Nanodiamond Effects on Cancer Cell Radiosensitivity: The Interplay between Their Chemical/Physical Characteristics and the Irradiation Energy.

Nanoparticles are being increasingly studied to enhance radiation effects. Among them, nanodiamonds (NDs) are taken into great consideration due to their low toxicity, inertness, chemical stability, and the possibility of surface functionalization. The objective of this study is to explore the influence of the chemical/physical properties of NDs on cellular radiosensitivity to combined treatments with radiation beams of different energies. DAOY, a human radioresistant medulloblastoma cell line was treated with NDs-differing for surface modifications [hydrogenated (H-NDs) and oxidized (OX-NDs)], size, and concentration-and analysed for (i) ND internalization and intracellular localization, (ii) clonogenic survival after combined treatment with different radiation beam energies and (iii) DNA damage and apoptosis, to explore the nature of ND-radiation biological interactions. Results show that chemical/physical characteristics of NDs are crucial in determining cell toxicity, with hydrogenated NDs (H-NDs) decreasing either cellular viability when administered alone, or cell survival when combined with radiation, depending on ND size and concentration, while OX-NDs do not. Also, irradiation at high energy (γ-rays at 1.25 MeV), in combination with H-NDs, is more efficient in eliciting radiosensitisation when compared to irradiation at lower energy (X-rays at 250 kVp). Finally, the molecular mechanisms of ND radiosensitisation was addressed, demonstrating that cell killing is mediated by the induction of Caspase-3-dependent apoptosis that is independent to DNA damage. Identifying the optimal combination of ND characteristics and radiation energy has the potential to offer a promising therapeutic strategy for tackling radioresistant cancers using H-NDs in conjunction with high-energy radiation.

Multiple Brain Metastases Radiosurgery with CyberKnife Device: Dosimetric Comparison between Fixed/Iris and Multileaf Collimator Plans.

Purpose: In our institution, stereotactic radiosurgery of multiple brain metastases is performed with the CyberKnife® (CK) device, using fixed/Iris collimators. In this study, nineteen fixed/Iris plans were recalculated with the multileaf collimator (MLC), to assess if it is possible to produce plans with comparable dosimetric overall quality. Materials and Methods: For consistent comparisons, MLC plans were re-optimized and re-normalized in order to achieve the same minimum dose for the total planning target volume (PTVtot). Conformation number (CN), homogeneity index (HI) and dose gradient index (DGI) metrics were evaluated. The dose to the brain was evaluated as the volume receiving 12 Gy (V12) and as the integral dose (ID). The normal tissue complication probability (NTCP) for brain radionecrosis was calculated as a function of V12. Results: The reoptimized plans were reviewed by the radiation oncologist and were found clinically acceptable according to the The American Association of Physicists in Medicine (AAPM) Task Group-101 protocol. However, fixed/Iris plans provided significantly higher CN (+8.6%), HI (+2.2%), and DGI (+44.0%) values, and significantly lower ID values (-35.9%). For PTVtot less than the median value of 2.58cc, fixed/Iris plans provided significantly lower NTCP values. On the other side, MLC plans provided significantly lower treatment times (-18.4%), number of monitor units (-33.3%), beams (-46.0%) and nodes (-21.3%). Conclusions: CK-MLC plans for the stereotactic treatment of brain multi metastases could provide an important advantage in terms of treatment duration. However, to contain the increased risk for brain radionecrosis, it could be useful to calculate MLC plans only for patients with large PTVtot.

Evaluation of a planar diode matrix for SRS patient-specific QA in comparison with GAFchromic films.

