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Patients that receive radiotherapy are at risk of late sensorineural hearing loss when the inner ear is included within the radiation field. Preclinical and human temporal bone studies have shown that there is differential damage to cochlear structures depending on the amount of dose delivered to the inner ear. In vitro studies have suggested that reactive oxygen species (ROS) are the main initial actors in radiation-induced damage. The interaction of ROS with different cellular components can result in different apoptotic pathways. Therefore, approaches to radioprotection are mainly aimed to reduce ROS production through antioxidants. This review summarizes recent research in the field that can improve the understanding and boost preventive efforts of this adverse effect., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: There is currently no treatment available to prevent radiation-induced sensorineural hearing loss. Metformin has antineoplastic effects and is able to regulate the mitochondrial production of reactive oxygen species after cellular stress, which is one of the mechanisms involved in apoptosis after radiation damage. The objective of this study was to determine the safety and radioprotective properties of metformin against radiation-induced cochlear damage both in vitro and in vivo., Study Design: In vitro and prospective animal study., Setting: Animal Care Facilities of the Montreal Children's Hospital Research Institute., Methods: Cultured auditory hair cells (HEI-OC1) were exposed to different concentrations of metformin to determine its safety. Cells were incubated with different metformin concentrations and subjected to radiation. Cell viability after experiments was determined with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Sixteen guinea pigs were divided in 2 groups: drinking tap water (n = 8) and drinking water containing metformin (n = 8). The animals were unilaterally irradiated for 20 days (total dose 70 Gy), and the ears were divided in 4 groups: control (n = 8), irradiated (n = 8), metformin (n = 8), and experimental (n = 8). Auditory brainstem responses were assessed before and 1, 6, and 16 weeks after completion of radiotherapy., Results: Metformin was not cytotoxic or radioprotective in cultured auditory hair cells. Experimental ears had less hearing loss than radiated ones; however, differences were not statistically significant (P > .05)., Conclusion: Metformin is not ototoxic or radioprotective in vitro or in vivo. Ears solely subjected to metformin had better hearing thresholds than the rest of the groups.

Purpose: A radiochromic film based dosimetry system for high dose rate (HDR) Iridium-192 brachytherapy source was described. A comparison between calibration curves established in water and Solid Water™ was provided., Methods: Pieces of EBT-2 model GAFCHROMIC™ film were irradiated in both water and Solid Water™ with HDR (192)Ir brachytherapy source in a dose range from 0 to 50 Gy. Responses of EBT-2 GAFCHROMIC™ film were compared for irradiations in water and Solid Water™ by scaling the dose between media through Monte Carlo calculated conversion factor for both setups. To decrease uncertainty in dose delivery due to positioning of the film piece with respect to the radiation source, traceable calibration irradiations were performed in a parallel-opposed beam setup., Results: The EBT-2 GAFCHROMIC™ film based dosimetry system described in this work can provide an overall one-sigma dose uncertainty of 4.12% for doses above 1 Gy. The ratio of dose delivered to the sensitive layer of the film in water to the dose delivered to the sensitive layer of the film in Solid Water™ was calculated using Monte Carlo simulations to be 0.9941 ± 0.0007., Conclusions: A radiochromic film based dosimetry system using only the green color channel of a flatbed document scanner showed superior precision if used alone in a dose range that extends up to 50 Gy, which greatly decreases the complexity of work. In addition, Solid Water™ material was shown to be a viable alternative to water in performing radiochromic film based dosimetry with HDR (192)Ir brachytherapy sources.

The rotational total skin electron irradiation (RTSEI) technique at our institution has undergone several developments over the past few years. Replacement of the formerly used linear accelerator has prompted many modifications to the previous technique. With the current technique, the patient is treated with a single large field while standing on a rotating platform, at a source-to-surface distance of 380 cm. The electron field is produced by a Varian 21EX linear accelerator using the commercially available 6 MeV high dose rate total skin electron mode, along with a custom-built flattening filter. Ionization chambers, radiochromic film, and MOSFET (metal oxide semiconductor field effect transistor) detectors have been used to determine the dosimetric properties of this technique. Measurements investigating the stationary beam properties, the effects of full rotation, and the dose distributions to a humanoid phantom are reported. The current treatment technique and dose regimen are also described.

