[Clinical research in radiation oncology: how to move from the laboratory to the patient?] / Recherche clinique en oncologie radiothérapie : comment passer du laboratoire au patient ?

Translational research in radiation oncology is undergoing intense development. An increasingly rapid transfer is taking place from the laboratory to the patients, both in the selection of patients who can benefit from radiotherapy and in the development of innovative irradiation strategies or the development of combinations with drugs. Accelerating the passage of discoveries from the laboratory to the clinic represents the ideal of any translational research program but requires taking into account the multiple obstacles that can slow this progress. The ambition of the RadioTransNet network, a project to structure preclinical research in radiation oncology in France, is precisely to promote scientific and clinical interactions at the interface of radiotherapy and radiobiology, in its preclinical positioning, in order to identify priorities for strategic research dedicated to innovation in radiotherapy. The multidisciplinary radiotherapy teams with experts in biology, medicine, medical physics, mathematics and engineering sciences are able to meet these new challenges which will allow these advances to be made available to patients as quickly as possible.

Rectal cancer radiotherapy.

We present the updated recommendations of the French society of oncological radiotherapy for rectal cancer radiotherapy. The standard treatment for locally advanced rectal cancer consists in chemoradiotherapy followed by radical surgery with total mesorectal resection and adjuvant chemotherapy according to nodal status. Although this strategy efficiently reduced local recurrences rates below 5% in expert centres, functional sequelae could not be avoided resulting in 20 to 30% morbidity rates. The early introduction of neoadjuvant chemotherapy has proven beneficial in recent trials, in terms of recurrence free and metastasis free survivals. Complete pathological responses were obtained in 15% of tumours treated by chemoradiation, even reaching up to 30% of tumours when neoadjuvant chemotherapy is associated to chemoradiotherapy. These good results question the relevance of systematic radical surgery in good responders. Personalized therapeutic strategies are now possible by improved imaging modalities with circumferential margin assessed by magnetic resonance imaging, by intensity modulated radiotherapy and by refining surgical techniques, and contribute to morbidity reduction. Keeping the same objectives, ongoing trials are now evaluating therapeutic de-escalation strategies, in particular rectal preservation for good responders after neoadjuvant treatment, or radiotherapy omission in selected cases (Greccar 12, Opera, Norad).

Time of PTV is ending, robust optimization comes next.

Continuous improvements have been made in the way to prescribe, record and report dose distributions since the therapeutic use of ionizing radiations. The international commission for radiation units and measurement (ICRU) has provided a common language for physicians and physicists to plan and evaluate their treatments. The PTV concept has been used for more than two decades but is becoming obsolete as the CTV-to-PTV margin creates a static dose cloud that does not properly recapitulate all planning vs. delivery uncertainties. The robust optimization concept has recently emerged to overcome the limitations of the PTV concept. This concept is integrated in the inverse planning process and minimizes deviations to planned dose distribution through integration of uncertainties in the planning objectives. It appears critical to account for the uncertainties that are specific to protons and should be accounted for to better exploit the clinical potential of proton therapy. It may also improve treatment quality particularly in hypofractionated photon plans of mobile tumors and more widely to photon radiotherapy. However, in contrast to the PTV concept, a posteriori evaluation of plan quality, called robust evaluation, using error-based scenarios is still warranted. Robust optimization metrics are warranted. These metrics are necessary to compare PTV-based photon and robustly optimized proton plans in general and in model-based NTCP approaches. Assessment of computational demand and approximations of robust optimization algorithms along with metrics to evaluate plan quality are needed but a step further to better prescribe radiotherapy may has been achieved.

Validation of the analytical irradiator model and Monte Carlo dose engine in the small animal irradiation treatment planning system µ-RayStation 8B.

