Non-invasive intracranial pressure monitoring for high-grade gliomas patients treated with radiotherapy: results of the GMaPIC trial

IntroductionPatients with high-grade gliomas are at risk of developing increased intracranial hypertension (ICHT) in relation to the increase in volume of their tumor. ICP change cannot be measured by invasive method but can be estimated by using routine clinical signs, in combination with a standard imaging method, magnetic resonance imaging (MRI). A non-invasive monitoring of ICP could be of interest in high-grade glioma, in particular after radiotherapy treatment with as major side effect a cerebral oedema.Patients and MethodsThis prospective clinical study aimed to compare the ICP changes (estimated by a non-invasive method based upon distortion product otoacoustic emissions (DPOAE) monitoring) with volume changes observed on MRI in patients with high-grade gliomas treated with radiotherapy. DPOAE measurements were performed one month after the end of radiotherapy and then every 3 months for one year. At each visit, the patient also underwent MRI as well as an evaluation of clinical signs.ResultsThe variation in the estimate of intracranial pressure readout measured at each follow-up visit (in absolute value with respect to the baseline measurements) was significantly associated with the variation of T2/FLAIR volume (n=125; p<0.001) with a cut off value of change ICP readout of 40.2 degrees (e.i. an estimated change of 16 mm Hg).DiscussionThe GMaPIC trial confirm the hypothesis that the ICP change estimated by DPOAEs measurement using a non-invasive medical device is correlated with the change of the tumor or edema in high grade glioma after radiotherapy. The device could thus become an easy-to-use and non-invasive intracranial pressure monitoring tool for these patients.Clinical Trial RegistrationClinicaltrials.gov, identifier (NCT02520492

Outcomes among oropharyngeal and oral cavity cancer patients treated with postoperative volumetric modulated arctherapy

BackgroundPresently, there are few published reports on postoperative radiation therapy for oropharyngeal and oral cavity cancers treated with IMRT/VMAT technique. This study aimed to assess the oncological outcomes of this population treated with postoperative VMAT in our institution, with a focus on loco-regional patterns of failure.Material and methodsBetween 2011 and 2019, 167 patients were included (40% of oropharyngeal cancers, and 60% of oral cavity cancers). The median age was 60 years. There was 64.2% of stage IV cancers. All patients had both T and N surgery. 34% had a R1 margin, 42% had perineural invasion. 72% had a positive neck dissection and 42% extranodal extension (ENE). All patients were treated with VMAT with simultaneous integrated boost with three dose levels: 66Gy in case of R1 margin and/or ENE, 59.4-60Gy on the tumor bed, and 54Gy on the prophylactic areas. Concomittant cisplatin was administrated concomitantly when feasible in case of R1 and/or ENE.ResultsThe 1- and 2-year loco-regional control rates were 88.6% and 85.6% respectively. Higher tumor stage (T3/T4), the presence of PNI, and time from surgery >45 days were significant predictive factors of worse loco-regional control in multivariate analysis (p=0.02, p=0.04, and p=0.02). There were 17 local recurrences: 11 (64%) were considered as infield, 4 (24%) as marginal, and 2 (12%) as outfield. There were 9 regional recurrences only, 8 (89%) were considered as infield, and 1 (11%) as outfield. The 1- and 2-year disease-free survival (DFS) rates were 78.9% and 71.8% respectively. The 1- and 2-year overall survival (OS) rates were 88.6% and 80% respectively. Higher tumor stage (T3/T4) and the presence of ENE were the two prognostic factors significantly associated with worse DFS and OS in multivariate analysis.ConclusionOur outcomes for postoperative VMAT for oral cavity and oropharyngeal cancers are encouraging, with high rates of loco-regional control. However, the management of ENE still seems challenging