Kilovolt x-rays are clearly suboptimal compared to MV photon beams for radiotherapy of deep-seated tumours because of the increased attenuation in tissue, causing a rapid dose fall-off. This picture could change drastically when tumours can be labelled with contrast medium, containing high atomic number elements. This causes a significant dose enhancement to the tumour by exploiting the high cross sections for the photo-electric effect for kV x-rays. In this work, we have investigated the dosimetric and microdosimetric characteristics of kV contrast-enhanced radiation therapy (CERT) for different photon energies, contrast-medium concentrations and types (I and Gd). Two idealized patient treatment plans (head and lung) for irradiation with CT-arc beams were calculated. It is shown that the dose enhancement in tumours can be highly significant (up to about sixfold for realistic 80-120 kVp x-ray spectra and an iodine concentration of 50 mg ml-1) but that dose homogeneity in the tumour depends on photon energy, contrast-medium concentration and type, and irradiation scheme. An attempt to optimize the irradiation scheme is discussed. The microdosimetric study of the dose mean lineal energy shows that radiation quality changes in the contrast-medium-labelled region compared to homogeneous tissue are fairly small and limited to 10%. It is concluded that kV-CERT is a promising radiotherapy technique, provided contrast medium can be delivered reliably to tumours.

Simple Summary: With the introduction of better-quality imaging for tumor visualization and treatment planning, a new conformed radiation treatment was introduced with high-dose-rate endorectal brachytherapy (HDREBT). The advantage of this treatment is allowing for better sparing of normal tissues surrounding the tumor during treatment while delivering higher dose to the tumor. This diminishes the number and severity of side effects and results in more effective treatment. This manuscript summarizes two decades of technological evolution and progress in clinical studies to validate this treatment concept from the pre-operative setting to prevent tumor recurrence and, more recently, the introduction of the objective of cure without surgery; i.e., non-operative management (NOM) for patients with curable rectal cancer. HDREBT is a conformed radiation modality, shown to be safe and efficient both in the pre-operative setting and is presently being explored with interest in NOM in a multicenter study. (1) Background: The introduction of total mesorectal excision (TME) for rectal cancer has led to improvement in local recurrence (LR) outcomes. Furthermore, the addition of preoperative external beam radiotherapy to TME reduces LR to less than 6%. As a trade-off to these gradual improvements in local therapies, the oncology community's work is now focusing on mitigating treatment-related toxicities. In other words, if a small proportion of 4–6% of rectal cancer patients benefit from additional local therapy beyond TME, the burden of acute and long-term side effects must be considered with care. (2) Methods: With the introduction of better-quality imaging for tumor visualization and treatment planning, a new conformed radiation treatment was introduced with high-dose-rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies: first in the pre-operative setting, and then as a boost after external beam radiation therapy, as a dose-escalation study, to achieve higher local tumor control. (3) Results: HDREBT is safe and effective in achieving a high tumor regression rate and was well tolerated in a phase II multicenter and two matched-pair studies. (4) Conclusions: HDREBT is a conformed radiation therapy that is safe and effective, and is presently explored in a phase III dose-escalation study in the NOM of patients with operable rectal cancer. [ABSTRACT FROM AUTHOR]

A novel low toxic normoxic polymer gel dosimeter containing acrylic acid monomer is prepared and characterized for dosimetry in radiotherapy. Gel samples were fabricated under normal atmospheric conditions. The gels were irradiated to different doses using a medical linear accelerator at 6 MV X-ray energy to investigate the dose response and other characteristics. The dose response was evaluated in terms of relaxation rate using NMR relaxometry, which was carried out using a 0.5 T NMR technique. The sample temperature during the NMR relaxometry was fixed at 20.0 ± 0.1 °C using a thermostatic circulating water bath connected to the NMR relaxometry. A significant improvement in the performance of the dosimeter was noticed for acrylic acid gel with the addition of MgCl2 salt. The sensitivity of gel with 0.6 M MgCl2 was about 4.6 times of the same gel without MgCl2. The total uncertainty of the R2 measurements was about 5%. Different important parameters such as dose rate, beam quality, NMR scanning temperature, and stability of the dose response were investigated in this study. [ABSTRACT FROM AUTHOR]

