Toward Neuro-Oncologic Clinical Trials of High-Dose-Rate Synchrotron Microbeam Radiation Therapy: First Treatment of a Spontaneous Canine Brain Tumor.

PURPOSE: The high potential of microbeam radiation therapy (MRT) in improving tumor control while reducing side effects has been shown by numerous preclinical studies. MRT offers a widened therapeutic window by using the periodical spatial fractionation of synchrotron generated x-rays into an array of intense parallel microbeams. MRT now enters a clinical transfer phase. As proof of principle and cornerstone for the safe clinical transfer of MRT, we conducted a "first in dog" trial under clinical conditions. In this report, we evaluated whether a 3-dimensional conformal MRT can be safely delivered as exclusive radiosurgical treatment in animal patients METHODS AND MATERIALS: We irradiated a 17.5-kg French bulldog for a spontaneous brain tumor (glioma suspected on magnetic resonance imaging) with conformal high-dose-rate microbeam arrays (50-µm-wide microbeams, replicated with a pitch of 400 µm) of synchrotron-generated x-rays. The dose prescription adjusted a minimal cumulated valley dose of 2.8 Gy to the plnning target volume (PTV) (cinical target volume (CTV)+ 1 mm). Thus, each beam delivered 20 to 25 Gy to the target as peak doses, and ∼1 Gy as valley doses RESULTS: The treatment was successfully delivered. Clinical follow-up over 3 months showed a significant improvement of the dog's quality of life: the symptoms disappeared. Magnetic resonance imaging, performed 3 months after irradiation, revealed reduction in tumor size (-87.4%) and mass effect with normalization of the left lateral ventricle. CONCLUSIONS: To our knowledge, this neuro-oncologic veterinary trial is the first 3-dimensional conformal synchrotron x-ray MRT treatment of a spontaneous intracranial tumor in a large animal. It is an essential last step toward the clinical transfer of MRT in the near future to demonstrate the feasibility and safety of treating deep-seated tumors using synchrotron-generated microbeams.

Doses delivered by portal imaging quality assurance in routine practice of adjuvant breast radiotherapy worth to by monitored and compensated in some cases.

BACKGROUND: Imaging, in radiotherapy, has become a routine tool for repositioning of the target volume at each session. The repositioning precision, currently infracentimetric, evolves along with the irradiation techniques. This retrospective study aimed to identify practices and doses resulting from the use of high energy planar imaging (portal imaging) in daily practice. METHODS: A retrospective survey of portal images (PIs) was carried out over 10 years for 2,403 patients and for three linacs (1 Elekta SLi, 2 Varian Clinac) for postoperative mammary irradiations. Images were taken using a standardized number of monitor units (MU) for all patients. Due to the variable sensitivities of the detectors and the possibility of adjustment of the detector-patient distance, the number of MU were 3; 2 and 1 respectively, for Elekta SLi®, Clinac 600® and Clinac 2100®. Then, a representative cumulated dose was calculated in simplified reference conditions (5 cm depth, beam of 10 cm × 10 cm, 6 MV), considering the total number of images taken during the whole treatment course. The consistency between the representative doses and the actual absorbed doses received by the patients was verified by simulating a series of typical cases with the treatment plan dose calculation system. RESULTS: The delivered doses differ significantly between the three linacs. The mean representative dose values by complete treatment were 0.695; 0.241 and 0.216 Gy, respectively, for SLi, Clinac 600 and Clinac 2100. However, 15 patients were exposed to a dose >2 Gy with a maximum dose of 5.05 Gy. The simulated doses were very similar to the representative doses. CONCLUSIONS: A significant dose delivery was highlighted by this study. These representative doses are presently communicated weekly to the radiation oncologist for the radiation protection of their patients. Moreover, they should be taken into account in a possible study of long-term stochastic risks.

Theranostic AGuIX nanoparticles as radiosensitizer: A phase I, dose-escalation study in patients with multiple brain metastases (NANO-RAD trial).

