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[en] Cell experiments have shown the proton relative biological effectiveness (RBE) to vary with dose and linear energy transfer (LET), which has led to development of variable RBE models. The RBE is normally estimated from two independent functions, the RBEmax and RBEmin, describing the extreme RBE at low and high doses. While there is consensus that RBEmax increases with increasing LET, the RBEmin is not uniformly defined and its dependency on LET is deviating. In this work, we analysed this dependency and its sensitivity to variations of the experimental dose range. We performed a literature search to find data from existing monoenergetic proton cell survival experiments with (α/β)x values below 5 Gy and dose averaged LET (LETd) values below 20 keV µm−1. From the experiments the doses and their corresponding survival data were extracted. Based on these data, multiple restricted databases were generated by sequential exclusion of low dose data in the experiments followed by a linear-quadratic (LQ) fit. The quadratic component from the LQ-fit was used to estimate RBEmin. The LETd dependency of RBEmin was determined by fitting a linear function to the RBEmin values estimated from the restricted databases. Our analysis showed the LETd dependency of RBEmin to be significantly influenced by the experimental dose range. By including experiments with doses below 1 Gy in the database, we found that RBEmin increased with increasing LETd. By excluding the low dose experiments in our database, the RBEmin became constant for all LETd values. For an LETd value of 5 keV µm−1, a restricted database including the data with the lowest doses gave an RBEmin of 1.4 ± 0.1, while databases with only high dose data (>2 Gy) gave an RBEmin of 1.0 ± 0.1. None of our restricted databases gave a decreasing RBEmin with increasing LETd. Our study showed that RBEmin has a small yet significant dependency on LETd for tissues with low (α/β)x ratio. The LETd dependency of RBEmin varied substantially with the experimental dose range. Including experiments with high minimum dose in RBE models may lead to underestimation of the RBE. (paper)
[en] We developed and evaluated a novel inverse optimization (IO) model to estimate objective function weights from clinical dose-volume histograms (DVHs). These weights were used to solve a treatment planning problem to generate ‘inverse plans’ that had similar DVHs to the original clinical DVHs. Our methodology was applied to 217 clinical head and neck cancer treatment plans that were previously delivered at Princess Margaret Cancer Centre in Canada. Inverse plan DVHs were compared to the clinical DVHs using objective function values, dose-volume differences, and frequency of clinical planning criteria satisfaction. Median differences between the clinical and inverse DVHs were within 1.1 Gy. For most structures, the difference in clinical planning criteria satisfaction between the clinical and inverse plans was at most 1.4%. For structures where the two plans differed by more than 1.4% in planning criteria satisfaction, the difference in average criterion violation was less than 0.5 Gy. Overall, the inverse plans were very similar to the clinical plans. Compared with a previous inverse optimization method from the literature, our new inverse plans typically satisfied the same or more clinical criteria, and had consistently lower fluence heterogeneity. Overall, this paper demonstrates that DVHs, which are essentially summary statistics, provide sufficient information to estimate objective function weights that result in high quality treatment plans. However, as with any summary statistic that compresses three-dimensional dose information, care must be taken to avoid generating plans with undesirable features such as hotspots; our computational results suggest that such undesirable spatial features were uncommon. Our IO-based approach can be integrated into the current clinical planning paradigm to better initialize the planning process and improve planning efficiency. It could also be embedded in a knowledge-based planning or adaptive radiation therapy framework to automatically generate a new plan given a predicted or updated target DVH, respectively. (paper)
[en] Clinical studies have demonstrated that HPV induced tumors constitute a specific subclass of cancer with a better response to radiation treatment. The purpose of this study was to investigate meaning of viral E2-gene for radiosensitivity. W12 cells contain episomal HPV 16 genomes, whereas S12 cells, which derive from the W12 line, contain HPV DNA as integrated copies. Clonogenic survival was analyzed using 96-well in vitro test. Using flow cytometry cell cycle analyses were performed. Expression of pRb and p53 were analyzed using intracellular staining. W12 cells (intact E2 gene) showed a lower survival fraction than S12 cells. W12 cells developed a G2/M block 24 h after irradiation with 2 Gy whereas S12 showed no G2/M bloc. After irradiation S12 cells developed polyploidy and pRb-positive cells decreased. W12 cells showed no change of pRb-positive cells. Depending on E2 gene status differences in cell cycle regulation might cause radioresistance. The E2/E7/pRb pathway seems to influence HPV-induced radiosensitivity. Our experiments demonstrated an effect of HPV on radiosensitivity of cervical keratinocytes via viral transcription regulator E2 pathway