PURPOSE: We validate the routine use of a two-dimensional (2D) diode matrix for patient specific pre-treatment verification for Cyberknife (CK) stereotactic radiosurgery and to compare it with film dosimetry. MATERIALS AND METHOD: A total of 46 patients were selected according to the most frequent diseases treated at our institution with the CK system, that is, brain metastases, meningiomas, spine metastases, and prostate tumors. All cases were evaluated with GAFChromic EBT-3 films and SRS MapCHECK for Fixed cone, IRIS, and MLC collimators of the CK. RESULTS: The highest mean passing rate was observed for the SRS MapCHECK system compared to films. In order to assess if the two techniques provide statistically different results, a Wilcoxon Signed-Rank non-parametric test was performed (p < 0.05) and we found gamma values significantly lower for EBT-3 films with respect to the SRS MapCHECK. We noticed a moderately significant association between the two techniques using Spearman's rank correlation coefficient (rs > 0.4). We also performed the Bland-Altman statistical method: less than 5% of the differences resulted outside the range (mean ± 1.96 × SD), so the two methods can be considered interchangeable within the combined inaccuracy. CONCLUSIONS: The use of SRS MapCHECK for CK patient specific quality assurance (QA) is feasible for a variety of clinical districts and could be reliably used as a replacement for radiochromic films.

Implementation of a voluntary deep inspiration breath hold technique (vDIBH) using BrainLab ExacTrac infrared optical tracking system.

BACKGROUND: Voluntary deep inspiration breath hold technique (vDIBH) is considered as the key to achieving the widest cardiac sparing in whole breast irradiation. Several techniques have been implemented to achieve a reproducible, fast and friendly treatment. The aim of the present study is to implement vDIBH using the ExacTrac (BrainLAB AG, Germany) monitoring system. METHODS: Women with left-sided breast cancer, younger than 50 years or with cardiac disease, underwent whole breast RT with vDIBH using the ExacTrac (BrainLAB AG, Germany) monitoring system. Simulations were performed with patients positioned supine on a breast board with both arms raised above the head. Five optical markers were placed on the skin around the border of the left breast gland and their position was referenced with ink marking. Each patient received a training session to find the individual deep inspiration level. Finally, a vDIBH CT was taken. All patients were also studied in free breathing (FB) in order to compare the dose distribution for PTV, heart and left anterior descending coronary artery (LAD). Pre-treatment verification was carried out through the ExacTrac (BrainLAB AG, Germany) system and verified with electronic portal imaging (EPI). Moreover, daily real time EPIs in during modality (captured during the beam delivery) were taken in order to check the reproducibility. RESULTS: 34 patients have been evaluated and 30 were eligible for vDIBH. Most patients showed small setup errors during the treatment course of below 5 mm in 94.9% of the recorded fields. Mean Displacement was less in cranio-caudal direction. Mean intra-fraction displacement was below 3 mm in all directions. vDIBH plans provided better cardiac dosimetry. CONCLUSIONS: vDIBH technique using ExacTrac (BrainLAB AG, Germany) monitoring system was applied with good reproducibility.

Clinical utility of RapidArc™ radiotherapy technology.

RapidArc™ is a radiation technique that delivers highly conformal dose distributions through the complete rotation (360°) and speed variation of the linear accelerator gantry. This technique, called volumetric modulated arc therapy (VMAT), compared with conventional radiotherapy techniques, can achieve high-target volume coverage and sparing damage to normal tissues. RapidArc delivers precise dose distribution and conformity similar to or greater than intensity-modulated radiation therapy in a short time, generally a few minutes, to which image-guided radiation therapy is added. RapidArc has become a currently used technology in many centers, which use RapidArc technology to treat a large number of patients. Large and small hospitals use it to treat the most challenging cases, but more and more frequently for the most common cancers. The clinical use of RapidArc and VMAT technology is constantly growing. At present, a limited number of clinical data are published, mostly concerning planning and feasibility studies. Clinical outcome data are increasing for a few tumor sites, even if only a little. The purpose of this work is to discuss the current status of VMAT techniques in clinical use through a review of the published data of planning systems and clinical outcomes in several tumor sites. The study consisted of a systematic review based on analysis of manuscripts retrieved from the PubMed, BioMed Central, and Scopus databases by searching for the keywords "RapidArc", "Volumetric modulated arc radiotherapy", and "Intensity-modulated radiotherapy".