BACKGROUND AND PURPOSE: Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy. MATERIALS AND METHODS: Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03. RESULTS: Fifteen patients with 354 metastases were included. No dose-limiting toxic effects were observed up to AGuIX 100 mg/kg. Plasma elimination half-life of AGuIX was similar for all groups (mean 1.3 h; range 0.8-3 h). Efficient targeting of metastases (T1 MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or reduction of tumor volume. MRI analysis showed significant correlation between contrast enhancement and tumor response, thus supporting a radiosensitizing effect. CONCLUSION: Combining AGuIX with radiotherapy for patients with brain metastases is safe and feasible. AGuIX specifically targets brain metastases and is retained within tumors for up to 1 week; ongoing phase II studies will more definitively assess efficacy.

Film dosimetry studies for patient specific quality assurance in microbeam radiation therapy.

Microbeam radiation therapy (MRT) uses synchrotron arrays of X-ray microbeams to take advantage of the spatial fractionation effect for normal tissue sparing. In this study, radiochromic film dosimetry was performed for a treatment where MRT is introduced as a dose boost in a hypofractionated stereotactic radiotherapy (SRT) scheme. The isocenter dose was measured using an ionization chamber and two dimensional dose distributions were determined using radiochromic films. To compare the measured dose distribution to the MRT treatment plan, peak and valley were displayed in separate dosemaps. The measured and computed isocenter doses were compared and a two-dimensional 2%/2 mm normalized γ-index analysis with a 90% passing rate criterion was computed. For SRT, a difference of 2.6% was observed in the dose at the isocenter from the treatment plan and film measurement, with a passing rate of 96% for the γ-index analysis. For MRT, peak and valley doses differences of 25.6% and 8.2% were observed, respectively but passing rates of 96% and 90% respectively were obtained from the normalized γ-index maps. The differences in isocenter doses measured in MRT should be further investigated. We present the methodology of patient specific quality assurance (QA) for studying MRT dose distributions and discuss ideas to improve absolute dosimetry. This patient specific QA will be used for large animal trials quality assurance where MRT will be administered as a dose boost in conventional SRT. The observed remaining discrepancies should be studied against approximations in the TPS phantom materials, beams characteristics or film read-out procedures.

Influence of Linear Energy Transfer on the Nucleo-shuttling of the ATM Protein: A Novel Biological Interpretation Relevant for Particles and Radiation.

PURPOSE: Linear energy transfer (LET) plays an important role in radiation response. Recently, the radiation-induced nucleo-shuttling of ATM from cytoplasm to the nucleus was shown to be a major event of the radiation response that permits a normal DNA double-strand break (DSB) recognition and repair. Here, we aimed to verify the relevance of the ATM nucleo-shuttling model for high-LET particles and various radiation types. METHODS AND MATERIALS: ATM- and H2AX-immunofluorescence was used to assess the number of recognized and unrepaired DSB in quiescent fibroblast cell lines exposed to x-rays, γ-rays, 9- and 12-MeV electrons, 3- and 65-MeV protons and 75-MeV/u carbon ions. RESULTS: The rate of radiation-induced ATM nucleo-shuttling was found to be specific to each radiation type tested. By increasing the permeability of the nuclear membrane with statin and bisphosphonates, 2 fibroblast cell lines exposed to high-LET particles were shown to be protected by an accelerated ATM nucleo-shuttling. CONCLUSIONS: Our findings are in agreement with the conclusion that LET and the radiation/particle type influence the formation of ATM monomers in cytoplasm that are required for DSB recognition. A striking analogy was established between the DSB repair kinetics of radioresistant cells exposed to high-LET particles and that of several radiosensitive cells exposed to low-LET radiation. Our data show that the nucleo-shuttling of ATM provides crucial elements to predict radiation response in human quiescent cells, whatever the LET value and their radiosensitivity.

Dosimetrical and radiobiological approach to manage the dosimetric shift in the transition of dose calculation algorithm in radiation oncology: how to improve high quality treatment and avoid unexpected outcomes?