A novel composition of normoxic polymer gel dosimeters based on radiation-induced polymerization of N-(Hydroxymethyl)acrylamide (NHMA) is introduced in this study for 3D dosimetry for Quality Assurance (QA) in radiation therapy. Dosimeters were irradiated by 6, 10 and 18 MV photon beams of a medical linear accelerator at various dose rates to doses of up to 20 Gy. The dose response of polymer gel dosimeters was studied using nuclear magnetic resonance (NMR) spin-spin relaxation rate ( R 2 ) of hydrogen protons within the water molecule. Also, we measured gel response using absorption spectroscopy and found that this novel gel can be successfully utilized for both MRI- and OCT- (Optical Computed Tomography) based 3D dosimetry. We investigated dosimetric properties of six different compositions of the new NHMA-based gel in terms of dose rate, radiation beam quality and stability of dose-dependent polymerization after irradiation. We found no significant effects of these parameters on the novel gel dosimeter performance in both relaxation rate and absorbance measurements. [ABSTRACT FROM AUTHOR]

Objective: Integration of fluorine-18 fludeoxyglucose (18F-FDG)-positron emission tomography (PET) functional data into conventional anatomically based gross tumour volume delineation may lead to optimization of dose to biological target volumes (BTV) in radiotherapy. We describe a method for defining tumour subvolumes using 18F-FDG-PET data, based on the decomposition of differential uptake volume histograms (dUVHs). Methods: For 27 patients with histopathologically proven non-small-cell lung carcinoma (NSCLC), background uptake values were sampled within the healthy lung contralateral to a tumour in those image slices containing tumour and then scaled by the ratio of mass densities between the healthy lung and tumour. Signal-to-background (S/B) uptake values within volumes of interest encompassing the tum ou r were used to reconstruct the dUVHs. These were subsequently decomposed into the minimum number of analytical functions (in the form of differential uptake values as a function of S/B) that yielded acceptable netfits, as assessed by x2 values. Results: Six subvolumes consistently emerged from the fitted dUVHs over the sampled volume of interest on PET images. Based on the assumption that each function used to decompose the dUVH may correspond to a single subvolume, the intersection between the two adjacent functions could be interpreted as a threshold value that differentiates them. Assuming that the first two subvolumes spread over the tumour boundary, we concentrated on four subvolumes with the highest uptake values, and their S/B thresholds [mean ± standard deviation (SD)] were 2.88 ±0 .9 8, 4.05 ±1.55, 5.48 ± 2 .0 6 and 7.34 ± 2.89 for adenocarcinoma, 3.01 ±0.71, 4.40 ±0.91, 5.99 ±1.31 and 8.17 ± 2.42 for large-cell carcinoma and 4.54 ± 2.11, 6.46 ± 2.43, 8.87 ± 5.37 and 12.11 ± 7.28 for squamous cell carcinoma, respectively. Conclusion: lsF-FDG-based PET data may potentially be used to identify BTV within the tumour in patients with NSCLC. Using the one-way analysis of variance statistical tests, we found a significant difference among all threshold levels among adenocarcinomas, large-cell carcinoma and squamous cell carcinomas. On the other hand, the observed significant variability in threshold values through out the patient coh ort (expressed as large SDs) can be explained as a consequence of differences in the physiological status of the tumour volume for each patient at the time of the PET/CT scan. This further suggests that patient-specific threshold values for the definition of BTVs could be determined by creation and curve fitting of dUVHs on a patient-by-patient basis. Advances in knowledge: The method of 18F-FDG-PETbased dUVH decomposition described in this work may lead to BTV segmentation in tumours. [ABSTRACT FROM AUTHOR]

