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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., (© 2023. The Author(s).)

(1) Background: Glioblastoma multiforme (GBM) shows complex mechanisms of spreading of the tumor cells, up to remote areas, and little is still known of these mechanisms, thus we focused on MRI abnormalities observable in the tumor and the brain adjacent to the lesion, up to the contralateral hemisphere, with a special interest on tensor diffusion imaging informing on white matter architecture; (2) Material and Methods: volumes, macroscopic volume (MV), brain-adjacent-tumor (BAT) volume and abnormal color-coded DTI volume (aCCV), and region-of-interest samples (probe volumes, ipsi, and contra lateral to the lesion), with their MRI characteristics, apparent diffusion coefficient (ADC), fractional anisotropy (FA) values, and number of fibers (DTI fiber tracking) were analyzed in patients suffering GBM ( n = 15) and metastasis ( n = 9), and healthy subjects ( n = 15), using ad hoc statistical methods (type I error = 5%) (3) Results: GBM volumes were larger than metastasis volumes, aCCV being larger in GBM and BAT ADC was higher in metastasis, ADC decreased centripetally in metastasis, FA increased centripetally either in GBM or metastasis, MV and BAT FA values were higher in GBM, ipsi FA values of GBM ROIs were higher than those of metastasis, and the GBM ipsi number of fibers was higher than the GBM contra number of fibers; (4) Conclusions: The MV, BAT and especially the aCCV, as well as their related water diffusion characteristics, could be useful biomarkers in oncology and functional oncology.

Background: 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., (© 2021. The Author(s).)

Purpose: Stereotactic radiotherapy (SRT) is the standard treatment for brain metastases of non-small-cell lung cancer (NSCLC) and melanoma, mostly in combination with immunotherapy. The objective was to retrospectively evaluate the influence of the time-lapse between immunotherapy and stereotactic radiotherapy on toxicity., Patients and Methods: From 2016 to 2019, 59 patients treated with SRT for 103 brain metastases of NSCLC (60%) and melanoma (40%) in combination with concomitant immunotherapy (≤30 days) were included. The prescribed dose was 20Gy/1f or 33Gy/3f at the isocentre and 14Gy or 23.1Gy (70%) respectively at the PTV envelope (PTV=GTV+2mm). The mean tumour diameter was 14mm (4-52mm). The immunotherapies used were anti-PD1 and anti-PDL1. The 103 metastases were classified into 3 groups according to the time-lapse between instatement of immunotherapy and instatement of SRT for the patient concerned: 7 (7%) in group A (≤7 days), 38 (37%) in group B (7 to 14 days) and 58 (56%) in group C (14 to 30 days)., Results: The mean follow-up was 10.1 months. The median overall survival was 11.5 months for NSCLC and 12.5 months for melanoma. The percentage of local control (LC) at one year was 65.1% (93.6% for NSCLC and 26.5% for melanoma). The time-lapse between immunotherapy and SRT was not a significant predictor of LC (P=0.86), while the histology was (P<0.001). The proportion of grade≥3 toxicities was 5.1%, and that of radionecrosis was 9.7% (among these patients, 80% were non-symptomatic): 0%, 13.1% and 8.6% for groups A, B and C respectively. The time-lapse between immunotherapy and SRT was not a significant predictor of toxicity. Only tumour volume was a significant predictive factor (P=0.03)., Conclusion: The time lapse between immunotherapy and SRT does not influence brain toxicity. The tumour volume remains the main factor., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background and Purpose: This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients., Materials and Methods: The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m 2 /day) and 6 cycles of adjuvant TMZ (150-200 mg/m 2 on days 1-5 every 28 days)., Results: The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (-54%) was observed in peripheral blood mononuclear cells., Conclusion: This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a "real-life" patient cohort (i.e. unselected) comprising consecutive glioblastoma patients aged 70 years or more, treated with different radiotherapy +/- temozolomide regimens., Methods: From 2003 to 2016, 104 patients ≥ 70 years of age, consecutively treated by radiotherapy for glioblastoma, were included in this study. All patients were diagnosed with IDH-wild type glioblastoma according to pathological criteria., Results: Our patient cohort comprised 51 female patients (49%) and 53 male. The median cohort age was 75 years (70-88), and the median Karnofsky performance status (KPS) was 70 (30-100). Five (5%) patients underwent macroscopic complete resection, 9 (9%) had partial resection, and 90 (86%), a stereotactic biopsy. The MGMT promoter was methylated in 33/73 cases (45%). Fifty-two (50%), 38 (36%), and 14 (14%) patients were categorized with RPA scores of III, IV, and I-II. Thirty-three (32%) patients received normofractionated radiotherapy (60 Gy, 30 sessions) with temozolomide (Stupp), 37 (35%) received hypofractionated radiotherapy (median dose 40 Gy, 15 sessions) with temozolomide (HFRT + TMZ), and 34 (33%) HFRT alone. Patients receiving only HFRT were significantly older, with lower KPSs. The median overall survival (OS; all patients) was 5.2 months. OS rates at 12, 18, and 24 months, were 19%, 12%, and 5%, respectively, with no statistical differences between patients receiving Stupp or HFRT + TMZ (P = 0.22). In contrast, patients receiving HFRT alone manifested a significantly shorter survival time (3.9 months vs. 5.9 months, P = 0.018). In multivariate analyses, the prognostic factors for OS were: i) the type of surgery (HR: 0.47 [0.26-0.86], P = 0.014), ii) RPA class (HR: 2.15 [1.17-3.95], P = 0.014), and iii) temozolomide use irrespective of radiotherapy schedule (HR: 0.54 [0.33-0.88], P < 0.02). MGMT promoter methylation was neither a prognostic nor a predictive factor., Conclusions: These outcomes agree with the literature in terms of optimal surgery and the use of HFRT as a standard treatment for elderly GBM patients. Our study emphasizes the potential benefit of using temozolomide with radiotherapy in a real-life cohort of elderly GBM patients, irrespective of their MGMT status.