Relations doses / effets en radiothérapie externe des tumeurs radiorésistantes

External radiotherapy is one of the major treatment methods used in oncology. Despite recent advances in external radiotherapy, this treatment remains insufficiently effective in some cases, with the emergence of resistance. This radioresistance can lead to recurrence, and thus to an unfavorable prognosis for patients with high-grade glioma.This clinical research thesis focused on three clinical trials of radiotherapy for high-grade gliomas. The first was the elaboration of a clinical trial to evaluate plasma concentrations of hPG80, potentially involved in radioresistance, in patients with high-grade brain tumors: the PROGLIO clinical trial (NCT05157594). In the same line, the second work consisted in the analysis and evaluation of a clinical trial proposing a non-invasive method of monitoring intracranial pressure after radiotherapy. The results of the GMaPIC clinical trial (NCT02520492) demonstrated a significant rate of increase of intracranial pressure in this population, and a significant correlation with T2/Flair volume increase. Finally, with the aim of enhancing radiotherapy, this work involved setting up a clinical trial to test the association of AGuIX® nanoparticles with radio-chemotherapy and concomitant temozolomide in patients with newly diagnosed glioblastoma: the NANO-GBM clinical trial (NCT04881032).The aim of this clinical research thesis was to study dose-effect relationships in external radiotherapy of radioresistant tumors such as high-grade gliomas, with the aim of improving patient management.La radiothérapie externe constitue l'une des modalités majeures dans la prise en charge en cancérologie. Malgré les progrès récents en radiothérapie externe, ce traitement reste cependant insuffisamment efficace dans certains cas, du fait d'une résistance. Ces phénomènes de radiorésistance peuvent conduire à une récidive et ainsi à une évolution défavorable du pronostic, notamment pour les patients atteints d'un gliome de haut grade. Ces travaux de thèse en recherche clinique ont porté principalement sur trois essais cliniques sur la radiothérapie des gliomes de haut grade. Le premier travail a été l'élaboration d'un essai clinique visant à évaluer les concentrations plasmatiques de l'hPG80, potentiellement impliquée dans la radiorésistance : L'essai clinique PROGLIO (NCT05157594). Dans cette continué, le deuxième travail a consisté à l'analyse et à la valorisation d'un essai clinique proposant une méthode non invasive de suivi de la pression intracrânienne après radiothérapie. Les résultats de l'essai clinique GMaPIC (NCT02520492) ont mis en évidence un taux important d'augmentation de la pression intracrânienne au sein de cette population et une corrélation significative avec l'augmentation du volume T2/Flair. Pour finir, dans le but de potentialiser la radiothérapie, le troisième travail a consisté à l'élaboration d'un essai clinique visant à tester l'association de nanoparticules AGuIX®, à une radio-chimiothérapie avec témozolomide concomitant chez des patients présentant un glioblastome nouvellement diagnostiqué : L'essai clinique NANO-GBM (NCT04881032). Cette thèse de recherche clinique a ainsi permis d'étudier les relations doses /effets en radiothérapie externe de tumeurs radiorésistantes que sont les gliomes de haut grade dans le but d'améliorer la prise en charge des patients

hPG80 (circulating progastrin) as a blood biomarker for high-grade glial tumors: A pilot study

International audienceCurrently, the long-term prognosis and survival rate of patients with high-grade glial tumors remains poor and there are no biomarkers. hPG 80 (circulating progastrin) secreted into the blood by tumor cells has been widely studied in colorectal cancer. Its involvement in tumorigenesis has been demonstrated in the literature. Moreover, according to a recent study, hPG 80 is expressed in the blood of cancer patients at a significantly higher concentration than in the control group composed of healthy blood donors.The PROGLIO study is a pilot, single-center, longitudinal study that primarily seeks to evaluate circulating plasma hPG 80 concentrations over time in patients with high-grade glial tumors. A fasting blood sample will be taken on the start and end day of radiotherapy and during the adjuvant chemotherapy (every 3 cycles). Follow-up monitoring will be performed for 9 months, with a blood sample taken every 3 months on the day of the follow-up MRI. The study plans to recruit 30 patients and recruitment started in February 2022. Trial registration ClinicalTrials.gov , ID NCT05157594; registered on October 27, 2021

Nanoparticules AGuIX1 et radiothérapie : du développement préclinique aux premiers essais chez l’homme

