved to be an accurate instrument for measuring the dose delivered to the rectal wall in HDR prostate brachytherapy. The delivered doses may differ significantly from those calculated in the treatment plan., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose/objective: Prospectively assessing clinical/dosimetry factors affecting the acute worsening of urinary functionality after radiotherapy for prostate cancer., Material/methods: DUE01 population was considered, including patients treated with conventional or moderate hypo-fractionation (2.2-2.7 Gy/fr). Relevant clinical factors were collected, urinary symptoms were self-reported through the International Prostate Symptom Score (IPSS) before and at the end of radiotherapy; while absolute weekly dose-surface histograms (DSHw) were chosen as dosimetry descriptors. An IPSS increase of at least 10 and 15 points (ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15) were chosen as endpoints. Patients with baseline IPSS>20 were excluded. Relevant factors were chosen through a bootstrap-based in silico methodology., Results: Complete information was available for 380 patients: 77/380 (20%) and 28/380 (7%) with ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15, respectively. Neoadjuvant hormone was protective (OR=0.49 and 0.69). DSHw at 8.5 Gy/week and 12 Gy/week were risk factors, with additional risk for patients who use cardiovascular drugs and anti-hypercholesterolemia drugs. In the hypo-fractionated subgroup (n=209) the role of cardiovascular drugs (OR=2.16) for ΔIPSS ⩾ 10 and anti-hypercholesterolemia drugs (OR=2.80) for ΔIPSS⩾15, together with DSHw (10 Gy/week and 12.5 Gy/week, respectively), was confirmed., Conclusion: Current study shows a dose-surface/volume effect for acute large worsening of urinary functionality; several clinical variables largely impact the risk and especially all the factors related with vascular diseases., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: To compare volumetric modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) plans for treatment of unresectable paranasal sinuses cancers (PNSCs) with different clinical presentations., Material and Methods: Four patients treated for primary target volume only (group 1), four requiring elective nodal irradiation (group 2) and four with positive nodes in macroscopic disease (group 3) were selected. For each patient were generated 7 fields IMRT, coplanar VMAT (c-VMAT) and non-coplanar VMAT (nc-VMAT) treatment plans. Total doses were 70Gy and 54Gy to high dose planning target volume (HD-PTV) and low-dose-PTV, respectively. Dose-volume histogram, conformity and homogeneity index (CI and HI), and monitor units (MUs) per Gy were evaluated., Results: VMAT provided significantly better target coverage, in terms of V100% (Volume encompassed by the isodose 100%), than IMRT, in particular when nc-VMAT was used. In general, organ at risk sparing is similar with the three approaches, although nc-VMAT can allow a statistically significant reduction of dose to contralateral parotid gland and cochlea for all three groups., Conclusions: VMAT can offer significant improvement of treatment for all unresectable PNSCs over existing IMRT techniques. In particular, nc-VMAT may be a further advantage for those patients with sinonasal cancers and involvement of the nodes in whom large volumes and complex/irregular shape have to be irradiated, even if clinical benefits should be established in the future., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aims: To evaluate technical issues and clinical outcomes after postoperative volumetric-modulated arc therapy (VMAT) in two cases of malignant lacrimal gland cancer., Patients & Methods: Patients were treated by postoperative VMAT and post-treatment clinical outcomes were followed-up to 18 months., Results: Dosimetric results were acceptable and acute toxicity was manageable in both patients. No evidence of disease was found at latest follow-up. One patient underwent corneal transplant for central corneal ulceration, experiencing reduction of visual acuity., Conclusion: Postoperative VMAT for treatment of lacrimal gland tumors offers improved outcome, with manageable side effects. In the context of photon beam radiotherapy, VMAT emerged as a valuable treatment option for these malignant tumors.