Dose calculation in preclinical context with a clinical level of accuracy is a challenge due to the small animal scale and the medium photon energy range. In this work, we evaluate the effectiveness and accuracy of an analytical irradiator model combined with Monte Carlo (MC) calculations in the irradiated volume to calculate the dose delivered by a modern small animal irradiator. A model of the XRAD225Cx was created in µ-RayStation 8B, a preclinical treatment planning system, allowing arc and static beams for seven cylindrical collimators. Calculations with the µ-RayStation MC dose engine were compared with EBT3 measurements in water for all static beams and with a validated GATE model in water, heterogeneous media and a mouse CT. The GATE model is a complete MC representation of the XRAD225Cx. In water, µ-RayStation calculations, compared to GATE calculations and EBT3 measurements, agreed within a maximal error of 3.2% (mean absolute error of 0.6% and 0.8% respectively) and maximal distance-to-agreement (DTA) was 0.2 mm at 50% of the central dose. For a 5 mm static beam in heterogeneous media, the maximal absolute error between µ-RayStation and GATE calculations was below 1.3% in each medium and DTA was 0.1 mm at interfaces. For calculations on a mouse CT, µ-RayStation and GATE calculations agreed well for both static and arc beams. The 2D local gamma passing rate was >98.9% for 1%/0.3 mm criteria and >92.9% for 1%/0.2 mm criteria. Moreover, µ-RayStation reduces calculation time significantly comparing with GATE (speed-up factor between 120 and 680). These findings show that the analytical irradiator model presented in this work combined with the µ-RayStation MC dose engine accurately computes dose for the XRAD225Cx irradiator. The improvements in calculation time and availability of functionality and tools for managing, planning and evaluating the irradiation makes this platform very useful for pre-clinical irradiation research.

A new tissue segmentation method to calculate 3D dose in small animal radiation therapy.

BACKGROUND: In pre-clinical animal experiments, radiation delivery is usually delivered with kV photon beams, in contrast to the MV beams used in clinical irradiation, because of the small size of the animals. At this medium energy range, however, the contribution of the photoelectric effect to absorbed dose is significant. Accurate dose calculation therefore requires a more detailed tissue definition because both density (ρ) and elemental composition (Zeff) affect the dose distribution. Moreover, when applied to cone beam CT (CBCT) acquisitions, the stoichiometric calibration of HU becomes inefficient as it is designed for highly collimated fan beam CT acquisitions. In this study, we propose an automatic tissue segmentation method of CBCT imaging that assigns both density (ρ) and elemental composition (Zeff) in small animal dose calculation. METHODS: The method is based on the relationship found between CBCT number and ρ*Zeff product computed from known materials. Monte Carlo calculations were performed to evaluate the impact of ρZeff variation on the absorbed dose in tissues. These results led to the creation of a tissue database composed of artificial tissues interpolated from tissue values published by the ICRU. The ρZeff method was validated by measuring transmitted doses through tissue substitute cylinders and a mouse with EBT3 film. Measurements were compared to the results of the Monte Carlo calculations. RESULTS: The study of the impact of ρZeff variation over the range of materials, from ρZeff = 2 g.cm- 3 (lung) to 27 g.cm- 3 (cortical bone) led to the creation of 125 artificial tissues. For tissue substitute cylinders, the use of ρZeff method led to maximal and average relative differences between the Monte Carlo results and the EBT3 measurements of 3.6% and 1.6%. Equivalent comparison for the mouse gave maximal and average relative differences of 4.4% and 1.2%, inside the 80% isodose area. Gamma analysis led to a 94.9% success rate in the 10% isodose area with 4% and 0.3 mm criteria in dose and distance. CONCLUSIONS: Our new tissue segmentation method was developed for 40kVp CBCT images. Both density and elemental composition are assigned to each voxel by using a relationship between HU and the product ρZeff. The method, validated by comparing measurements and calculations, enables more accurate small animal dose distribution calculated on low energy CBCT images.

Respiratory-gated bilateral pulmonary radiotherapy for Ewing's sarcoma and nephroblastoma in children and young adults: Dosimetric and clinical feasibility studies.

PURPOSE: Bilateral pulmonary radiotherapy in children and young adults aims to reduce the recurrence of lung metastases. The radiation field includes liver tissue, which is sensitive to even low radiation doses. We investigated the feasibility of respiratory gating radiotherapy using voluntary deep inspiration breath hold and its toxicity in these patients. PATIENTS AND METHOD: A retrospective clinical review was conducted for all patients who had undergone bilateral pulmonary radiotherapy, with or without deep inspiration breath hold, treated in our institution between October 1999 and May 2012. A dosimetric study was conducted on seven consecutive children using 4D-scan data on free-breathing and a SpiroDyn'RX-system-scan on deep inspiration breath hold. A radiation treatment of 20Gy was simulated. RESULTS: Concerning the clinical study, seven patients of mean age 11.9 years (range: 4.9-21.1 years) were treated with free-breathing and ten patients of mean age 15.6 years (range: 8.6-19.7 years) were treated with deep inspiration breath hold for mainly Ewing sarcoma and nephroblastoma. Within six months of radiotherapy, all patients experienced mild liver toxicity (grade 1 or 2 altered levels of alanine/aspartate aminotransferase [n=8 of 9] or cholestasis [n=1 of 9]), which resolved completely with no difference between deep inspiration breath hold and free-breathing technique. Over a median follow-up of 2.6 years (range: 0.1-9.3 years), four patients died from disease progression (mean 1.5 years post-radiotherapy [range: 1.1-1.6 years]) and three experienced grade III-V lung toxicity. Concerning the dosimetric study, the irradiated liver volume was significantly lower with deep inspiration breath hold than free-breathing, for each isodose (V5: 73.80% versus 86.74%, P<0.05; V20: 5.70% versus 26.44%, P<0.05). CONCLUSIONS: The dosimetric data of respiratory-gated bilateral pulmonary radiotherapy showed a significantly spare of normal liver tissue. Clinical data showed that this technique is feasible even in young children. However, no liver toxicity difference between deep inspiration breath hold and free-breathing was shown.