BACKGROUND: For a given prescribed dose of radiotherapy, with the successive generations of dose calculation algorithms, more monitor units (MUs) are generally needed. This is due to the implementation of successive improvements in dose calculation: better heterogeneity correction and more accurate estimation of secondary electron transport contribution. More recently, there is the possibility to report the dose-to-medium, physically more accurate compared to the dose-to-water as the reference one. This last point is a recent concern and the main focus of this study. METHODS: In this paper, we propose steps for a general analysis procedure to estimate the dosimetric alterations, and the potential clinical changes, between a reference algorithm and a new one. This includes dosimetric parameters, gamma index, radiobiology indices based on equivalent uniform dose concept and statistics with bootstrap simulation. Finally, we provide a general recommendation on the clinical use of new algorithms regarding the dose prescription or dose limits to the organs at risks. RESULTS: The dosimetrical and radiobiological data showed a significant effect, which might exceed 5-10%, of the calculation method on the dose the distribution and clinical outcomes for lung cancer patients. Wilcoxon signed rank paired comparisons indicated that the delivered dose in MUs was significantly increased (> 2%) using more advanced dose calculation methods as compared to the reference one. CONCLUSION: This paper illustrates and explains the use of dosimetrical, radiobiologcal and statistical tests for dosimetric comparisons in radiotherapy. The change of dose calculation algorithm may induce a dosimetric shift, which has to be evaluated by the physicists and the oncologists. This includes the impact on tumor control and on the risk of toxicity based on normal tissue dose constraints. In fact, the alteration in dose distribution makes it hard to keep exactly the same tumor control probability along with the same normal tissue complication probability.

The choice of statistical methods for comparisons of dosimetric data in radiotherapy.

PURPOSE: Novel irradiation techniques are continuously introduced in radiotherapy to optimize the accuracy, the security and the clinical outcome of treatments. These changes could raise the question of discontinuity in dosimetric presentation and the subsequent need for practice adjustments in case of significant modifications. This study proposes a comprehensive approach to compare different techniques and tests whether their respective dose calculation algorithms give rise to statistically significant differences in the treatment doses for the patient. METHODS: Statistical investigation principles are presented in the framework of a clinical example based on 62 fields of radiotherapy for lung cancer. The delivered doses in monitor units were calculated using three different dose calculation methods: the reference method accounts the dose without tissues density corrections using Pencil Beam Convolution (PBC) algorithm, whereas new methods calculate the dose with tissues density correction for 1D and 3D using Modified Batho (MB) method and Equivalent Tissue air ratio (ETAR) method, respectively. The normality of the data and the homogeneity of variance between groups were tested using Shapiro-Wilks and Levene test, respectively, then non-parametric statistical tests were performed. Specifically, the dose means estimated by the different calculation methods were compared using Friedman's test and Wilcoxon signed-rank test. In addition, the correlation between the doses calculated by the three methods was assessed using Spearman's rank and Kendall's rank tests. RESULTS: The Friedman's test showed a significant effect on the calculation method for the delivered dose of lung cancer patients (p <0.001). The density correction methods yielded to lower doses as compared to PBC by on average (-5 ± 4.4 SD) for MB and (-4.7 ± 5 SD) for ETAR. Post-hoc Wilcoxon signed-rank test of paired comparisons indicated that the delivered dose was significantly reduced using density-corrected methods as compared to the reference method. Spearman's and Kendall's rank tests indicated a positive correlation between the doses calculated with the different methods. CONCLUSION: This paper illustrates and justifies the use of statistical tests and graphical representations for dosimetric comparisons in radiotherapy. The statistical analysis shows the significance of dose differences resulting from two or more techniques in radiotherapy.

Development of a novel robot for transperineal needle based interventions: focal therapy, brachytherapy and prostate biopsies.