Background and Purpose: DUE01 is an observational study aimed at developing predictive models of genito-urinary toxicity of patients treated for prostate cancer with conventional (1.8-2Gy/fr, CONV) or moderate hypo-fractionation (2.35-2.7Gy/fr, HYPO). The current analysis focused on the relationship between bladder DVH/DSH and the risk of International Prostate Symptoms Score (IPSS)⩾15/20 at the end of radiotherapy., Materials and Methods: Planning and relevant clinical parameters were prospectively collected, including DVH/DSH, LQ-corrected (DVHc/DSHc) and weekly (DVHw/DSHw) histograms. Best parameters were selected by the differences between patients with/without IPSS⩾15/20 at the end of radiotherapy. Logistic uni- and backward multi-variable (MVA) analyses were performed., Results: Data of 247 patients were available (CONV: 116, HYPO: 131). Absolute DVHw/DSHw and DVHc/DSHc predicted the risk of IPSS⩾15 at the end of radiotherapy (n=77/247); an MVA model including baseline IPSS, anti-hypertensive, T stage, the absolute surface receiving ⩾8.5Gy/week and ⩾12.5Gy/week was developed (AUC=0.78, 95% CI: 0.72-0.83). Similar AUC values were found if replacing DSHw with DVHw/DVHc/DSHc parameters. The impact of dose-volume/surface parameters remained when excluding patients with baseline IPSS⩾15 and in HYPO. IPSS⩾20 at the end of radiotherapy (n=27/247) was mainly correlated to baseline IPSS and T stage., Conclusions: Although the baseline IPSS was the main predictor, constraining v8.5w<56cc and v12.5w<5cc may significantly reduce acute GU toxicity., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

MOSkin detectors were studied to perform real-time in vivo dose measurements in high dose rate prostate brachytherapy. Measurements were performed inside an urethral catheter in a gel phantom simulating a real prostate implant. Measured and expected doses were compared and the discrepancy was found to be within 8.9% and 3.8% for single MOSkin and dual-MOSkin configurations, respectively. Results show that dual-MOSkin detectors can be profitably adopted in prostate brachytherapy treatments to perform real-time in vivo dosimetry inside the urethra., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Treatment plans for prostate cancer patients undergoing stereotactic body radiation therapy (SBRT) are often challenging due to the proximity of organs at risk. Today, there are no objective criteria to determine whether an optimal treatment plan has been achieved, and physicians rely on their personal experience to evaluate the plan's quality. In this study, we propose a method for determining rectal and bladder dose constraints achievable for a given patient's anatomy. We expect that this method will improve the overall plan quality and consistency, and facilitate comparison of clinical outcomes across different institutions. The 3D proximity of the organs at risk to the target is quantified by means of the expansion-intersection volume (EIV), which is defined as the intersection volume between the target and the organ at risk expanded by 5 mm. We determine a relationship between EIV and relevant dosimetric parameters, such as the volume of bladder and rectum receiving 75% of the prescription dose (V75%). This relationship can be used to establish institution-specific criteria to guide the treatment planning and evaluation process. A database of 25 prostate patients treated with CyberKnife SBRT is used to validate this approach. There is a linear correlation between EIV and V75% of bladder and rectum, confirming that the dose delivered to rectum and bladder increases with increasing extension and proximity of these organs to the target. This information can be used during the planning stage to facilitate the plan optimization process, and to standardize plan quality and consistency. We have developed a method for determining customized dose constraints for prostate patients treated with robotic SBRT. Although the results are technology specific and based on the experience of a single institution, we expect that the application of this method by other institutions will result in improved standardization of clinical practice.

Hypothyroidism remains a common late effect after irradiation of the neck/mediastinum for Hodgkins lymphoma (HL). We evaluated the protective effect of TSH suppression during neck/mediastinum irradiation. From 1998 to 2001, 14 consecutive euthyroid children were given, before and until the end of their radiotherapy on neck/mediastinum, L-thyroxine at TSH-suppressive doses. The 14 patients had adequate TSH suppression during irradiation in 8, inadequate in 6. The 8-year hypothyroidism-free-survival after irradiation was 75 ± 15% for the former group, 0% for the latter (P = 0.009). TSH suppression could have a protective effect on thyroid function as shown in a small group of patients with HL., (Copyright © 2011 Wiley-Liss, Inc.)