Validation of fast Monte Carlo dose calculation in small animal radiotherapy with EBT3 radiochromic films.

In preclinical studies, the absorbed dose calculation accuracy in small animals is fundamental to reliably investigate and understand observed biological effects. This work investigated the use of the split exponential track length estimator (seTLE), a new kerma based Monte Carlo dose calculation method for preclinical radiotherapy using a small animal precision micro irradiator, the X-RAD 225Cx. Monte Carlo modelling of the irradiator with GATE/GEANT4 was extensively evaluated by comparing measurements and simulations for half-value layer, percent depth dose, off-axis profiles and output factors in water and water-equivalent material for seven circular fields, from 20 mm down to 1 mm in diameter. Simulated and measured dose distributions in cylinders of water obtained for a 360° arc were also compared using dose, distance-to-agreement and gamma-index maps. Simulations and measurements agreed within 3% for all static beam configurations, with uncertainties estimated to 1% for the simulation and 3% for the measurements. Distance-to-agreement accuracy was better to 0.14 mm. For the arc irradiations, gamma-index maps of 2D dose distributions showed that the success rate was higher than 98%, except for the 0.1 cm collimator (92%). Using the seTLE method, MC simulations compute 3D dose distributions within minutes for realistic beam configurations with a clinically acceptable accuracy for beam diameter as small as 1 mm.

[Small animal image-guided radiotherapy: A new era for preclinical studies]. / Radiothérapie guidée par l'image pour les petits animaux: une nouvelle ère pour les études précliniques.

Preclinical external beam radiotherapy irradiations used to be delivered with a static broad beam. To promote the transfer from animal to man, the preclinical treatment techniques dedicated to the animal have been optimized to be similar to those delivered to patients in clinical practice. In this context, preclinical irradiators have been developed. Due to the small sizes of the animals, and the irradiation beams, the scaling to the small animal dimensions involves specific problems. Reducing the size and energy of the irradiation beams require very high technical performance, especially for the mechanical stability of the irradiator and the spatial resolution of the imaging system. In addition, the determination of the reference absorbed dose rate must be conducted with a specific methodology and suitable detectors. To date, three systems are used for preclinical studies in France. The aim of this article is to present these new irradiators dedicated to small animals from a physicist point of view, including the commissioning and the quality control.

[Image-guided radiotherapy: Overview of devices and practice in France in 2015]. / État des lieux des dispositifs et des pratiques de radiothérapie guidée par l'image en France en 2015.

Image-guided radiation therapy consists in acquiring in-room images to improve patient and mainly tumour set up accuracy. Many devices based on ionising or non-ionising radiations were designed in recent years. The use of such devices is of major importance in the management of patient radiotherapy courses. Those imaging sessions require to clearly define procedures in each radiotherapy department (image modality, acquisition frequency, corrective action, staff training and tasks). A quick review of the different existing image-guided radiation therapy devices is presented. In addition, the results of a French national survey about image-guided radiation therapy are presented: the survey is about both equipment and procedures. A total of 57 radiotherapy departments have participated, representing more than 160 treatment devices. About three linear accelerators out of four are equipped with an image-guiding device. The most common equipment is the CBCT system. Most centres have set up training sessions for the technicians to allow them to analyse online daily images. The management of in-room imaging dose is still under investigation, but many centres use an accounting scheme. While the devices are used to adjust the positioning of patients, in more than half of the centres, the practice had an impact on the choice of clinical and planning target volume margins. This survey led to an inventory in 2015, and could be renewed in some years.

