[Implementing new technology in radiation oncology: The French agency for nuclear safety (ASN) report]. / Conditions de mise en œuvre des « nouvelles techniques et pratiques ¼ en radiothérapie. Synthèse du rapport du groupe de travail issu du groupe permanent d'experts en radioprotection médicale de l'Autorité de sûreté nucléaire.

In August 2013, the French nuclear safety agency (ASN) requested the permanent group of experts in radiation protection in medicine (GPMED) to propose recommendations on the implementation of new technology and techniques in radiation oncology. These recommendations were finalized in February 2015 by the GPMED. In April 2015, the ASN sent a letter to the French ministry of health (DGS/DGOS), and its national health agencies (ANSM, INCa, HAS). In these letters, ASN proposed that, from the 12 recommendations made by the GPMED, an action plan should be established, whose control could be assigned to the French national cancer institute (INCa), as a pilot of the national committee for radiotherapy and that this proposal has to be considered at the next meeting of the national committee of radiotherapy.

A new single crystal diamond dosimeter for small beam: comparison with different commercial active detectors.

Recent developments of new therapy techniques using small photon beams, such as stereotactic radiotherapy, require suitable detectors to determine the delivered dose with a high accuracy. The dosimeter has to be as close as possible to tissue equivalence and to exhibit a small detection volume compared to the size of the irradiation field, because of the lack of lateral electronic equilibrium in small beam. Characteristics of single crystal diamond (tissue equivalent material Z = 6, high density) make it an ideal candidate to fulfil most of small beam dosimetry requirements. A commercially available Element Six electronic grade synthetic diamond was used to develop a single crystal diamond dosimeter (SCDDo) with a small detection volume (0.165 mm(3)). Long term stability was studied by irradiating the SCDDo in a (60)Co beam over 14 h. A good stability (deviation less than ± 0.1%) was observed. Repeatability, dose linearity, dose rate dependence and energy dependence were studied in a 10 × 10 cm(2) beam produced by a Varian Clinac 2100 C linear accelerator. SCDDo lateral dose profile, depth dose curve and output factor (OF) measurements were performed for small photon beams with a micro multileaf collimator m3 (BrainLab) attached to the linac. This study is focused on the comparison of SCDDo measurements to those obtained with different commercially available active detectors: an unshielded silicon diode (PTW 60017), a shielded silicon diode (Sun Nuclear EDGE), a PinPoint ionization chamber (PTW 31014) and two natural diamond detectors (PTW 60003). SCDDo presents an excellent spatial resolution for dose profile measurements, due to its small detection volume. Low energy dependence (variation of 1.2% between 6 and 18 MV photon beam) and low dose rate dependence of the SCDDo (variation of 1% between 0.53 and 2.64 Gy min(-1)) are obtained, explaining the good agreement between the SCDDo and the efficient unshielded diode (PTW 60017) in depth dose curve measurements. For field sizes ranging from 0.6 × 0.6 to 10 × 10 cm(2), OFs obtained with the SCDDo are between the OFs measured with the PinPoint ionization chamber and the Sun Nuclear EDGE diode that are known to respectively underestimate and overestimate OF values in small beam, due to the large detection volume of the chamber and the non-water equivalence of both detectors.

Small fields output factors measurements and correction factors determination for several detectors for a CyberKnife® and linear accelerators equipped with microMLC and circular cones.

