Fractionated Stereotactic Radiotherapy with Helical Tomotherapy for Brain Metastases: A Mono-Institutional Experience.

Background: The present study reports on the outcomes of our mono-institutional experience of Helical Tomotherapy (HT)-based SRT for brain metastases. The use of this linac is less frequently reported for this kind of treatment. Methods: This retrospective study displays a series of patients treated with HT-SRT. The eligibility of using SRT for brain metastases was defined by a Karnofsky performance status of >70, a life expectancy of >6 months, and controlled extra-cranial disease; no SRT was allowed in the case of a number of brain metastases larger than 10. All the cases were discussed by a multidisciplinary board. Toxicity assessments were performed based on CTCAE v5.0. Survival endpoints were assessed using the Kaplan-Meier method, and univariate and multivariate analyses were carried out to identify any potential predictive factor for an improved outcome. Results: Sixty-four lesions in 37 patients were treated using HT-SRT with a median total dose of 30 Gy in five fractions. The median follow-up was 7 months, and the 1- and 2-year LC rates were both 92.5%. The IPFS rates were and 56.75% and 51.35%. The OS rates were 54% and 40%. The UA showed better IPFS rates significantly related to male sex (p = 0.049), a BED12 of ≥42 Gy (p = 0.006), and controlled extracranial disease (p = 0.03); in the MA, a favorable trend towards LC (p = 0.11) and higher BED (p = 0.11) schedules maintained a correlation with improved IPFS rates, although statistical significance was not reached. Conclusions: HT-based SRT for brain metastases showed safety and efficacy in our monoinstiutional experience. Higher RT doses showed statistical significance for improved outcomes of LC and OS.

Experimental and Modeling Analyses of Human Motion Across the Static Magnetic Field of an MRI Scanner.

It is established that human movements in the vicinity of a permanent static magnetic field, such as those in magnetic resonance imaging (MRI) scanners induce electric fields in the human body; this raises potential severe risks of health to radiographers and cleaners exposed routinely to these fields in MRI rooms. The relevant directives and parameters, however, are based on theoretical models, and accurate studies on the simulation of the effects based on human movement data obtained in real conditions are still lacking. Two radiographers and one cleaner, familiar with MRI room activities and these directives, were gait analyzed during the execution of routine job motor tasks at different velocities. Full body motion was recorded in a gait laboratory arranged to reproduce the workspace of a room with an MRI full-body scanner. Body segments were tracked with clusters of at least three markers, from which position and velocity of the centroids were calculated. These were used as input in an established computer physical model able to map the stray field in an MRI room. The spatial peak values of the calculated electric field induced by motion of the head and of the entire body during these tasks, for both the health and sensory effects, were found smaller than the thresholds recommended by the European directives, for both 1.5 T and 3.0 T MRI. These tasks therefore seem to guarantee the safety of MRI room operators according to current professional good practice for exposure risks. Physical modeling and experimental measures of human motion can also support occupational medicine.

Local Disease-Free Survival Rate (LSR) Application to Personalize Radiation Therapy Treatments in Breast Cancer Models.

Cancer heterogeneity represents the main issue for defining an effective treatment in clinical practice, and the scientific community is progressively moving towards the development of more personalized therapeutic regimens. Radiotherapy (RT) remains a fundamental therapeutic treatment used for many neoplastic diseases, including breast cancer (BC), where high variability at the clinical and molecular level is known. The aim of this work is to apply the generalized linear quadratic (LQ) model to customize the radiant treatment plan for BC, by extracting some characteristic parameters of intrinsic radiosensitivity that are not generic, but may be exclusive for each cell type. We tested the validity of the generalized LQ model and analyzed the local disease-free survival rate (LSR) for breast RT treatment by using four BC cell cultures (both primary and immortalized), irradiated with clinical X-ray beams. BC cells were chosen on the basis of their receptor profiles, in order to simulate a differential response to RT between triple negative breast and luminal adenocarcinomas. The MCF10A breast epithelial cell line was utilized as a healthy control. We show that an RT plan setup based only on α and ß values could be limiting and misleading. Indeed, two other parameters, the doubling time and the clonogens number, are important to finely predict the tumor response to treatment. Our findings could be tested at a preclinical level to confirm their application as a variant of the classical LQ model, to create a more personalized approach for RT planning.

Moderate hypofractionated helical tomotherapy for localized prostate cancer: preliminary report of an observational prospective study.

