Camille Verry

L'apparition de métastases cérébrales multiples est une évolution critique de nombreux cancers avec un impact majeur sur la survie globale. Une nouvelle nanoparticule à base de gadolinium, l’AGuIX®, a récemment démontré son efficacité en tant que radiosensibilisant et agent de contraste IRM dans plusieurs études précliniques. L’objectif de cette thèse est d’établir une preuve de concept sur un modèle animal puis de réaliser la première administration chez l’homme de ce nouveau médicament dans le cadre d’un essai de phase 1.La première partie de ce travail a consisté à l’irradiation en 6 MeV après injection d’AGuIX® d’un modèle de rat Fisher porteur du gliome cérébral 9L suivi par IRM. Nous avons mis en évidence une distribution favorable des nanoparticules dans la tumeur par effet EPR (Enhanced Permeability and Retention) avec une concentration de gadolinium dans la tumeur 20 fois plus importante que dans le cerveau sain. L’effet radiosensibilisant a été démontré avec une diminution significative (p=0.02) de la taille des tumeurs dans le groupe irradié après injection d’AGuIX®. Ces résultats, associés au profil de tolérance favorable sur les modèles animaux ont motivés le transfert chez l’homme de ce nouveau médicament dans une étude de phase 1 nommée NANO-RAD (EudraCT 2015-004259-30 ; NCT02820454). Il s’agit d’une étude monocentrique, ouverte, évaluant la faisabilité et la tolérance d'AGuIX® associé à une irradiation panencéphalique (30 Gy, 10 Fr de 3 Gy) pour des patients atteints de métastases cérébrales multiples. L'objectif principal est de déterminer la dose maximale tolérée des nanoparticules avec un schéma d’escalade de dose par palier de 3 patients à 15, 30, 50, 75 et 100 mg/kg. Les objectifs secondaires sont l’étude pharmacocinétique de la distribution d'AGuIX® par IRM, de la survie sans progression intracrânienne et de la survie globale. La première administration chez l’homme a été réalisée au CHU de Grenoble le 18 juillet 2016 et le dernier patient (n=15) a été inclus le 06 février 2018. L’ensemble des lésions, quelques soit l’origine histologique (poumon, mélanome, sein) ont eu une prise de contraste d’AGuIX® dont la concentration retrouvée dans la tumeur était proportionnelle à la dose injectée. La demi-vie sanguine moyenne est de 1h09 (± 26min). La tolérance au traitement a été bonne avec une escalade de dose jusqu’à 100 mg/kg qui devient ainsi la dose retenue pour la suite des essais cliniques. Sur les 14 patients évaluables, 12 ont eu un bénéfice clinique du traitement avec une diminution du volume tumoral. Les résultats préliminaires sont prometteurs en termes de tolérance, de distribution et d’efficacité et devront être confirmés par l’étude de phase 2 multicentrique randomisée prévue pour la fin de l’année 2018.

Synchrotron Microbeam Radiation Therapy (MRT) has repeatedly proven its superiority compared with conventional radiotherapy for glioma control in preclinical research. The clinical transfer phase of MRT has recently gained momentum; seven dogs with suspected glioma were treated under clinical conditions to determine the feasibility and safety of MRT. We administered a single fraction of 3D-conformal, image-guided MRT. Ultra-high-dose rate synchrotron X-ray microbeams (50 µm-wide, 400 µm-spaced) were delivered through five conformal irradiation ports. The PTV received ~25 Gy peak dose (within microbeams) per port, corresponding to a minimal cumulated valley dose (diffusing between microbeams) of 2.8 Gy. The dogs underwent clinical and MRI follow-up, and owner evaluations. One dog was lost to follow-up. Clinical exams of the remaining six dogs during the first 3 months did not indicate radiotoxicity induced by MRT. Quality of life improved from 7.3/10 [±0.7] to 8.9/10 [±0.3]. Tumor-induced seizure activity decreased significantly. A significant tumor volume reduction of 69% [±6%] was reached 3 months after MRT. Our study is the first neuro-oncologic veterinary trial of 3D-conformal Synchrotron MRT and reveals that MRT does not induce acute to subacute radiotoxicity in normal brain tissues. MRT improves quality of life and leads to remarkable tumor volume reduction despite low valley dose delivery. This trial is an essential step towards the forthcoming clinical application of MRT against deep-seated human brain tumors.