PURPOSE: The use of small photon fields is now an established practice in stereotactic radiosurgery and radiotherapy. However, due to a lack of lateral electron equilibrium and high dose gradients, it is difficult to accurately measure the dosimetric quantities required for the commissioning of such systems. Moreover, there is still no metrological dosimetric reference for this kind of beam today. In this context, the first objective of this work was to determine and to compare small fields output factors (OF) measured with different types of active detectors and passive dosimeters for three types of facilities: a CyberKnife(®) system, a dedicated medical linear accelerator (Novalis) equipped with m3 microMLC and circular cones, and an adaptive medical linear accelerator (Clinac 2100) equipped with an additional m3 microMLC. The second one was to determine the kQclin,Qmsr (fclin,fmsr) correction factors introduced in a recently proposed small field dosimetry formalism for different active detectors. METHODS: Small field sizes were defined either by microMLC down to 6 × 6 mm(2) or by circular cones down to 4 mm in diameter. OF measurements were performed with several commercially available active detectors dedicated to measurements in small fields (high resolution diodes: IBA SFD, Sun Nuclear EDGE, PTW 60016, PTW 60017; ionizing chambers: PTW 31014 PinPoint chamber, PTW 31018 microLion liquid chamber, and PTW 60003 natural diamond). Two types of passive dosimeters were used: LiF microcubes and EBT2 radiochromic films. RESULTS: Significant differences between the results obtained by several dosimetric systems were observed, particularly for the smallest field size for which the difference in the measured OF reaches more than 20%. For passive dosimeters, an excellent agreement was observed (better than 2%) between EBT2 and LiF microcubes for all OF measurements. Moreover, it has been shown that these passive dosimeters do not require correction factors and can then be used as reference dosimeters. Correction factors for the active detectors have then been determined from the mean experimental OF measured by the passive dosimeters. CONCLUSIONS: Four sets of correction factors needed to apply the new small field dosimetry formalism are provided for several active detectors. A protocol for small photon beams OF determination based on passive dosimeters measurements has been recently proposed to French radiotherapy treatment centers.

Comparison of organs' shapes with geometric and Zernike 3D moments.

The morphological similarity of organs is studied with feature vectors based on geometric and Zernike 3D moments. It is particularly investigated if outliers and average models can be identified. For this purpose, the relative proximity to the mean feature vector is defined, principal coordinate and clustering analyses are also performed. To study the consistency and usefulness of this approach, 17 livers and 76 hearts voxel models from several sources are considered. In the liver case, models with similar morphological feature are identified. For the limited amount of studied cases, the liver of the ICRP male voxel model is identified as a better surrogate than the female one. For hearts, the clustering analysis shows that three heart shapes represent about 80% of the morphological variations. The relative proximity and clustering analysis rather consistently identify outliers and average models. For the two cases, identification of outliers and surrogate of average models is rather robust. However, deeper classification of morphological feature is subject to caution and can only be performed after cross analysis of at least two kinds of feature vectors. Finally, the Zernike moments contain all the information needed to re-construct the studied objects and thus appear as a promising tool to derive statistical organ shapes.

[Recommendation of the working group commissioned by the French Nuclear Safety Authority on stereotactic radiation therapy]. / Avis du groupe de travail missionné par l'Autorité de sûreté nucléaire concernant la radiothérapie stéréotaxique.

PURPOSE: At the request of the French nuclear safety authority (Autorité de Sûreté Nucléaire, ASN) a working party of multidisciplinary experts was initiated to elaborate a report regarding propositions for the clinical practice of stereotactic radiation therapy and the related medical physics. MATERIAL AND METHODS: Several stereotactic radiation therapy experts were audited by the working party, especially neurosurgeons and neuroradiologists, as well as radiation oncologists, medical physicists and radiation technologists. An international survey was conducted looking at legal requirements and guidelines concerning stereotactic radiation therapy. A national survey was conducted in France among 29 departments performing stereotactic radiation therapy. The working party report was submitted for advice to the permanent group of medical experts of ASN. RESULTS: Among the 13 countries who responded, very few have legal documents. Some of them are stating that stereotactic radiation therapy must be performed in a radiotherapy department and only by well-trained professionals. Guidelines describing the role of each participant have been published in the USA. In France, stereotactic radiation therapy is performed with dedicated machines or adapted linear accelerators. In 2009, within the 29 departments, 4247 patients were treated with stereotactic radiation therapy representing 4% of the patients treated with external beam radiation therapy. Intracranial lesions were: 3383 and extracranial: 864. The working party of multidisciplinary experts made 7 recommendations. The first one saying that stereotactic radiation therapy must be considered as a radiotherapy. The permanent group of medical experts is asking to modify the "décret du 19 mars 2007" regarding "radiosurgery". CONCLUSION: The medical benefit of stereotactic radiation therapy is well admitted and it is an increasingly used technique. This work through practical guidelines and legal propositions intends to promote a well-controlled development of this radiotherapy technique.

Lessons from recent accidents in radiation therapy in France.