[Which rules apply to hypofractionated radiotherapy?]. / Radiothérapie hypofractionnée : quelles sont les règles à suivre ?

Hypofractionated radiotherapy is now more widely prescribed due to improved targeting techniques (intensity modulated radiotherapy, image-guided radiotherapy and stereotactic radiotherapy). Low dose hypofractionated radiotherapy is routinely administered mostly for palliative purposes. High or very high dose hypofractionated irradiation must be delivered according to very strict procedures since every minor deviation can lead to major changes in dose delivery to the tumor volume and organs at risk. Thus, each stage of the processing must be carefully monitored starting from the limitations and the choice of the hypofractionation technique, tumour contouring and dose constraints prescription, planning and finally dose calculation and patient positioning verification.

Split exponential track length estimator for Monte-Carlo simulations of small-animal radiation therapy.

We propose the split exponential track length estimator (seTLE), a new kerma-based method combining the exponential variant of the TLE and a splitting strategy to speed up Monte Carlo (MC) dose computation for low energy photon beams. The splitting strategy is applied to both the primary and the secondary emitted photons, triggered by either the MC events generator for primaries or the photon interactions generator for secondaries. Split photons are replaced by virtual particles for fast dose calculation using the exponential TLE. Virtual particles are propagated by ray-tracing in voxelized volumes and by conventional MC navigation elsewhere. Hence, the contribution of volumes such as collimators, treatment couch and holding devices can be taken into account in the dose calculation.We evaluated and analysed the seTLE method for two realistic small animal radiotherapy treatment plans. The effect of the kerma approximation, i.e. the complete deactivation of electron transport, was investigated. The efficiency of seTLE against splitting multiplicities was also studied. A benchmark with analog MC and TLE was carried out in terms of dose convergence and efficiency.The results showed that the deactivation of electrons impacts the dose at the water/bone interface in high dose regions. The maximum and mean dose differences normalized to the dose at the isocenter were, respectively of 14% and 2% . Optimal splitting multiplicities were found to be around 300. In all situations, discrepancies in integral dose were below 0.5% and 99.8% of the voxels fulfilled a 1%/0.3 mm gamma index criterion. Efficiency gains of seTLE varied from 3.2 × 10(5) to 7.7 × 10(5) compared to analog MC and from 13 to 15 compared to conventional TLE.In conclusion, seTLE provides results similar to the TLE while increasing the efficiency by a factor between 13 and 15, which makes it particularly well-suited to typical small animal radiation therapy applications.

Underestimation of dose delivery in preclinical irradiation due to scattering conditions.

UNLABELLED: The aim of this study was to evaluate, by comparing simulation results with measurement results, the impact of the lack of scattering volume in experimental conditions of preclinical irradiation. First, a Monte Carlo model of a small animal irradiator, the Faxitron CP-160, was developed with GATE (Geant4 Application for Tomography Emission). To validate the model, simulated data were compared to depth dose and off-axis ratio profiles measured with a plane-parallel ionization chamber and Gafchromic(®) EBT films, respectively, in a solid water phantom. The AAPM TG-61 protocol was applied to measure the dose rate at the surface of a semi-infinite reference phantom. Then, the model was used to determine the dose distributions in three different phantom settings: a semi-infinite water phantom, a 2.8-cm-thick water phantom and a 2.8-cm-diameter cylindrical water phantom. The dose distributions measured and simulated with Monte Carlo methods in a semi-infinite water phantom were similar (<2%), thus validating our Monte Carlo model. The highest dose underestimation was observed between the reference and the cylindrical phantom (more than 15% difference for the entrance dose) and was due to the lack of lateral scatter and backscatter. The use of standard backscatter factors and AAPM TG-61 protocol may result in a significant underestimation of the dose absorbed by small irradiated phantoms, such as mice or cells, in preclinical studies. BACKGROUND: For preclinical radiotherapy studies, radiobiologists were used to determine the irradiation time depending only on the source surface distance. This work aimed to demonstrate that scatter conditions have a large impact on dose rate. Measurements and Monte Carlo simulations were used.

[In room delivered doses during image-guided radiotherapy courses]. / Doses délivrées par l'imagerie de contrôle en radiothérapie externe guidée par l'image.