OBJECTIVE: To report preliminary findings of a phase II study exploring the clinical outcomes of moderate hypofractionated radiotherapy performed with helical tomotherapy (HT) using computed tomography-magnetic resonance imaging-based planning for localized prostate cancer. METHODS: The phase II prospective study received ethics approval from our institutional ethics committee. A dose of 60 Gy/20 fractions for low-intermediate risk prostate cancer by means of HT was explored. Primary endpoints of the study were acute and late gastrointestinal (GI) and genitourinary (GU) toxicities. Secondary endpoints were quality of life and biochemical-free survival. RESULTS: A total of 35 patients were included in this interim report. At the time of the analysis, median follow-up was 36 months (range, 13-62). Acute GI toxicity was recorded as follows: grade 1 in 34% and grade 2 in 14%; acute GU toxicity was grade 1 in 71% and grade 2 in 11%. For the entire population of the study, no acute toxicities ⩾ grade 3 occurred. A single case of late grade 3 GU toxicity was registered, whereas no late GI toxicity ⩾grade 3 was recorded. At the time of the final assessment, no biochemical failure was detected. CONCLUSIONS: The preliminary results of the present phase II trial, using HT for moderate hypofractionation in localized prostate cancer, are optimal. In fact, HT guaranteed an acceptable tolerability profile with low rates of GU and GI side effects and, more specifically, no acute severe adverse events were recorded. Long-term findings are warranted.

Radiosensitizing effect of curcumin-loaded lipid nanoparticles in breast cancer cells.

In breast cancer (BC) care, radiotherapy is considered an efficient treatment, prescribed both for controlling localized tumors or as a therapeutic option in case of inoperable, incompletely resected or recurrent tumors. However, approximately 90% of BC-related deaths are due to the metastatic tumor progression. Then, it is strongly desirable to improve tumor radiosensitivity using molecules with synergistic action. The main aim of this study is to develop curcumin-loaded solid nanoparticles (Cur-SLN) in order to increase curcumin bioavailability and to evaluate their radiosensitizing ability in comparison to free curcumin (free-Cur), by using an in vitro approach on BC cell lines. In addition, transcriptomic and metabolomic profiles, induced by Cur-SLN treatments, highlighted networks involved in this radiosensitization ability. The non tumorigenic MCF10A and the tumorigenic MCF7 and MDA-MB-231 BC cell lines were used. Curcumin-loaded solid nanoparticles were prepared using ethanolic precipitation and the loading capacity was evaluated by UV spectrophotometer analysis. Cell survival after treatments was evaluated by clonogenic assay. Dose-response curves were generated testing three concentrations of free-Cur and Cur-SLN in combination with increasing doses of IR (2-9 Gy). IC50 value and Dose Modifying Factor (DMF) was measured to quantify the sensitivity to curcumin and to combined treatments. A multi-"omic" approach was used to explain the Cur-SLN radiosensitizer effect by microarray and metobolomic analysis. We have shown the efficacy of the Cur-SLN formulation as radiosensitizer on three BC cell lines. The DMFs values, calculated at the isoeffect of SF = 50%, showed that the Luminal A MCF7 resulted sensitive to the combined treatments using increasing concentration of vehicled curcumin Cur-SLN (DMF: 1,78 with 10 µM Cur-SLN.) Instead, triple negative MDA-MB-231 cells were more sensitive to free-Cur, although these cells also receive a radiosensitization effect by combination with Cur-SLN (DMF: 1.38 with 10 µM Cur-SLN). The Cur-SLN radiosensitizing function, evaluated by transcriptomic and metabolomic approach, revealed anti-oxidant and anti-tumor effects. Curcumin loaded- SLN can be suggested in future preclinical and clinical studies to test its concomitant use during radiotherapy treatments with the double implications of being a radiosensitizing molecule against cancer cells, with a protective role against IR side effects.

Moving across the static magnetic field of a 1.5 T MRI scanner: Analysing compliance with Directive 2013/35/EU.

Does the exposure of magnetic resonance imaging personnel to static magnetic fields fully comply with Directive 2013/35/EU? Despite the obligation to satisfy this question, a general answer cannot be provided, nor are final satisfying good practices methods for exposure assessment currently available. In order to contribute to fix this problem, three different 1.5 T scanners are analysed and - by a new theoretical insight - a positive answer is provided.

Hypo-fractionated stereotactic radiation therapy for lung malignancies by means of helical tomotherapy: report of feasibility by a single-center experience.