Many accidents in radiotherapy have been reported in France over the last years. This is due to the recent legal obligation to declare to the national safety authorities any significant incident relative to the use of ionising radiation including medical applications. The causes and consequences of the most serious events in radiotherapy are presented in this paper. Lessons can be learned from possible technical dysfunctions, from human errors or organisational weaknesses as to how such events can be prevented. The technical aspects are addressed here: in particular, dosimetric issues.

Impact of CpG methylation on structure, dynamics and solvation of cAMP DNA responsive element.

Methylation of CpG motifs in DNA is involved in the control of gene expression and in several other epigenic effects. It suppresses also the immuno-stimulation properties of bacterial or viral DNAs that contain CPGS: However, effects of methylation on the DNA structure and dynamics are not clear. Here we carried out a 10 ns MD simulation, confronted to an NMR analysis, of a hexadecanucleotide with the cAMP responsive element (CRE) DNA methylated at its center: d(GAGATGAmCGTCATCTC)(2) (CREmet). Methylation does not introduce significant structure modification but reduces the dynamics. Molecular mechanics and generalized Born solvation energy calculations showed that the stiffness of CREmet arises from both a restriction of the conformational space by the bulky methyl groups and a folding of DNA around the hydrophobic methyls. The latter effect is favored when the GpA steps belonging to the TGA binding half-sites adopt the BII conformation. The inability of the methylated DNAs to interact with their protein partners-either transcription factors for gene regulation or a Toll-like receptor for immunostimulation-could result from both the obstacle created by methyls, preventing crucial interactions, and the loss of DNA flexibility, reducing its adaptability. Results are discussed in the light of NMR and crystallographic data.

Bending and adaptability to proteins of the cAMP DNA-responsive element: molecular dynamics contrasted with NMR.

DNA bending is assumed to play a crucial role during recognition of the cAMP-responsive element (CRE) by transcription factors. However, diverging results have been obtained for the bending direction of the unbound double helix. The refined NMR structures present a bend directed toward the minor groove, while biochemical methods conclude that there is a bend toward the major groove. The present 10-ns molecular dynamics (MD) simulation of d(GAGATGACGTCATCTC)(2), which contains the octamer CRE in its center, was carried out with AMBER in explicit water and counterions. It shows that CRE is a flexible segment, although it is bent slightly toward the major groove (7 degrees -8 degrees ) on the average. The MD structure agrees with both the biochemical results and unrefined NMR data. The divergence with the NMR refined structures suggests an improper electrostatic parameterization in the refinement software. The malleability of the central CpG is certainly the major contribution to the curving of the whole CRE segment in both the unbound and bound states. Comparison with the crystal structure of CRE bound to GCN4 shows that the deformation induced by the protein is concentrated mainly on the CpG step, rendering the bound structure of CRE closer to the structure of the 12-0 tetradecanoylphorbol-beta-acetate-responsive element.

An intrinsic curvature towards the minor groove in the cAMP-responsive element DNA found by combined NMR and molecular modelling studies.

The cAMP-responsive element (CRE, 5'-TGACGTCA-3') is essential to the transcriptional function of numerous gene promoters in eukaryotic cells. We carried out NMR restrained molecular mechanics studies using two different force fields (Flex and "AMBER94") on a hexadecanucleotide d(GAGATGACGTCATCTC) containing CRE. Results indicated that free CRE is a B-DNA that is intrinsically curved towards the minor groove. To our knowledge, NMR restraints have not previously been useful in accounting for a global DNA curvature. In order to validate the bend in CRE, we applied a new strategy in which DNA structures displaying different curvatures were generated and then compared with NMR data. Conformations of CRE curved towards the minor groove provided the best agreement with NMR data. Our results contrast with previous results obtained from NMR restrained modelling and gel methods; these suggested conformations that were straight or curved towards the major groove, respectively. The curve in free CRE is spread along the DNA helix: several kinks are repeated in phase within the helical turn, although they are centred mainly on CpG in between the TGA half-sites, thus slightly increasing their spacing within the major groove. Comparison with the crystal structure of CRE complexed to general control protein 4 showed that the curve orientation is reversed from the minor to the major groove upon protein binding, due to a helix distortion concentrated mainly on CpG.