PURPOSE: We report what is to our knowledge the initial experience with a new 3-dimensional ultrasound robotic system for prostate brachytherapy assistance, focal therapy and prostate biopsies. Its ability to track prostate motion intraoperatively allows it to manage motions and guide needles to predefined targets. MATERIALS AND METHODS: A robotic system was created for transrectal ultrasound guided needle implantation combined with intraoperative prostate tracking. Experiments were done on 90 targets embedded in a total of 9 mobile, deformable, synthetic prostate phantoms. Experiments involved trying to insert glass beads as close as possible to targets in multimodal anthropomorphic imaging phantoms. Results were measured by segmenting the inserted beads in computerized tomography volumes of the phantoms. RESULTS: The robot reached the chosen targets in phantoms with a median accuracy of 2.73 mm and a median prostate motion of 5.46 mm. Accuracy was better at the apex than at the base (2.28 vs 3.83 mm, p <0.001), and similar for horizontal and angled needle inclinations (2.7 vs 2.82 mm, p = 0.18). CONCLUSIONS: To our knowledge this robot for prostate focal therapy, brachytherapy and targeted prostate biopsies is the first system to use intraoperative prostate motion tracking to guide needles into the prostate. Preliminary experiments show its ability to reach targets despite prostate motion.

Quality assurance in the 22991 EORTC ROG trial in localized prostate cancer: dummy run and individual case review.

INTRODUCTION: EORTC trial 22991 was designed to evaluate the addition of concomitant and adjuvant short-term hormonal treatments to curative radiotherapy in terms of disease-free survival for patients with intermediate risk localized prostate cancer. In order to assess the compliance to the 3D conformal radiotherapy protocol guidelines, all participating centres were requested to participate in a dummy run procedure. An individual case review was performed for the largest recruiting centres as well. MATERIALS AND METHODS: CT-data of an eligible prostate cancer patient were sent to 30 centres including a description of the clinical case. The investigator was requested to delineate the volumes of interest and to perform treatment planning according to the protocol. Thereafter, the investigators of the 12 most actively recruiting centres were requested to provide data on five randomly selected patients for an individual case review. RESULTS: Volume delineation varied significantly between investigators. Dose constraints for organs at risk (rectum, bladder, hips) were difficult to meet. In the individual case review, no major protocol deviations were observed, but a number of dose reporting problems were documented for centres using IMRT. CONCLUSIONS: Overall, results of this quality assurance program were satisfactory. The efficacy of the combination of a dummy run procedure with an individual case review is confirmed in this study, as none of the evaluated patient files harboured a major protocol deviation. Quality assurance remains a very important tool in radiotherapy to increase the reliability of the trial results. Special attention should be given when designing quality assurance programs for more complex irradiation techniques.

High conformality radiotherapy in Europe: thirty-one centres participating in the quality assurance programme of the EORTC prostate trial 22991.

Today, conformality in radiotherapy is at the centre of many investments in equipment and staffing. To estimate the current situation within the European Organisation for Research and Treatment of Cancer (EORTC) conformal radiotherapy trial for prostate cancer, a technology questionnaire was designed to assess whether participating centres can comply with the required radiotherapy procedures of EORTC trial 22991, where a high dose is prescribed to the prostate. Questions covered various items of computed tomography, data acquisition, treatment planning, delivery and verification. All centres (n=31) replied to the questionnaire. All generate beam's eye views and dose volume histograms. All, but two, centres use digitally reconstructed radiographs to display images. The vast majority of the centres perform at least weekly treatment verification and half have access to individual in vivo dosimetry. The results of the questionnaire indicate that participating centres have access to the equipment and apply the procedures that are essential for conformal prostate radiotherapy. The technology questionnaire is the first step in the extensive quality assurance programme dedicated to this high-tech radiotherapy trial.

Quality assurance of the 22961 EORTC trial. A phase III study of the optimal combination of hormonal adjuvant treatment by LHRH analogue and radiation therapy for the management of locally advanced prostate cancer: the dummy run.