[en] This paper reports the Electron Spin Resonance (ESR) and Thermoluminescence (TL) dosimetric and kinetic characteristics of commercial watch glass. Both of the ESR and TL response of the watch glass sample yielded linear behavior in the 0.5–135 Gy gamma dose range. ESR dosimetric properties of watch glass sample like dose-rate dependence, signal reproducibility and fading behavior have also been studied in detail. Kinetic behavior and activation energy of the radiation induced free radicals responsible from the ESR spectra of watch glass sample were determined. The TL kinetic parameters such as activation energy (E), frequency factor (s), order of kinetics (b) were also calculated by applying the methods of initial rise (IR), isothermal decay (ID), variable heating rate (VHR) and de-convolution. - Highlights: • Linear dose response of watch glass sample are observed in the 0.5–135 Gy range. • Kinetic parameters were determined applying various methods of analysis. • ESR and TL dosimetric characteristics of watch glass samples were investigated. • Watch glass samples can be used as alternative accident dosimeter using ESR and TL.
[en] The MR-Linac will provide excellent soft tissue contrast for on-treatment imaging. It is well known that the electron return effect (ERE) results in areas of increased and decreased dose at air/tissue boundaries, which can be compensated for in plan optimisation. However, anatomical changes may affect the quality of this compensation. In this paper we aim to quantify the interaction of anatomical changes with ERE in head and neck (H and N) cancer patients. Twenty patients treated with either 66 Gy or 60 Gy in 30 fractions were selected. Ten had significant weight-loss during treatment requiring repeat CT (rCT) and ten had PTVs close to the sinus cavity. Plans were optimised using Monaco to meet the departmental dose constraints and copied to the rCT and re-calculated. For the sinus patients, we optimised plans with full and empty sinus at both 0 T and 1.5 T. The effect of the opposite filling state was next evaluated. No clinically relevant difference between the doses in the PTV and OARs were observed related to weight-loss in 0 T or 1.5 T fields. Variable sinus filling caused greater dosimetric differences near the walls of the sinus for plans optimised with a full cavity in 1.5 T, indicating that optimising with an empty sinus makes the plan more robust to changes in filling. These findings indicate that current off-line strategies for adaptive planning for H and N patients are also valid on an MR-linac, if care is taken with sinus filling. (paper)
[en] Background and purpose: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95 Gy (tumour) and 74 Gy (lymph nodes), was pursued and compared to standard 66 Gy/33 F plans. Material and methods: Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue. Results: The median dose-escalation in FDG-avid areas was 93.9 Gy (tumour) and 73.0 Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5 Gy (GTV-T) and 81.3 Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74 Gy due to escalation. Conclusions: FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.
[en] The primary objective was to determine maximum tolerated radiation dose in patients with metastatic renal cell carcinoma on pazopanib treatment. Treatment-naïve patients received pazopanib according to standard of care. Stereotactic body radiotherapy (SBRT) was delivered concurrently to the largest metastatic lesion at day 8, 10 and 12. SBRT doses were escalated in 3 dose levels (24 Gy/3, 30 Gy/3 and 36 Gy/3). Dose level was assigned using Time-to-Event Continual Reassessment Method with the target dose-limiting toxicity rate set to 0.25. Thirteen patients were included. One patient experienced dose limiting toxicity (DLT) at dose level 3 (grade 4 hypoglycemia). Maximum tolerated dose was not reached with a recommended dose of 36 Gy/3 having a probability of DLT of 11%. One-year local control was 83% (95% confidence interval 61–100) and 1-year progression-free survival was 28% (95% confidence interval 1–55). SBRT in combination with pazopanib is well tolerated with good local control and response rates outside the radiation field. This trial was retrospectively registered on clinicaltrials.gov( https://clinicaltrials.gov/ct2/show/NCT02334709 ) on January 6th, 2015. The online version of this article (10.1186/s13014-017-0893-x) contains supplementary material, which is available to authorized users.