International audienceFor several years, the use of nanotechnology has been at the heart of research. The use of nanoparticles in oncology opens a vast field of clinical applications. Indeed, nanoparticles have the ability to act as radiosensitizers. They enhance the effectiveness of irradiation in tumor cells, and may represent a promising approach for the local treatment of tumors by external radiotherapy. In this context, the biotechnology company, NH TherAguix (Grenoble, France), has developed AGuIX (Activation and Guidance of Irradiation by X-ray) nanoparticles. These ultra-small nanoparticles, around 5 nm, are composed of a polysiloxane matrix and gadolinium chelates. The nanoparticles have very high radiosensitizing properties as well as contrast agent properties due to the presence of gadolinium. According to the various studies carried out, no signs of toxicity were observed in two animal species (rodents and monkeys) after intravenous administration. The biodistribution in different animal models has shown that the nanoparticles accumulate passively and selectively in tumours due to the EPR effect (Enhanced Permeability and Retention effect) and are cleared via renal elimination. A radiosensitizing effect has also been observed with different types of irradiation in vitro and in vivo on several types of cancers, including radio-resistant models. These promising nanoparticles are therefore currently undergoing clinical trials combined with radiotherapy in several centres in France and in the USA. This review summarizes the main preclinical results that have led to the first administration of AGuIX nanoparticles in humans.Depuis quelques années, l’utilisation des nanotechnologies est au cœur des recherches thérapeutiques. L’utilisation en cancérologie de nanoparticules ouvre un vaste champ d’applications cliniques. En effet, les nanoparticules ont la capacité d’agir comme des radiosensibilisants. Elles permettent d’améliorer l’efficacité de l’irradiation au niveau des cellules tumorales. Leur utilisation pourrait donc être une approche prometteuse pour le traitement local des tumeurs par radiothérapie externe. Dans ce contexte, la société de biotechnologies NH TherAguix (Grenoble, France) développe les nanoparticules AGuIX (Activation and Guidance of Irradiation by X-ray). Ce sont des nanoparticules de très petite taille, de l’ordre de 5 nm, constituées d’une matrice de polysiloxane et de chélates de gadolinium. Elles possèdent des propriétés radiosensibilisantes très importantes ainsi que des propriétés d’agent de contraste, grâce à la présence de gadolinium. D’après les différentes études réalisées, aucun signe de toxicité n’a été observé sur deux espèces animales (rongeurs et singes) après une administration intraveineuse. La biodistribution sur différents modèles animaux a prouvé une accumulation passive et sélective dans les tumeurs grâce à l’effet EPR (Enhanced Permeability and Retention effect) et une élimination rénale des nanoparticules après administration. Un effet radiosensibilisant a également été observé avec différents types d’irradiations in vitro et in vivo, sur plusieurs types de cancers, y compris des modèles radiorésistants. Ces nanoparticules prometteuses sont actuellement en cours d’évaluation dans des essais cliniques, en association avec la radiothérapie dans plusieurs centres en France et aux États-Unis. Cette revue résume ainsi les principaux résultats précliniques qui ont conduit à la première administration chez l’homme des nanoparticules AGuIX

Preoperative stereotactic radiosurgery for brain metastases: the STEP study protocol for a multicentre, prospective, phase-II trial