PURPOSE: The EORTC trial 22961, opened in 1997, was designed to investigate the optimal combination of hormonal adjuvant treatment by LHRH analogue and radiation therapy for the management of locally advanced prostate cancer. A dummy run was established to assess centre compliance to the radiotherapy protocol. MATERIALS AND METHODS: Medical and anatomical data obtained from 37 CT slices (5mm thickness) of an eligible patient were sent to 19 participating centres, which were asked to complete a questionnaire according to their practice and plan a theoretical radiotherapy treatment. The Planning Target Volume 1 (PTV1) should include prostate, seminal vesicles, internal iliac lymph nodes and inferior part of common iliac lymph nodes (extended pelvic fields). Centres which usually irradiate with small pelvic fields (N0 patients), were allowed to include the prostate, seminal vesicles and internal iliac lymph nodes plus a safety margin of 2 cm. For the Planning Target Volume 2 (PTV2), a safety margin of 1.5 to 2 cm should be around the prostate and seminal vesicles. Checks included patient positioning, treatment simulation, target volume definition, treatment set-up and clinical controls during treatment. RESULTS: Eleven institutions with actual 81% of patients' accrual in the protocol have responded. All centres used a supine treatment position and positioning lasers for the set-up, while 73 and 45% of the centres performed cystograms and used rectal contrast, respectively. Among the participating centres, 45% and 55% used blocks and MLC, respectively, to treat patients. Extended pelvic fields in terms of PTV1 were used by 63% of the centres. The remaining centres treated a small PTV1 with a 10-20 mm margin around to CTV1. All centres defined PTV2 according to protocol guidelines. Doses to PTV1 and PTV2 were correctly prescribed. It was difficult to assess the treated volumes due to a lack of standardisation in DVH calculations. CONCLUSION: In general, centres participating in the dummy run adhered to the guidelines. The dummy run enhances the reliability of the conclusions of the trial.

MRI/TRUS data fusion for prostate brachytherapy. Preliminary results.

Prostate brachytherapy involves implanting radioactive seeds (I125 for instance) permanently in the gland for the treatment of localized prostate cancers, e.g., cT1c-T2a N0 M0 with good prognostic factors. Treatment planning and seed implanting are most often based on the intensive use of transrectal ultrasound (TRUS) imaging. This is not easy because prostate visualization is difficult in this imaging modality particularly as regards the apex of the gland and from an intra- and interobserver variability standpoint. Radioactive seeds are implanted inside open interventional MR machines in some centers. Since MRI was shown to be sensitive and specific for prostate imaging whilst open MR is prohibitive for most centers and makes surgical procedures very complex, this work suggests bringing the MR virtually in the operating room with MRI/TRUS data fusion. This involves providing the physician with bi-modality images (TRUS plus MRI) intended to improve treatment planning from the data registration stage. The paper describes the method developed and implemented in the PROCUR system. Results are reported for a phantom and first series of patients. Phantom experiments helped characterize the accuracy of the process. Patient experiments have shown that using MRI data linked with TRUS data improves TRUS image segmentation especially regarding the apex and base of the prostate. This may significantly modify prostate volume definition and have an impact on treatment planning.

Quality assurance of the EORTC trial 22911. A phase III study of post-operative external radiotherapy in pathological stage T3N0 prostatic carcinoma: the dummy run.

INTRODUCTION: A dry run of a clinical trial (EORTC 22911) is presented in which 12 centres have participated. These are the centres which have contributed the largest number of patients to the trial. MATERIAL AND METHODS: Each participating centre received data from a suitable patient. Investigators were asked to plan and 'treat' the patient according to the protocol guidelines and return the data for evaluation of compliance. RESULTS: The results show that compliance to the protocol guidelines was generally good. There were a few minor deviations in the dose and fractionation schedule, in the volume reduction for the booster dose and in the dose prescription point. None of these deviations will affect the outcome of the study. The most important observation is the large inter-centre variation in target volumes. CONCLUSIONS: The results of this study underlines the need for a strict definition of the target volume and the adoption of the ICRU 50 recommendations in future protocols.