For decades, film was used as a powerful two-dimensional (2D) dosimetry tool for radiotherapy treatment verification and quality assurance. Unlike the old silver-halide based radiographic films, radiochromic films change its color upon irradiation without the need for chemical development. Radiation dose deposited within a sensitive layer of the radiochromic film initiates polymerization of the active component, the degree of which depends on the amount of energy deposited. Response of the film to radiation is commonly expressed in terms of optical density change, which can be easily measured by any photometric device. However, a number of factors may have an impact on the signal detected by the measuring device. This review summarizes technical aspects associated with the establishment of reference radiochromic film dosimetry and its subsequent use for either clinical or research applications. [ABSTRACT FROM AUTHOR]

Purpose Radiochromic films change their color upon irradiation due to polymerization of the sensitive component embedded within the sensitive layer. However, agents, other than monitored radiation, can lead to a change in the color of the sensitive layer (temperature, humidity, UV light) that can be considered as a background signal and can be removed from the actual measurement by using a control film piece. In this work, we investigate the impact of the use of control film pieces on both accuracy and uncertainty of dose measured using radiochromic film based reference dosimetry protocol. Methods We irradiated “control” film pieces (EBT3 GafChromic TM film model) to known doses in a range of 0.05–1 Gy, and five film pieces of the same size to 2, 5, 10, 15 and 20 Gy, considered to be “unknown” doses. Depending on a dose range, two approaches to incorporating control film piece were investigated: signal and dose corrected method. Results For dose values greater than 10 Gy, the increase in accuracy of 3% led to uncertainty loss of 5% by using dose corrected approach. At lower doses and signals of the order of 5%, we observed an increase in accuracy of 10% with a loss of uncertainty lower than 1% by using the corrected signal approach. Conclusions Incorporation of the signal registered by the control film piece into dose measurement analysis should be a judgment call of the user based on a tradeoff between deemed accuracy and acceptable uncertainty for a given dose measurement. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: The purpose of this study is to assess the effect of fractionated radiotherapy on sensorineural hearing loss using an animal model. Study Design: In vivo animal study. Methods: Ears of 25 guinea pigs were divided into three groups: control, irradiated with a total of 48 gray (Gy), and 71 Gy. Unilateral exposure of 48 Gy and 71 Gy fractionated irradiation was given for a 4-week period. Auditory brainstem response and distortion products otoacoustic emissions (DPOAE) were tested prior to irradiation and 1, 6, 10, and 16 weeks after completion of radiotherapy to assess the hearing threshold shift postradiotherapy over time. Results: No significant differences in hearing thresholds between the low dose radiation (48 Gy) and the control group (no radiation) underlined that 48 Gy caused no hearing deficits (P = 0.37). The higher dose (71 Gy) showed progressive deterioration of the hearing function over time. Three-way ANOVA interactions revealed significant group-time effects (F= 9.261; P < 0.0001). DPOAE analysis demonstrated hearing loss at 71 Gy without progression or recovery at all time points, predominantly in the higher frequencies tested. Conclusion: The present study suggests that in the presence of sensorineural hearing loss due to high- dose fractionated radiotherapy, there is an initial sensorial component; however, the neural component is responsible for its progressivity. [ABSTRACT FROM AUTHOR]

Over the last two decades, the computed tomography simulator became the standard of the contemporary radiotherapy treatment planning (RTP) process. Along the same time, the superb soft tissue contrast of magnetic resonance imaging (MRI) was widely incorporated into RTP through the process of image coregistration. This review summarizes the efforts of incorporation of MRI data into target definition process for RTP based on gained clinical evidence so far and opens a question whether the time is up for bringing a MRI-simulator as an additional standard imaging tool into radiation oncology departments. [ABSTRACT FROM AUTHOR]