Image-guided radiotherapy is defined by the use of images acquired in the treatment room to improve the accuracy of patient positioning. Most of imaging devices use X-rays and deliver an additional dose to the patients. These non-negligible doses have to be evaluated and reported. Several studies have investigated organ-absorbed dose due to in-room imaging. Some organ doses are reported to give an idea of the magnitude, in particular for prostate cancer. Then, principles based on the as low as reasonably achievable (ALARA) concept are described and adapted to image-guided radiotherapy. Justification (what is the patient outcome?) and optimisation (image modality, acquisition frequency, treatment site...) are two main issues. They have a really big impact on patient treatment and staff organization.

[Intensity modulated radiation therapy: analysis of patient specific quality control results, experience of René-Gauducheau Centre]. / Radiothérapie conformationnelle avec modulation d'intensité: analyse des résultats des contrôles précliniques, expérience du centre René-Gauducheau.

PURPOSE: Systematic verifications of patient's specific intensity-modulated radiation treatments are usually performed with absolute and relative measurements. The results constitute a database which allows the identification of potential systematic errors. MATERIAL AND METHODS: We analyzed 1270 beams distributed in 232 treatment plans. Step-and-shoot intensity-modulated radiation treatments were performed with a Clinac (6 and 23 MV) and sliding window intensity-modulated radiation treatments with a Novalis (6 MV). RESULTS: The distributions obtained do not show systematic error and all the control meet specified tolerances. CONCLUSION: These results allow us to reduce controls specific patients for treatments performed under identical conditions (location, optimization and segmentation parameters of treatment planning system, etc.).

Validation of a personalized dosimetric evaluation tool (Oedipe) for targeted radiotherapy based on the Monte Carlo MCNPX code.

Dosimetric studies are necessary for all patients treated with targeted radiotherapy. In order to attain the precision required, we have developed Oedipe, a dosimetric tool based on the MCNPX Monte Carlo code. The anatomy of each patient is considered in the form of a voxel-based geometry created using computed tomography (CT) images or magnetic resonance imaging (MRI). Oedipe enables dosimetry studies to be carried out at the voxel scale. Validation of the results obtained by comparison with existing methods is complex because there are multiple sources of variation: calculation methods (different Monte Carlo codes, point kernel), patient representations (model or specific) and geometry definitions (mathematical or voxel-based). In this paper, we validate Oedipe by taking each of these parameters into account independently. Monte Carlo methodology requires long calculation times, particularly in the case of voxel-based geometries, and this is one of the limits of personalized dosimetric methods. However, our results show that the use of voxel-based geometry as opposed to a mathematically defined geometry decreases the calculation time two-fold, due to an optimization of the MCNPX2.5e code. It is therefore possible to envisage the use of Oedipe for personalized dosimetry in the clinical context of targeted radiotherapy.

Current developments at IRSN on computational tools dedicated to assessing doses for both internal and external exposure.

The paper presents the OEDIPE (French acronym that stands for tool for personalised internal dose assessment) and SESAME (for simulation of external source accident with medical images) computational tools, dedicated to internal and external dose assessment, respectively, and currently being developed at the Institute for Radiological Protection and Nuclear Safety. The originality of OEDIPE and SESAME, by using voxel phantoms in association with Monte Carlo codes, lies in their ability to construct personalised voxel phantoms from medical images and automatically generate the Monte Carlo input file and visualise the expected results. OEDIPE simulates in vivo measurements to improve their calibration, and calculates the dose distribution taking both internal contamination and internal radiotherapy cases into account. SESAME enables radiological overexposure doses to be reconstructed, as also victim, source and accident environment modelling. The paper presents the principles on which these tools function and an overview of specificities and results linked to their fields of application.

Dosimetric comparison of Monte Carlo codes (EGS4, MCNP, MCNPX) considering external and internal exposures of the Zubal phantom to electron and photon sources.

This paper aims at comparing dosimetric assessments performed with three Monte Carlo codes: EGS4, MCNP4c2 and MCNPX2.5e, using a realistic voxel phantom, namely the Zubal phantom, in two configurations of exposure. The first one deals with an external irradiation corresponding to the example of a radiological accident. The results are obtained using the EGS4 and the MCNP4c2 codes and expressed in terms of the mean absorbed dose (in Gy per source particle) for brain, lungs, liver and spleen. The second one deals with an internal exposure corresponding to the treatment of a medullary thyroid cancer by 131I-labelled radiopharmaceutical. The results are obtained by EGS4 and MCNPX2.5e and compared in terms of S-values (expressed in mGy per kBq and per hour) for liver, kidney, whole body and thyroid. The results of these two studies are presented and differences between the codes are analysed and discussed.