A European quality assurance network for radiotherapy: dose measurement procedure.

In the frame of the experimental implementation of a European quality assurance network for external radiotherapy, the methodology in the European Measuring Centre (MC) is presented. Mailed TL dosimeters are used for the check of the beam output and of the beam quality of photon beams. The thermoluminescent material is PTL 717 LiF powder. The readings were first performed on a manual, and then on an automatic reader, with standard deviations of the mean of 0.7% for one dosimeter. Corrections for supralinearity and for the energy dependence of the dosimeter response are applied. An original method has been developed to correct for the variation of the LiF response as a function of time. It is shown that the sensitivity of the powder changes during storage, leading to a kind of 'inverse fading'. The global uncertainty of the TL postal measurement procedure is estimated to be about 1.5% for the 60Co beams and 2% for the x-ray beams. Intercomparisons with the IAEA and with the EORTC have shown an agreement better than 2% for all energies. It can be concluded that the results of the MC are suitable for the requirements of a European quality assurance network.

Quality control of radiotherapy centres in Europe: beam calibration.

A European Quality Assurance Network for external radiotherapy was set up. In this, several countries participated on a voluntary basis to elaborate common protocols, using joint infrastructure. The support for the co-ordination of the project was given by the EC committee 'Europe Against Cancer'. In the first step of the programme, beam outputs and beam qualities are checked with mailed thermoluminescent dosimeters following the protocol prepared by the IAEA. The results concerning 125 beams from 66 centres are analysed. Twenty-two beams presented minor deviations (3-6%) and 15 beams (4/48 60Co beams and 11/77 X-ray beams) from 11 centres presented major deviations (> or = 6%). The analysis shows that 16/22 minor deviations and all major deviations have been detected in centres which have not benefited from an external check during the last 5 years. In 14 out of 15 large deviations, the measured dose was smaller than the stated dose. In most centres with major deviation the physicists did not have the necessary experience and did not regularly calibrate the beams. In 6 out of 11 centres there was no dosimeter or the dosimeter available had not been calibrated recently. In 3 centres, the physicist did not give any explanation.

Preliminary results of a quality assurance network for radiotherapy centres in Europe.

Based on the IAEA/WHO experience in mailed dosimetry, a Quality Assurance (QA) Network, sponsored by the EC committee "Europe Against Cancer", has been set up in 1991 for European centres, not involved in clinical research. Besides a survey of radiotherapy infrastructure, the project includes three measurement steps: primarily a check of beam output and quality in reference conditions with a mailed TLD-procedure, in a second step the mailed verification of other beam data and dose calculation procedures with a multipurpose phantom and finally in vivo dosimetry at the individual patient levels with mailed dosimeters. The results of infrastructure show good agreement with the data previously published by EORTC for research centres. Until January 1993, a total number of 37 centres (49 X-ray beams and 28 cobalt beams) from Belgium, France, Italy, The Netherlands, Sweden and The Czech and Slovak Republics have participated in the first measurement step. Deviations > 3% and < 6% from the stated dose are found in 17 out of the 79 checked beams. A deviation < 6% from the stated dose is detected in only 1 out of the 28 cobalt beams, but in 7 of the 49 X-ray beams. The large majority of the beams (23/25) with deviations > 3% belong to centres not having participated in external audits in the previous 5 years. A pilot study for the second step shows larger deviations in non reference conditions, especially for off-axis points and for oblique phantom surface. The third step has yet to be implemented.(ABSTRACT TRUNCATED AT 250 WORDS)

Is it possible to verify directly a proton-treatment plan using positron emission tomography?

A PET camera is used to visualize the positron activity induced during protonbeam therapy in order to verify directly the proton-treatment plans. The positron emitters created are predominantly the 15O and 11C, whose total activity amounts to 12 MBq after an irradiation with 85 MeV protons, delivering 3 Gy in a volume of approximately 300 cm3. Although this method is a useful verification of patient set-up, care must be taken when deriving dose distributions from activity distributions. Correlation between both quantities is difficult, moreover at the last millimeters of their range, protons will no longer activate tissue. Due to the short half-lives the PET camera must be located close to the treatment facility.