Introduction: the aims of this study were to analyze the systematic and random interfractional set-up errors during Intensity Modulated Radiation Therapy (IMRT) in 20 consecutive nasopharyngeal carcinoma (NPC) patients by means of Electronic Portal Images Device (EPID), to define appropriate Planning Target Volume (PTV) and Planning Risk Volume (PRV) margins, as well as to investigate set-up displacement trend as a function of time during fractionated RT course., Material and Methods: before EPID clinical implementation, an anthropomorphic phantom was shifted intentionally 5 mm to all directions and the EPIs were compared with the digitally reconstructed radiographs (DRRs) to test the system's capability to recognize displacements observed in clinical studies. Then, 578 clinical images were analyzed with a mean of 29 images for each patient., Results: phantom data showed that the system was able to correct shifts with an accuracy of 1 mm. As regards clinical data, the estimated population systematic errors were 1.3 mm for left-right (L-R), 1 mm for superior-inferior (S-I) and 1.1 mm for anterior-posterior (A-P) directions, respectively. Population random errors were 1.3 mm, 1.5 mm and 1.3 mm for L-R, S-I and A-P directions, respectively. PTV margin was at least 3.4, 3 and 3.2 mm for L-R, S-I and A-P direction, respectively. PRV margins for brainstem and spinal cord were 2.3, 2 and 2.1 mm and 3.8, 3.5 and 3.2 mm for L-R, A-P and S-I directions, respectively. Set-up error displacements showed no significant changes as the therapy progressed (p>0.05), although displacements >3 mm were found more frequently when severe weight loss or tumor nodal shrinkage occurred., Discussion: these results enable us to choose margins that guarantee with sufficient accuracy the coverage of PTVs and organs at risk sparing. Collected data confirmed the need for a strict check of patient position reproducibility in case of anatomical changes.

The simultaneous integrated boost (SIB)-IMRT technique allows the simultaneous delivery of different dose levels to different target volumes within a single treatment fraction. The most significant aspect associated with SIB-IMRT is related to the fractionation strategy, concerning two time-dose parameters: (1) the shortening of the overall treatment time (OTT); (2) the increase of fraction size (FS) to the boost volume. The SIB-IMRT technique represents, therefore, a new way to investigate the accelerated fractionation in definitive treatment of head and neck (H&N) cancers. The aims of this paper are the following: (1) to briefly review the influence of OTT and FS on H&N tumors and on acutely and late responding normal tissues; (2) to review the results of clinical studies of accelerated radiotherapy not employing IMRT in H&N cancer; (3) to review the clinical experiences of the SIB-IMRT technique and to compare the different SIB regimes in terms of radiobiological efficacy., (2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To report the outcome of a consecutive series of patients with nonmetastatic nasopharyngeal carcinoma (NPC), focusing on the impact of treatment-related factors., Methods and Materials: Between 2000 and 2006, 87 patients with NPC were treated with either conventional (two- or three-dimensional) radiotherapy (RT) or with intensity-modulated RT (IMRT). Of these patients, 81 (93%) received either concomitant CHT (24%) or both induction and concomitant chemotherapy (CHT) (69%). Stage was III in 36% and IV in 39% of patients. Outcomes in this study population were compared with those in the previous series of 171 patients treated during 1990 to 1999., Results: With a median follow-up of 46 months, actuarial rates at 3 years were the following: local control, 96%; local-regional control, 93%; distant control (DC), 90%; disease-free survival (DFS), 82%; overall survival, 90%. In Stage III to IV patients, distant control at 3 years was 56% in patients treated with concomitant CHT only and 92% in patients treated with both induction and concomitant CHT (p = 0.014). At multivariate analysis, histology, N-stage, RT technique, and total RT dose had the strongest independent impact on DFS (p < 0.05). Induction CHT had a borderline effect on DC (p = 0.07). Most dosimetric statistics were improved in the group of patients treated with IMRT compared with conventional 3D technique. All outcome endpoints were substantially better in the study population compared with those in the previous series., Conclusions: Outcome of NPC has further improved in the study period compared with the previous decade, with a significant effect of RT technique optimization. The impact of induction CHT remains to be demonstrated in controlled trials.