Estimation of patient setup uncertainty using BrainLAB Exatrac X-Ray 6D system in image-guided radiotherapy.

The purpose of this study was to evaluate setup uncertainties for brain sites with ExacTrac X-Ray 6D system and to provide optimal margin guidelines. Fifteen patients with brain tumor were included in this study. Two X-ray images with ExacTrac X-Ray 6D system were used to verify patient position and tumor target localization before each treatment. The 6D fusion software first generates various sets of DRRs with position variations in both three translational and three rotational directions (six degrees of freedom) for the CT images. Setup variations (translation and rotation) after correction were recorded and corrected before treatment. The 3D deviations are expressed as mean ± standard deviation. The random error (Σ(σi)), systematic error (µi), and group systematic error (M(µi)) for the different X-ray were calculated using the definitions of van Herk.(1) Mean setup errors were calculated from X-ray images acquired after all fractions. There is moderate patient-to-patient variation in the vertical direction and small variations in systematic errors and magnitudes of random errors are smaller. The global systematic errors were measured to be less than 2.0 mm in each direction. Random component of all patients are smaller ranging from 0.1-0.3 mm small. The safety margin (SM) to the lateral, is 0.5 mm and 2.6 mm for van Herk(1) and Stroom et al.,(2) respectively, craniocaudal axis is 1.5 mm and 3.4 mm, respectively, and with respect to the antero-posterior axis, 2.3 mm and 3.9 mm. Daily X-ray imaging is essential to compare and assess the accuracy of treatment delivery to different anatomical locations.

Initial experience of ArcCHECK and 3DVH software for RapidArc treatment plan verification.

The purpose of this study was to perform delivery quality assurance with ArcCHECK and 3DVH system (Sun Nuclear, FL) and to evaluate the suitability of this system for volumetric-modulated arc therapy (VMAT) (RapidArc [RA]) verification. This software calculates the delivered dose distributions in patients by perturbing the calculated dose using errors detected in fluence or planar dose measurements. The device is tested to correlate the gamma passing rate (%GP) and the composite dose predicted by 3DVH software. A total of 28 patients with prostate cancer who were treated with RA were analyzed. RA treatments were delivered to a diode array phantom (ArcCHECK), which was used to create a planned dose perturbation (PDP) file. The 3DVH analysis used the dose differences derived from comparing the measured dose with the treatment planning system (TPS)-calculated doses to perturb the initial TPS-calculated dose. The 3DVH then overlays the resultant dose on the patient's structures using the resultant "PDP" beams. Measured dose distributions were compared with the calculated ones using the gamma index (GI) method by applying the global (Van Dyk) normalization and acceptance criteria, i.e., 3%/3mm. Paired differences tests were used to estimate statistical significance of the differences between the composite dose calculated using 3DVH and %GP. Also, statistical correlation by means of logistic regression analysis has been analyzed. Dose-volume histogram (DVH) analysis for patient plans revealed small differences between treatment plan calculations and 3DVH results for organ at risk (OAR), whereas planning target volume (PTV) of the measured plan was systematically higher than that predicted by the TPS. The t-test results between the planned and the estimated DVH values showed that mean values were incomparable (p < 0.05). The quality assurance (QA) gamma analysis 3%/3mm showed that in all cases there were only weak-to-moderate correlations (Pearson r: 0.12 to 0.74). Moreover, clinically relevant differences increased with increasing QA passing rate, indicating that some of the largest dose differences occurred in the cases of high QA passing rates, which may be called "false negatives." The clinical importance of any disagreement between the measured and the calculated dose is often difficult to interpret; however, beam errors (either in delivery or in TPS calculation) can affect the effectiveness of the patient dose. Further research is needed to determinate the role of a PDP-type algorithm to accurately estimate patient dose effect.

Tomotherapy treatment plan quality assurance: the impact of applied criteria on passing rate in gamma index method.