Purpose: One of the fundamental parameters used for dose calculation is percentage depth-dose, generally measured employing ionization chambers. There are situations where use of ion chambers for measuring depth-doses is difficult or problematic. In such cases, radiochromic film might be an alternative. The EBT-2 model GAFCHROMIC™ film was investigated as a potential tool for depth-dose measurement in radiotherapy beams over a broad range of energies and modalities. Methods: Pieces of the EBT-2 model GAFCHROMIC™ EBT2 film were exposed to x-ray, electron, and proton beams used in radiotherapy. The beams employed for this study included kilovoltage x-rays (75 kVp), 60Co gamma-rays, megavoltage x-rays (18 MV), electrons (7 and 20 MeV), and pristine Bragg-peak proton beams (126 and 152 MeV). At each beam quality, film response was measured over the dose range of 0.4-8.0 Gy, which corresponds to optical densities ranging from 0.05 to 0.4 measured with a flat-bed document scanner. To assess precision in depth-dose measurements with the EBT-2 model GAFCHROMIC™ film, uncertainty in measured optical density was investigated with respect to variation in film-to-film and scanner-bed uniformity. Results: For most beams, percentage depth-doses measured with the EBT-2 model GAFCHROMIC™ film show an excellent agreement with those measured with ion chambers. Some discrepancies are observed in case of (i) kilovoltage x-rays at larger depths due to beam-hardening, and (ii) proton beams around Bragg-peak due to quenching effects. For these beams, an empirical polynomial correction produces better agreement with ion-chamber data. Conclusions: The EBT-2 model GAFCHROMIC™ film is an excellent secondary dosimeter for measurement of percentage depth-doses for a broad range of beam qualities and modalities used in radiotherapy. It offers an easy and efficient way to measure beam depth-dose data with a high spatial resolution. [ABSTRACT FROM AUTHOR]

Abstract: In radiation therapy, an accurate dose determination and a precise dose delivery to the tumour are directly associated with better treatment outcomes in terms of higher tumour control and lower post radiation therapy complications. Over the years, film dosimetry was developed into a powerful tool for radiotherapy treatment verification and quality assurance. This review summarizes development of GAFCHROMIC™ film models through improvement in their sensitivity and uniformity as two dimensional detectors. The most important characteristics as well as the limitations that can affect the performance of the radiochromic film dosimetry systems have been described. An outline of both clinical and research contemporary applications is given particularly emphasizing new applications like brachytherapy, diagnostic radiology and radiobiological experiments. Review concludes through an overview of future directions in development of this important dosimetric tool revolving around its possible use as a three-dimensional dosimeter and the energy dependence of the film''s response. [Copyright &y& Elsevier]

Abstract: This work represents our effort to test feasibility of FDG-based PET/CT on target volume delineation in radiotherapy treatment planning of NSCLC patients. Different methods have been developed to enable more precise target outlining using PET: Qualitative Visual Method, CTV=2.5 SUV units, linear SUV threshold function method, and CTV=40% Iso of Maximum Uptake Value. We are proposing reconstruction of three biological target volumes: necrotic BTV (same as PTV created by radiation oncologist using CT data), proliferating BTV (based on PET signal to background ratio 1:3) and hypoxic BTV (based on PET signal to background ratio of 1:19). Two IMRT plans were created and compared to the conventional treatment plan: “conservative” IMRT plan delivers 52.5Gy to the necrotic BTV and 65Gy to the hypoxic BTV; “radical” IMRT plan delivers 30Gy to necrotic BTV, 52.5Gy to proliferating BTV and 65Gy to hypoxic BTV. Use of BTVs in IMRT plans is attractive because it increases dose to targets considered to need higher doses. It reduces considerably dose to heart and spinal cord, organs considered to limit dose escalation approaches in NSCLC treatment. “Conservative” IMRT approach can be understood as a PET/CT-based concomitant boost to the tumor expressing the highest FDG uptake. “Radical” plan implies deviation from the traditional uniform dose target coverage approach, with the intention of achieving better surrounding tissue sparing and ultimately allowing for dose escalation protocols relying on biologically based treatment planning. [Copyright &y& Elsevier]