Purpose: Myeloablative regimens were frequently used for medulloblastoma relapsing after craniospinal irradiation (CSI): in 1997-2002, we used repeated surgery, standard-dose and myeloablative chemotherapy, and reirradiation., Methods and Materials: In 10 patients, reinduction included sequential high-dose etoposide, high-dose cyclophosphamide/vincristine, and high-dose carboplatin/vincristine, then two myeloablative courses with high-dose thiotepa (+/- carboplatin); 6 other patients received two of four courses of cisplatin/etoposide. Hematopoietic precursor mobilization followed high-dose etoposide or high-dose cyclophosphamide or cisplatin/etoposide therapy. After the overall chemotherapy program, reirradiation was prescribed when possible., Results: Seventeen patients were treated: previous treatment included CSI of 19.5-36 Gy with posterior fossa/tumor boost and chemotherapy in 16 patients. Fifteen patients were in their first and 2 in their second and third relapses, respectively. First progression-free survival had lasted a median of 26 months. Relapse sites included leptomeninges in 9 patients, spine in 4 patients, posterior fossa in 3 patients, and brain in 1 patient. Three patients underwent complete resection of recurrence, and 10 underwent reirradiation. Twelve of 14 patients with assessable tumor had an objective response after reinduction; 2 experienced progression and were not given the myeloablative courses. Remission lasted a median of 16 months. Additional relapses appeared in 13 patients continuing the treatment. Fifteen patients died of progression and 1 died of pneumonia 13 months after relapse. The only survivor at 93 months had a single spinal metastasis that was excised and irradiated. Survival for the series as a whole was 11-93 months, with a median of 41 months., Conclusions: Despite responses being obtained and ample use of surgery and reirradiation, second-line therapy with myeloablative schedules was not curative, barring a few exceptions. A salvage therapy for medulloblastoma after CSI still needs to be sought.

Purpose: With a view to improving the prognosis for patients with metastatic medulloblastoma, we tested the efficacy and toxicity of a hyperfractionated accelerated radiotherapy (HART) regimen delivered after intensive sequential chemotherapy., Patients and Methods: Between 1998 and 2007, 33 consecutive patients received postoperative methotrexate (8 g/m(2)), etoposide (2.4 g/m(2)), cyclophosphamide (4 g/m(2)), and carboplatin (0.8 g/m(2)) in a 2-month schedule, then HART with a maximal dose to the neuraxis of 39 Gy (1.3 Gy/fraction, 2 fractions/d) and a posterior fossa boost up to 60 Gy (1.5 Gy/fraction,2 fractions/d). Patients with persistent disseminated disease before HART were consolidated with two myeloablative courses and circulating progenitor cell rescue., Results: Patients were classified as having M1 (n = 9), M2 (n = 6), M3 (n = 17), and M4 (n = 1) disease. Seven patients younger than 10 years old who achieved complete response after chemotherapy received a lower dose to the neuraxis (31.2 Gy). Twenty-two of the 32 assessable patients responded to chemotherapy; disease was stable in five patients and progressed in five patients. One septic death occurred before radiotherapy. Eight patients experienced relapse after a median of 12 months. Fourteen of the 33 patients underwent consolidation therapy after HART. With a median 82-month survivor follow-up, the 5-year event-free, progression-free, and overall survival rates were 70%, 72%, and 73%, respectively. No severe clinical complications of HART have emerged so far., Conclusion: HART after intensive postoperative chemotherapy, followed by myeloablative chemotherapy in selected cases, proved feasible in children with metastatic medulloblastoma. The results of our treatment compare favorably with other series treated using conventional therapies.