For decades, BNCT was seen as an attractive concept and an intellectual challenge with no prospect of widespread clinical application. This situation has changed fundamentally in just a few years with the progress in accelerator technology. Low-energy, high-intensity neutron sources can now be integrated into hospitals and are therefore directly available for patient treatment. A pioneer in this field is the development in Japan, where patients are already being treated in three hospitals, using in-house accelerator-based systems. Furthermore, the costs associated with the BNCT treatment of recurrent tumors in the head and neck area are already covered by the healthcare system. It is time to keep up to date with this technology and work to make it available to patients in high-tech medicine in other countries, especially in Europe and North America. This short article summarizes the main principles of BNCT, outlines some aspects of its history and mentions ongoing projects as well as some hurdles that need to be overcome, as well as the scientific questions that need to be addressed for wider availability of the method.

Microbeam radiation therapy (MRT) is a radiotherapy technique combining spatial fractionation of the dose distribution on a micrometric scale, X-rays in the 50–500 keV range and dose rates up to 16 × 10³ Gy s⁻¹. Nowadays, in vivo dosimetry remains a challenge due to the ultra-high radiation fluxes involved and the need for high-spatial-resolution detectors. The aim here was to develop a striped diamond portal detector enabling online microbeam monitoring during synchrotron MRT treatments. The detector, a 550 µm bulk monocrystalline diamond, is an eight-strip device, of height 3 mm, width 178 µm and with 60 µm spaced strips, surrounded by a guard ring. An eight-channel ASIC circuit for charge integration and digitization has been designed and tested. Characterization tests were performed at the ID17 biomedical beamline of the European Synchrotron Radiation Facility (ESRF). The detector measured direct and attenuated microbeams as well as interbeam fluxes with a precision level of 1%. Tests on phantoms (RW3 and anthropomorphic head phantoms) were performed and compared with simulations. Synchrotron radiation measurements were performed on an RW3 phantom for strips facing a microbeam and for strips facing an interbeam area. A 2% difference between experiments and simulations was found. In more complex geometries, a preliminary study showed that the absolute differences between simulated and recorded transmitted beams were within 2%. Obtained results showed the feasibility of performing MRT portal monitoring using a microstriped diamond detector. Online dosimetric measurements are currently ongoing during clinical veterinary trials at ESRF, and the next 153-strip detector prototype, covering the entire irradiation field, is being finalized at our institution.

Background Prostate cancer (PCa) is the most frequently diagnosed cancer in men in Europe. The impact of PCa natural history and therapeutic management on the outcomes of castration-resistant prostate cancer patients with metastasis (mCRPC) remains unclear. Objective The objective of this study was to describe retrospectively patterns of clinical progression through diagnosis sequences before the mCRPC stage and to assess how these sequences impacted patients’ disease progression and overall survival at mCRPC stage. Patients and Methods Patients with mCRPC were identified from the Prostate Cancer Registry (PCR), an observational study in a real-world setting in 16 countries between 2013 and 2016. Patients were grouped in diagnosis sequences before mCRPC and defined by date of PCa diagnosis, first metastasis, and castration resistance. Distribution of time-to-event variables were estimated using Kaplan-Meier product-limit survival curves for overall survival (OS) and progression-free survival (PFS). Non-adjusted Cox models were conducted for efficacy endpoints (OS, PFS) to estimate hazard ratios between diagnosis sequences. Results At the end of study, 2859 mCRPC patients were included in this analysis. Among mCRPC four diagnosis sequences were identified: 35% developed metastases (mHSPC) before becoming castration resistant (sequence 1, metachronous mHSPC), 10% developed castration resistance (nmCRPC) before metastases (sequence 2), 27% developed metastases and castration resistance within 4 months (sequence 3) and 28% of patients were de novo mHSPC (sequence 4). Median OS was 17.7 months (interquartile range (IQR): 8.8–29.9) and PFS was 6.4 months (IQR: 3.2–12.0). The univariate analyses showed no correlation between mCRPC patients’ OS or PFS and the diagnosis sequence. Conclusion This large European study describe four different patterns of prostate cancer progression to mCRPC stage. Our results indicate that patient survival becomes comparable after progression to mCRPC, regardless of the diagnosis sequence. Trial Registration ClinicalTrials.gov identifier NCT02236637; registered September 2014.