BACKGROUND: Several experiences in the literature report SBRT as an effective treatment option for medically inoperable early stage non-small cell lung cancer (NSCLC) and oligometastatic disease. The optimal fractionation schedules and total dose remain controversial. In this study, we evaluated the safety in terms of toxicity and efficacy of using of 8-10 fractions schedules with Helical Tomotherapy (HT) for primary and metastatic lung lesions. METHODS: Between March 2014 and May 2016, a total of 39 patients (median age 72 years, range 26-91) were treated with HT-SBRT for malignant lung lesions: 22 patients with early stage NSCLC, 17 with oligometastases. Patients received 8-10 fractions with lower daily dose for central and ultracentral lesions. Treatment-related toxicity was evaluated using CTCAE v 4.0 scale. Local control (LC), overall survival (OS) and toxicity rates were prospectively collected. RESULTS: Median duration of RT was 15 days (range 10-26 days) and no interruption occurred. With a median follow-up of 13 months (range 3-29), we reported one G2 pneumonitis (2.6%) and one G2 chest pain (2.6%); no ≥ G2 esophagitis was registered. Actuarial local control rate was 95.5% both at 12 and 24 months for early stage NSCLC and 92.9% both at 12 and 24 months for metastatic patients. OS rate was 94.4 and 92.3% at 1 year, and 94.4 and 83.9% at 2 years in primary and metastatic group, respectively. CONCLUSIONS: The use of 8-10 fractions schedule HT-SBRT for lung malignancies results in high LC and OS rates with minimal toxicities reported.

Performance of commercially available deformable image registration platforms for contour propagation using patient-based computational phantoms: A multi-institutional study.

PURPOSE: To investigate the performance of various algorithms for deformable image registration (DIR) to propagate regions of interest (ROIs) using multiple commercial platforms. METHODS AND MATERIALS: Thirteen institutions participated in the study with six commercial platforms: RayStation (RaySearch Laboratories, Stockholm, Sweden), MIM (Cleveland, OH, USA), VelocityAI and Smart Adapt (Varian Medical Systems, Palo Alto, CA, USA), Mirada XD (Mirada Medical Ltd, Oxford, UK), and ABAS (Elekta AB, Stockholm, Sweden). The DIR algorithms were tested on synthetic images generated with the ImSimQA package (Oncology Systems Limited, Shrewsbury, UK) by applying two specific Deformation Vector Fields (DVF) to real patient data-sets. Head-and-neck (HN), thorax, and pelvis sites were included. The accuracy of the algorithms was assessed by comparing the DIR-mapped ROIs from each center with those of reference, using the Dice Similarity Coefficient (DSC) and Mean Distance to Conformity (MDC) metrics. Statistical inference on validation results was carried out in order to identify the prognostic factors of DIR performances. RESULTS: DVF intensity, anatomic site and participating center were significant prognostic factors of DIR performances. Sub-voxel accuracy was obtained in the HN by all algorithms. Large errors, with MDC ranging up to 6 mm, were observed in low-contrast regions that underwent significant deformation, such as in the pelvis, or large DVF with strong contrast, such as the clinical tumor volume (CTV) in the lung. Under these conditions, the hybrid DIR algorithms performed significantly better than the free-form intensity based algorithms and resulted robust against intercenter variability. CONCLUSIONS: The performances of the systems proved to be site specific, depending on the DVF type and the platforms and the procedures used at the various centers. The pelvis was the most challenging site for most of the algorithms, which failed to achieve sub-voxel accuracy. Improved reproducibility was observed among the centers using the same hybrid registration algorithm.

Characterization of phenolic pellets for ESR dosimetry in photon beam radiotherapy.

This work deals with the dosimetric features of a particular phenolic compound (IRGANOX 1076®) for dosimetry of clinical photon beams by using electron spin resonance (ESR) spectroscopy. After the optimization of the ESR readout parameters (namely modulation amplitude and microwave power) to maximise the signal without excessive spectrum distortions, basic dosimetric properties of laboratory-made phenolic dosimeters in pellet form, such as reproducibility, dose-response, sensitivity, linearity and dose rate dependence were investigated. The dosimeters were tested by measuring the depth dose profile of a 6 MV photon beam. A satisfactory intra-batch reproducibility of the ESR signal of the manufactured dosimeters was obtained. The ESR signal proved to increase linearly with increasing dose in the investigated dose range 1-13 Gy. The presence of an intrinsic background signal limits the minimum detectable dose to a value of approximately 0.6 Gy. Reliable and accurate assessment of the dose was achieved, independently of the dose rate. Such characteristics, together with the fact that IRGANOX 1076® is almost tissue-equivalent, and the stability of the ESR signal, make these dosimeters promising materials for ESR dosimetric applications in radiotherapy.

Moderate hypofractionation and simultaneous integrated boost by helical tomotherapy in prostate cancer: monoinstitutional report of acute tolerability assessment with different toxicity scales.