Patients with diffuse pontine gliomas have a median survival of less than one year and represent a challenge for pediatric oncologists, prompting them to attempt experimental therapies. From 1987 to 2005, 62 children with diffuse pontine glioma, not amenable to curative surgery, were treated according to four successive pilot protocols: (1) concomitant chemo-radiotherapy (etoposide, cytarabine, ifosfamide, cisplatin, and dactinomycin); (2) intensive high-dose courses chemotherapy (cisplatin/etoposide, cyclophosphamide/vincristine/methotrexate) and a subsequent course of myeloablative thiotepa followed by radiation and maintenance chemotherapy; (3) cisplatin/etoposide followed by isotretinoin before, during and after focal irradiation; and (4) iv vinorelbine before, during, and after irradiation. Considering all patients, 77% experienced a transient response to treatment, always detectable after radiotherapy. The progression-free survival (PFS) rate was 25 +/- 6% at one year, median PFS was seven months; overall survival (OS) was 45 +/- 6%, median OS was eleven months: no statistical differences in the four studies in terms of outcome were detected. Despite improved diagnostic, therapeutic, and supportive tools in pediatric neuro-oncology, little has been achieved for patients with diffuse pontine tumors.

Purpose: Hypothyroidism is one of the earliest endocrine effects of craniospinal irradiation (CSI). The effects of radiation also depend on circulating thyroid-stimulating hormone (TSH), which acts as an indicator of thyrocyte function and is the most sensitive marker of thyroid damage. Hence, our study was launched in 1998 to evaluate the protective effect of TSH suppression during CSI for medulloblastoma/primitive neuroectodermal tumor., Patients and Methods: From Jan 1998 to Feb 2001, a total of 37 euthyroid children scheduled for CSI for medulloblastoma/primitive neuroectodermal tumor underwent thyroid ultrasound and free triiodothyronine (FT3), free thyroxine (FT4), and TSH evaluation at the beginning and end of CSI. From 14 days before and up to the end of CSI, patients were administered l-thyroxine at suppressive doses; every 3 days, TSH suppression was checked to ensure a value <0.3 mum/ml. During follow-up, blood tests and ultrasound were repeated after 1 year; primary hypothyroidism was considered an increased TSH level greater than normal range. CSI was done using a hyperfractionated accelerated technique with total doses ranging from 20.8-39 Gy; models were used to evaluate doses received by the thyroid bed., Results: Of 37 patients, 25 were alive a median 7 years after CSI. They were well matched for all clinical features, except that eight children underwent adequate TSH suppression during CSI, whereas 17 did not. Hypothyroidism-free survival rates were 70% for the "adequately TSH-suppressed" group and 20% for the "inadequately TSH-suppressed" group (p = 0.02)., Conclusions: Thyroid-stimulating hormone suppression with l-thyroxine had a protective effect on thyroid function at long-term follow-up. This is the first demonstration that transient endocrine suppression of thyroid activity may protect against radiation-induced functional damage.

Aims and Background: In vivo and phantom dosimetry is reported to estimate the fetal dose and evaluate the effectiveness of a special shielding device to reduce fetal exposure in a woman undergoing postoperative radiation therapy for synovial oral cavity sarcoma at the 30th week of pregnancy., Methods: In vivo measurements were performed by placing thermoluminescent dosimeters on 3 points for fetal dose estimation: uterine fundus, umbilicus and pubis. A Rando anthropomorphic phantom was used to simulate radiotherapy. We also performed off-axis dose measurements for wedged beams to estimate the dose contribution of this accessory used in the treatment., Results: The special shielding device reduced the fetal dose by 70% on average, despite the presence of wedges, which increased the dose by a factor of about 2.5. Before delivery the patient received 48 Gy, and from the in vivo measurements a fetal dose of 8.5, 1.7 and 0.7 cGy was estimated to the uterine fundus, umbilicus and pubis, respectively., Conclusions: Pre-treatment simulation in the same irradiation conditions is the only reliable approach to predict the fetal dose. By using a special shielding device, radiotherapy can be optimized while keeping the fetal exposure below the risk of deterministic damage.