[en] We herein report on the calculation of the activation energy (Ea) from the thermoluminescence (TL) glow curves performed by the initial rise method that allows us to discriminate between irradiated and non-irradiated sesame seeds. Ea values of natural TL (0.68 ± 0.03 eV) and gamma-induced TL (never lower than 0.82 ± 0.02 eV) appear as a complementary criterion to be used differentiating between irradiated and non-irradiated foodstuffs with the position and the intensity of the main peak of the TL emission. In addition, E a values taken from irradiated sesame samples at different doses (1, 5 and 10 kGy) and stored up to 15 months after being processed were compared to a 'positive' Spanish blend (i.e. at least one component was commercially irradiated). (author)
[en] The use of electronic equipment in harsh nuclear environments is a topic of controversial discussions within the nuclear community. However, the advances in electronics design of the past decade offer new standard electronic components and chip technologies. Based on appropriate selection criteria, these components are well suited for applications in harsh nuclear environments. In this context, AREVA NP developed an innovative power line communication system. The power line data acquisition (PLDA) system aims at the online signal acquisition, in particular in high dose rate areas during full plant operation. The acquired signals are bundled and transmitted through existing power lines. For this purpose, the PLDA-system uses point-to-point connections for unidirectional analog signal transmission. Possible access points for the PLDA-system are power terminals of electrical consumers. Thus, this technology offers a complementary kind of signal transmission. (orig.)
[en] Standard of care primary treatment of carcinoma of locally advanced squamous cell head and neck cancer (LAHNSCC) consists of platinum-based concomitant chemo-irradiation. Despite progress in the treatment of LAHNSCC using modern radiotherapy techniques the outcome remains still poor. Using IMRT with SIB the escalation of total dose to the GTV is possible with the aim to improve clinical outcome. This study tests the hypothesis if radiation dose escalation to the GTV improves 2-year-LRC and -OS after concomitant chemo-irradiation. The ESCALOX trial is a prospective randomized phase III study using cisplatin chemo-irradiation and the SIB-IMRT concept in patients with LAHNSCC of the oral cavity, oropharynx or hypopharynx to escalate the total dose to the GTV up to 80.5 Gy. Chemotherapy is planned either in the 1st and 5th week (cisplatin 20 mg/m2/d d 1–5 and d 29–33) or weekly (cisplatin 40 mg/m2/d) during RT. RT is delivered as SIB with total doses of 80.5 Gy/70.0 Gy/56.0 Gy with 2.3 Gy/2.0 Gy and 1.6 Gy in the experimental arm and in the control arm with 70.0 Gy/56.0 Gy with 2.0 Gy and 1.6 Gy. A pre-study with dose escalation up to 77.0 Gy/70.0 Gy/56.0 Gy with 2.2 Gy/2.0 Gy and 1.6 Gy is demanded by the German federal office of radiation protection (BfS). In the translational part of the trial 100 of the randomised patients will be investigated by 18-F-FMiso-PET-CT for the presence and behaviour of tumor hypoxia twice in the week before treatment start. The primary endpoint of the pre-study is acute radiation induced toxicity. Primary endpoint of the main trial is 2-year-LRC. By using the dose escalation up to 80.5 Gy to the GTV of the primary tumor and lymph nodes > 2 cm a LRC benefit of 15% at 2 years should be expected. The ESCALOX trial is supported by Deutsche Forschungsgemeinschaft (DFG); Grant No.: MO-363/4-1. ClinicalTrials.gov Identifier: https://clinicaltrials.gov/ct2/show/NCT01212354?term , EudraCT-No.: 2010-021139-15