PURPOSE: Pretreatment patient plan verification with gamma index (GI) metric analysis is standard procedure for intensity modulated radiation therapy (IMRT) treatment. The aim of this paper is to evaluate the variability of the local and global gamma index obtained during standard pretreatment quality assurance (QA) measurements for plans performed with Tomotherapy unit. The QA measurements were performed with a 3D diode array, using variable passing criteria: 3%∕3 mm, 2%∕2 mm, 1%∕1 mm, each with both local and global normalization. METHODS: The authors analyzed the pretreatment QA results for 73 verifications; 37 were prostate cancer plans, 16 were head and neck plans, and 20 were other clinical sites. All plans were treated using the Tomotherapy Hi-Art System. Pretreatment QA plans were performed with the commercially available 3D diode array ArcCHECK™. This device has 1386 diodes arranged in a helical geometry spaced 1 cm apart. The dose measurements were acquired on the ArcCHECK™ and then compared with the calculated dose using the standard gamma analysis method. The gamma passing rate (%GP), defined as the percentage of points satisfying the condition GI < 1, was calculated for different criteria (3%∕3 mm, 2%∕2 mm, 1%∕1 mm) and for both global and local normalization. In the case of local normalization method, the authors set three dose difference threshold (DDT) values of 2, 3, and 5 cGy. Dose difference threshold is defined as the minimum absolute dose error considered in the analysis when using local normalization. Low-dose thresholds (TH) of 5% and 10% were also applied and analyzed. RESULTS: Performing a paired-t-test, the authors determined that the gamma passing rate is independent of the threshold values for all of the adopted criteria (5%TH vs 10%TH, p > 0.1). Our findings showed that mean %GPs for local (or global) normalization for the entire study group were 93% (98%), 84% (92%), and 66% (61%) for 3%∕3 mm, 2%∕2 mm, and 1%∕1 mm criteria, respectively. DDT was equal to 2 cGy for the local normalization analysis cases. The authors observed great variability in the resulting %GP. With 3%∕3 mm gamma criteria, the overall passing rate with local normalization was 4.6% less on the average than with global one, as expected. The wide difference between %GP calculated with global or local approach is also confirmed by an unpaired t-test statistical analysis. CONCLUSIONS: The variability of %GP obtained confirmed the necessity to establish defined agreement criteria that could be universal and comparable between institutions. In particular, while the gamma passing rate does not depend on the choice of threshold, the choice of DDT strongly influences the gamma passing rate for local calculations. The difference between global and local %GP was statistically significant for prostate and other treatment sites when DDT was changed from 2 to 3 cGy.

Dosimetric and clinical advantages of deep inspiration breath-hold (DIBH) during radiotherapy of breast cancer.

BACKGROUND: To investigate the potential dosimetric and clinical benefits of Deep Inspiration Breath-Hold (DIBH) technique during radiotherapy of breast cancer compared with Free Breathing (FB). METHODS: Eight left-sided breast cancer patients underwent a supervised breath hold during treatment. For each patient, two CT scans were acquired with and without breath hold, and virtual simulation was performed for conventional tangential fields, utilizing 6 or 15 MV photon fields. The resulting dose-volume histograms were calculated, and the volumes of heart/lung irradiated to given doses were assessed. The left anterior descending coronary artery (LAD) mean and maximum doses were calculated, together with tumour control probability (TCP) and normal tissue complication probabilities (NTCP) for lung and heart. RESULTS: For all patients a reduction of at least 16% in lung mean dose and at least 20% in irradiated pulmonary volumes was observed when DIBH was applied. Heart and LAD maximum doses were decreased by more than 78% with DIBH. The NTCP values for pneumonitis and long term cardiac mortality were also reduced by about 11% with DIBH. The NTCP values for pericarditis were zero for both DIBH and FB. CONCLUSION: Delivering radiation in DIBH conditions the dose to the surrounding normal structures could be reduced, in particular heart, LAD and lung, due to increased distance between target and heart, and to reduced lung density.