Purpose: Organ preservation or nonoperative management of rectal cancer is of growing interest. Image guided adaptive endorectal brachytherapy is a radiation dose escalation modality: we explored its role in elderly patients unfit for surgery and patients refusing surgery.Methods and Materials: In this registry study, patients with rectal cancer who were ineligible for surgery received 40 Gy in 16 fractions of pelvic external beam radiation therapy. They subsequently received 3 weekly image guided adaptive brachytherapy boosts of 10 Gy to the residual tumor, for a total of 30 Gy in 3 fractions. Complete clinical response (cCR) and local control were the primary endpoints.Results: 94 patients were included; the median age was 81.1 years. With a median follow-up of 1.9 years, the proportion of cCR was 86.2%, the tumor regrowth proportion was 13.6%, and the cumulative incidence of local relapse was 2.7% at 1 year and 16.8% at 2 years. When considering responders and nonresponders, the 2-year local control was 71.5%. The overall survival at 2 years was 63.6%. Acute rectal grade 1 to 2 toxicity included all patients: 12.8% of patients had late bleeding requiring iron replacement, blood transfusions, or argon plasma therapy.Conclusions: Results of this registry study, evaluating radiation dose escalation for elderly medically unfit patients with unselected tumors, reveal that a high proportion of patients achieved cCR with a manageable toxicity profile. This technology will likely contribute to the challenging nonoperative management paradigm of rectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: Fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) is more accurate than CT in determining the extent of non–small-cell lung cancer. We performed a study to evaluate the impact of FDG-PET/CT on the radiotherapy volume delineation compared with CT without using any mathematical algorithm and to correlate the findings with the pathologic examination findings. Methods and Materials: A total of 32 patients with proven non–small-cell lung cancer, pathologic specimens from the mediastinum and lung primary, and pretreatment chest CT and FDG-PET/CT scans were studied. For each patient, two data sets of theoretical gross tumor volumes were contoured. One set was determined using the chest CT only, and the second, done separately, was based on the co-registered FDG-PET/CT data. The disease stage of each patient was determined using the TNM staging system for three data sets: the CT scan only, FDG-PET/CT scan, and pathologic findings. Results: Pathologic examination altered the CT-determined stage in 22 (69%) of 32 patients and the PET-determined stage in 16 (50%) of 32 patients. The most significant alterations were related to the N stage. PET altered the TNM stage in 15 (44%) of 32 patients compared with CT alone, but only 7 of these 15 alterations were confirmed by the pathologic findings. With respect to contouring the tumor volume for radiotherapy, PET altered the contour in 18 (56%) of 32 cases compared with CT alone. Conclusion: The contour of the tumor volume of non–small-cell lung cancer patients with co-registered FDG-PET/CT resulted in >50% alterations compared with CT targeting, findings similar to those of other publications. However, the significance of this change is unknown. Furthermore, pathologic examination showed that PET is not always accurate and histologic examination should be obtained to confirm the findings of PET whenever possible. [Copyright &y& Elsevier]

Purpose: This study reports the results of a single-institution experience with high-dose-rate brachytherapy (HDRBT) used as a boost in the treatment of esophageal cancer with external beam radiation therapy (ERT) with or without chemotherapy. Methods and Materials: Patients without evidence of metastatic disease were identified. HDRBT was given before ERT with a dose of 20 Gy in 5 fractions. Patients with a Karnofsky performance of more than 70 received treatment with 50 Gy in 25 fractions and concurrent 5-fluorouracil and cis-platinum during Weeks 1 and 5, whereas patients with a Karnofsky performance of less than 70 were treated with radiation therapy alone with 35 Gy in 14 fractions. Results: Fifty-three patients received HDRBT treatment with combined ERT and chemotherapy and 17 patients with ERT alone. The incidence of acute bone marrow toxicity was 55% Grade 2 and 15% Grade 3, and 85% of patients had Grade 2 esophagitis. With a median follow-up time of 26 months, the median survival was 21 months; the 2-year local recurrence was 25%, and the 5-year survival rate was 28%. Conclusion: HDRBT is safe and beneficial for local control in the radical treatment of patients with esophageal cancer. [Copyright &y& Elsevier]