International audienceBackground: Surgery is an important therapeutic option for brain metastases. Currently, postoperative stereotactic radiosurgery (SRT) leads to 6-month and 1-year local control estimated at 70 and 62% respectively. However, there is an increased risk of radio-necrosis and leptomeningeal relapse. Preoperative SRT might be an alternative, providing local control remains at least equivalent. It is an innovative concept that could enable the stereotactic benefits to be retained with advantages over post-operative SRT.Methods: STEP has been designed as a national, multicentre, open-label, prospective, non-randomized, phase-II trial. Seventeen patients are expected to be recruited in the study from 7 sites and they will be followed for 12 months. Patients with more than 4 distinct brain metastases, including one with a surgical indication, and an indication for SRT and surgery, are eligible for enrolment. The primary objective of the trial is to assess 6-month local control after preoperative SRT. The secondary objectives include the assessment of local control, radio-necrosis, overall survival, toxicities, leptomeningeal relapse, distant control, cognitive function, and quality of life. The experimental design is based on a Flemming plan.Discussion There is very little data available in the literature on preoperative SRT: there have only been 3 American single or two-centre retrospective studies. STEP is the first prospective trial on preoperative SRT in Europe. Compared to postoperative stereotactic radiotherapy, preoperative stereotactic radiotherapy will enable reduction in the irradiated volume, leptomeningeal relapse and the total duration of the combined treatment (from 4 to 6 weeks to a few days).Trial registration number Clinicaltrials.gov: NCT04503772 , registered on August 07, 2020. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID RCB 2020-A00403–36, registered in February 2020. Protocol: version 4, 07 December 2020

Postoperative SBRT in the treatment of early-stage oropharyngeal and oral cavity cancers with high-risk margins: A dosimetric comparison of volumetric modulated arc therapy with or without non-coplanar arcs and acute toxicity outcomes from the STEREOPOSTOP GORTEC 2017–03 phase 2 trial

International audienceThe STEREO POSTOP GORTEC 2017-03 phase 2 trial (NCT03401840) evaluates postoperative stereotactic body radiotherapy (SBRT) in case of high-risk margins for pT1-T2/N0 oropharyngeal and oral cavity tumors. The present ancillary study aimed to compare the dosimetric impact of adding non-coplanar arcs to the volumetric modulated arc therapy (VMAT) technique and to evaluate acute toxicities on the first patients included in this trial

Phase I/II study testing the combination of AGuIX nanoparticles with radiochemotherapy and concomitant temozolomide in patients with newly diagnosed glioblastoma (NANO-GBM trial protocol)

Abstract Background Despite standard treatments including chemoradiotherapy with temozolomide (TMZ) (STUPP protocol), the prognosis of glioblastoma patients remains poor. AGuIX nanoparticles have a high radiosensitizing potential, a selective and long-lasting accumulation in tumors and a rapid renal elimination. Their therapeutic effect has been proven in vivo on several tumor models, including glioblastoma with a potential synergetic effect when combined with TMZ based chemoradiotherapy, and they are currently evaluated in 4 ongoing Phase Ib and II clinical trials in 4 indications (brain metastases, lung, pancreatic and cervix cancers) (> 100 patients received AGuIX). Thus, they could offer new perspectives for patients with newly diagnosed glioblastoma. The aim of this study is to determine the recommended dose of AGuIX as a radiosensitizer in combination with radiotherapy and TMZ during the concurrent radio-chemotherapy period for phase II (RP2D) and to estimate the efficacy of the combination. Methods NANO-GBM is a multicenter, phase I/II, randomized, open-label, non-comparative, therapeutic trial. According to a dose escalation scheme driven by a TITE-CRM design, 3 dose levels of AGuIX (50, 75 and 100 mg/kg) will be tested in phase I added to standard concomitant radio-chemotherapy. Patients with grade IV glioblastoma, not operated or partially operated, with a KPS ≥ 70% will be eligible for the study. The primary endpoints are i) for phase I, the RP2D of AGuIX, with DLT defined as any grade 3–4 NCI-CTCAE toxicity and ii) for phase II, the 6-month progression-free survival rate. The pharmacokinetics, distribution of nanoparticles, tolerance of the combination, neurological status, overall survival (median, 6-month and 12-month rates), response to treatment, and progression-free survival (median and 12-month rates) will be assessed as secondary objectives. Maximum sixty-six patients are expected to be recruited in the study from 6 sites. Discussion The use of AGuIX nanoparticles could allow to overpass the radioresistance to the reference treatment of newly diagnosed glioblastomas that have the poorest prognosis (incomplete resection or biopsy only). Trial registration Clinicaltrials.gov: NCT04881032 , registered on April 30, 2021. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°Eudra CT 2020-004552-15. Protocol: version 3, 23 May 2022