INTRODUCTION: In spite of the promising results of systemic treatment in melanoma, the development of brain metastases remains a common issue, often prompting use of Radiation Therapy (RT). The purpose of this study is to assess the safety and outcomes of Immune Checkpoint Inhibitor (ICI) and brain RT with a focus on timing of both treatments. METHODS This retrospective study included all consecutive patients treated for a brain metastatic melanoma with an ICI (anti – CTLA4 or anti – PD1 or both) and brain RT from December 1, 2010 and April 30, 2018. The concurrent group was defined by an ICI performed within 4 weeks before or after RT. Primary endpoint was neurological adverse events graded with Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS Fifty - three consecutive patients were included. A total of 81 RT courses were performed: 23 with whole brain radiotherapy (WBRT) and 58 with stereotactic radiotherapy (SRT). The majority of RT (63%, n = 51) was delivered with concurrent ICI. Acute neurological Adverse Events (AE) ≥ grade 3 occurred for 12.3% of RT course, with no difference between concurrent and non – concurrent groups. The median OS after RT was 11.5 months for the entire cohort with 15.9 months for SRT in comparison to 2.7 months for WBRT. The objective response rate was significantly better for concurrent ICI – SRT group at 66.7% compared to 40% for non-– concurrent group (p = 0.04). One-year LC probability was higher in the concurrent group than in the non-concurrent group, respectively 72. % vs 38.5% (p = 0.007). CONCLUSIONS Combined RT and ICI is well tolerated with acceptable neurological adverse events. Stereotactic radiation therapy delivered concurrently with ICI is associated with improved local control.

Delivery of high-radiation doses to brain tumors via multiple arrays of synchrotron X-ray microbeams permits huge therapeutic advantages. Brain tumor (9LGS)-bearing and normal rats were irradiated using a conventional, homogeneous Broad Beam (BB), or Microbeam Radiation Therapy (MRT), then studied by behavioral tests, MRI, and histopathology. A valley dose of 10 Gy deposited between microbeams, delivered by a single port, improved tumor control and median survival time of tumor-bearing rats better than a BB isodose. An increased number of ports and an accumulated valley dose maintained at 10 Gy delayed tumor growth and improved survival. Histopathologically, cell death, vascular damage, and inflammatory response increased in tumors. At identical valley isodose, each additional MRT port extended survival, resulting in an exponential correlation between port numbers and animal lifespan (r² = 0.9928). A 10 Gy valley dose, in MRT mode, delivered through 5 ports, achieved the same survival as a 25 Gy BB irradiation because of tumor dose hot spots created by intersecting microbeams. Conversely, normal tissue damage remained minimal in all the single converging extratumoral arrays. Multiport MRT reached exceptional ~2.5-fold biological equivalent tumor doses. The unique normal tissue sparing and therapeutic index are eminent prerequisites for clinical translation.

Background: To assess whether whole-body (WB) bone SPECT/CT provides additional diagnostic information over [18F]-FCH PET/CT for the detection of bone metastases in the setting of prostate cancer biochemical recurrence (PC-BR). Methods: Patients referred for a PC-BR and whom benefited from a WB bone SPECT/CT and FCH PET/CT were retrospectively included. Tests were classified as positive, equivocal, or negative for bone metastases. A best valuable comparator (BVC) strategy including imaging and follow-up data was used to determine the metastatic status in the absence of systematic histological evaluation. Results: Between January 2011 and November 2017, 115 consecutive patients with a PC-BR were evaluated. According to the BVC, 30 patients had bone metastases and 85 patients did not present with bone lesions. The sensitivity, specificity, positive and negative predictive values were respectively 86.7% [69.3–96.2], 98.8% [93.6–100.0], 96.3% [78.7–99.5], and 95.5% [89.4–98.1] for WB bone SPECT/CT and 93.3% [77.9–99.2], 100.0% [95.8–100.0], 100.0 and 97.7% [91.8–99.4] for FCH PET/CT. There was no significant difference in diagnostic accuracy of bone metastases between WB Bone SPECT/CT (AUC 0.824 [0.74–0.90]) and FCH PET/CT (AUC 0.829 [0.75–0.90], p = 0.41). Conclusion: Despite good performances for the diagnosis of bone metastases in PC-BR, WB bone SPECT/CT does not provide additive diagnostic information over concomitant FCH PET/CT.