INTRODUCTION: Based on radiobiology evidence, hypofractionated radiotherapy has the potential of improving treatment outcome in prostate cancer patients. In this study, we evaluated the safety, in terms of acutetoxicity, of using moderate hypofractionated radiotherapy delivered with Helical Tomotherapy (HT) to treat prostate cancer patients. MATERIALS AND METHODS: Between December 2012 and April 2014, 42 consecutive patients were treated with hypofractionated radiotherapy using HT. All patients received 70 Gy in 28 fractions to PTV1, which included the prostate. In the intermediate risk group, 61.6 Gy were delivered to PTV2, which included the seminal vesicles. In high risk patients, the pelvic nodes were added (PTV3) and received 50.4 Gy. Acute toxicity was recorded prospectively with RTOG and Common Terminology Criteria for Adverse Events 3.0, retrospectively with CTCAE 4.0. Expanded Prostate Cancer Index Composite (EPIC) was measured at baseline and 3 months after end of treatment, to investigate health related quality of life with regards to bladder and gastrointestinal function. RESULTS: Acute toxicity was acceptable, independently from the system used to score side effects. Moderate genitourinary toxicity was more frequent than gastrointestinal toxicity. No correlation between acute side effects and patients' characteristics or physical dose parameters was registered. EPIC evaluation showed a negligible difference in urinary and bowel function post-treatment, that did not reach statistical significance. CONCLUSIONS: Our experience confirms the safety of moderate hypofractionation delivered with HT in prostate cancer patients with low, intermediate and high risk.

Organ sparing and clinical outcome with step-and-shoot IMRT for head and neck cancer: a mono-institutional experience.

PURPOSE: Intensity-modulated radiotherapy has been suggested as the technique of choice for locally advanced head and neck cancer patients. In the last decade, most radiotherapy departments have focused their efforts in programs to implement this technique. We report our experience for parotid gland and constrictor muscle sparing with intensity-modulated radiotherapy in head and neck cancer using a step-and-shoot technique. METHODS: Thirty-four consecutive patients with squamous cell carcinoma of the nasopharynx, oropharynx and larynx treated between June 2008 and June 2011 were retrospectively evaluated. A simultaneous integrated boost was adopted to treat different volumes in 30 fractions over 6 weeks. Priority as organs at risk was given to the parotid glands as well as the constrictor muscle of the pharynx in 53 % (n = 18). Dysphagia and xerostomia were evaluated according to RTOG/EORTC scale at 6, 12 and 24 months. Outcomes were analysed using Kaplan-Meier curves. RESULTS: The median follow-up was 43 months. The 5-year overall survival was 70 %, and local control was 94 %. Grade 2 dysphagia and xerostomia at 6, 12 and 24 months were as follows: 26 % (n = 9), 23 % (n = 8), 23 % (n = 8) and 21 % (n = 7), 12 % (n = 4), 12 % (n = 4), respectively. No grade 3 or 4 toxicity was found. Ordinal logistic regression analysis demonstrated that hyposalivation was the main predictive factor for late dysphagia. CONCLUSION: Excellent loco-regional results were achieved with acceptable acute and late toxicities. The low rate of late dysphagia was related to parotid gland sparing; we did not observe a correlation between late dysphagia and dose to pharyngeal constrictors.

Optimal local control and tolerability of three-dimensional conformal radiation therapy in prostate cancer: a single institutional experience of dose escalation in 125 patients.

AIMS: To evaluate long-term late side effects, clinical and biochemical relapse in non-metastatic prostate cancer patients treated with dose escalation, from 74 to 78 Gy, by means of three dimensional conformal radiation therapy. MATERIALS AND METHODS: Clinical data of 125 patients with prostate cancer who underwent three-dimensional conformal radiation therapy were retrospectively evaluated. All patients were stratified, according to the NCCN classification, in low, intermediate and high risk, and all of them showed histologically proven adenocarcinoma stage T1-T3 with at least 2 years of follow-up. Late toxicity was analyzed using a modified Radiation Therapy Oncology Group toxicity scale. RESULTS: With a median of follow-up of 48 months, grade ≥2 late genitourinary toxicity was reported in 18% and grade ≥2 gastrointestinal toxicity was detected in 12%. The PSA relapse rate was 20% in the high-risk group, 7% in the intermediate-risk group, and 3% in the low-risk group. CONCLUSIONS: Late side effects and tumor control in patients with non-metastatic prostate cancer in dose escalation from 74 to 78 Gy was acceptable. Three-dimensional conformal radiation therapy still represents a valid therapeutic option for departments where intensity-modulated radiation therapy or image-guided radiation therapy is still not available.