Aims and Background: We designed a comparative planning study aimed at quantifying the advantages of intensity-modulated radiotherapy (IMRT) over the conventional 3-field technique (3FT) and a 5-field conformal technique (5FCT) for head and neck (HN) cancer., Methods: We selected 9 patients treated at our institution with curative radiotherapy for a HN cancer. For all cases 4 plans were generated: 2 plans using the "standard" techniques (3FT and 5FCT), a third plan using IMRT, and a fourth "mixed" plan using IMRT followed by a conventional boost., Results: Our study confirmed literature data on the ability of IMRT to significantly decrease the dose received by organs at risk, compared with previous techniques. Target coverage was systematically better with 5FCT and IMRT than with 3FT. However, the increase in coverage of both PTV2 and PTV1 was only about 3-5% and this was achieved at the price of a similar increase in maximum dose (D1%). Volumetric parameters (V100%, V95%) were much more sensitive in detecting the improvement with IMRT., Conclusions: The improvement of target coverage attained by IMRT, as compared with conventional and conformal techniques, might be overestimated by data currently available in the medical literature. If treatment with conventional techniques is planned using all tools provided by currently available fully 3-D planning systems, excellent target coverage can be obtained.

Purpose: Supratentorial primitive neuroectodermal tumors (S-PNET) are rare and have a grim prognosis, frequently taking an aggressive course with local relapse and metastatic spread. We report the results of a mono-institutional therapeutic trial., Methods and Materials: We enrolled 15 consecutive patients to preradiation chemotherapy (CT) consisting of high-dose methotrexate, high-dose etoposide, high-dose cyclophosphamide, and high-dose carboplatin, craniospinal irradiation (CSI) with hyperfractionated accelerated radiotherapy (HART) plus focal boost, maintenance with vincristine/lomustine or consolidation with high-dose thiotepa followed by autologous stem-cell rescue., Results: Median age was 9 years; 7 were male, 8 female. Site of disease was pineal in 3, elsewhere in 12. Six patients were had no evidence of disease after surgery (NED). Of those with evidence of disease after surgery (ED), 2 had central nervous system spread. Of the 9 ED patients, 2 had complete response (CR) and 2 partial response (PR) after CT, 4 stable disease, and 1 progressive disease. Of the 7 ED patients before radiotherapy, 1 had CR, 4 PR, and 2 minor response, thus obtaining a 44% CR + PR after CT and 71% after HART. Because of rapid progression in 2 of the first 5 patients, high-dose thiotepa was systematically adopted after HART in the subsequent 10 patients. Six of 15 patients relapsed (4 locally, 1 locally with dissemination, 1 with dissemination) a mean of 6 months after starting CT, 2 developed second tumors; 5 of 6 relapsers died at a median of 13 months. Three-year progression-free survival, event-free survival, and overall survival were 54%, 34%, and 61%, respectively., Conclusion: Hyperfractionated accelerated RT was the main tool in obtaining responses in S-PNET; introducing the myeloablative phase improved the prognosis (3/10 vs. 3/5 relapses), though the outcome remained unsatisfactory despite the adoption of this intensive treatment.

We retrospectively studied 26 consecutive adults treated for medulloblastoma using paediatric protocols. Between 1987 and 2003, patients 18 years old were given adjuvant chemotherapy consisting of one of two 'paediatric' regimens (depending on the time of presentation) and craniospinal local-boost radiotherapy: regimen A (n = 12), vincristine (VCR), intrathecal and/or intravenous methotrexate and conventional radiotherapy; or regimen B (n = 11) sequencing intensive doses of multiple agents followed by hyperfractionated accelerated radiotherapy (HART). A VCR-lomustine-based maintenance followed both regimens. Three additional patients received a tailored treatment due to their impaired neurological status after surgery. The median age at diagnosis was 26 years (range 18-41 years). With a median follow-up of 46 months, 5-year disease-free and overall survival rates were 65+/-11% and 73+/-10%, respectively, for the series as a whole. All patients who received regimen B (5 of whom had metastatic Chang M2-M3 disease) are alive with no evidence of disease at 39 months. Although the number of patients is limited, our data suggest that the sandwich sequential, moderately intensive chemotherapy in combination with HART is an effective treatment for medulloblastoma in adults, and this approach seems to overcome previously-recognised risk factors.