Glioblastoma is the most common malignant brain tumor in adults. Baseline health-related quality of life (HRQoL) is a major subject of concern for these patients. We aimed to assess the independent prognostic value of HRQoL in unresectable glioblastoma (UGB) patients for death risk stratification. One hundred and thirty-four patients with UGB were enrolled from the TEMAVIR trial. HRQoL was evaluated at baseline using the EORTC QLQ-C30 and BN20 brain cancer module. Clinical and HRQoL parameters were evaluated in univariable and multivariable Cox analysis as prognostic factors for overall survival (OS). Performance assessment and internal validation of the final model were evaluated with Harrel's C-index, calibration plot, and bootstrap sample procedure. Two OS independent predictors were identified: future uncertainty and sensitivity deficit. The final model exhibited good calibration and acceptable discrimination (C statistic = 0.63). The internal validity of the model was verified with robust uncertainties around the hazard ratio. The prognostic score identified three groups of patients with distinctly different risk profiles with median OS estimated at 16.2, 9.2, and 4.5 months. We demonstrated the additional prognostic value of HRQoL in UGB for death risk stratification and provided a score that may help to guide clinical management and stratification in future clinical trials., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: We aimed to study the potential clinical relevance of 9p allelic loss, with or without copy number variation, in 1p/19q codeleted anaplastic oligodendroglial tumors (AOTs)., Methods: This study enrolled 216 patients with 1p/19q codeleted AOT. The prognostic value of 9p allelic loss was investigated using a French nation-wide prospective registry, POLA (prise en charge des tumeurs oligodendrogliales anaplasiques) and high-density single nucleotide polymorphism arrays. We validated our results using the Repository of Molecular Brain Neoplasia Data (REMBRANDT) dataset., Results: The minimal common region of allelic loss in chromosome arm 9p was 9p21.3. Allelic loss of 9p21.3, detected in 41.7% of tumors, was associated with shorter progression-free and overall survival rates in univariate (p = 0.008 and p < 0.001, respectively) and multivariate analyses (p = 0.009 and p = 0.009, respectively). This finding was validated in the REMBRANDT dataset in univariate and multivariate analysis (p = 0.01 and p = 0.01, respectively)., Conclusion: Our study highlights a novel potential prognostic biomarker in 1p/19q codeleted AOT. Further prospective studies are warranted to investigate our finding., (© 2015 American Academy of Neurology.)

The incidence of glioblastoma increases with age, with a median age, at diagnosis, of 65 years. Indeed, the optimization of standard of care of elderly glioblastoma patients in an aging population in Western countries becomes crucial. The age remains the main prognostic factor of glioblastoma. Survival among elderly patients is significantly less than among younger patients. The median survival of elderly glioblastoma patients is generally inferior to 6 months. More aggressive tumor behavior, less aggressive treatments, increased toxicity of therapies and more unfavorable clinical factors and comorbidities could explain a higher severity of the disease in the elderly. The balance between treatment efficacy and quality of life is a major focus because of the shorter life expectancy of patients. The standard of care of glioblastoma in elderly patients remains controversial. Large optimal resection, when achievable, should be preferred to biopsy. Survival is longer after adjuvant radiotherapy, either normofractionated over 6-weeks course or hypofractionated over 3-weeks course, for patients with good clinical status. Hypofractionation is often preferred because of shorter procedure. Chemotherapy alone with temozolomide can be proposed to patients with methylated MGMT promoter. A phase III randomized study, testing short-course adjuvant radiotherapy with or without temozolomide in elderly patients with good clinical status, is ongoing., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Prognosis of unresectable glioblastoma (GB) remains poor, despite temozolomide (TMZ)-based chemoradiation. Activity of bevacizumab (BEV) and irinotecan (IRI) has been reported in recurrent disease. We evaluated BEV and IRI as neo-adjuvant and adjuvant treatment combined with TMZ-based chemoradiation for unresectable GB., Patients and Methods: Patients with unresectable GB, age 18-70, IK ≥50 were eligible. The experimental arm (BEV/IRI) consisted of neo-adjuvant intravenous BEV, 10 mg/kg, and IRI, 125 mg/m(2), every 2 weeks for four cycles before radiotherapy (RT) (60 Gy), concomitant oral TMZ, 75 mg/m(2)/day, and BEV, 10 mg/kg every 2 weeks. Adjuvant BEV and IRI were given every 2 weeks for 6 months. The control arm consisted of concomitant oral TMZ, 75 mg/m(2)/day during RT, and 150-200 mg/m(2) for 5 days every 28 days for 6 months. The use of BEV was allowed at progression in the control arm., Results: Patients (120) were included from April 2009 to January 2011. The working hypothesis was that treatment would increase the progression-free survival at 6 month (PFS-6) from 50% to 66%. The primary objective was not achieved, and only 30 out of 60 patients were alive without progression at 6 months (50.0% [IC95% (36.8; 63.1)] in the BEV/IRI arm when 37 out of 60 patients were required according to the Fleming decision rules. PFS-6 was 7.1 months in BEV/IRI versus 5.2 months in the control arm. The median overall survival was not different between the two arms (11.1 months). Main toxicities were three fatal intracranial bleedings, three bile duct or digestive perforations/infections (1 fatal), and six thrombotic episodes in the BEV/IRI arm, whereas there was one intracranial bleeding, two bile duct or digestive perforations/infections (1 fatal), and one thrombotic episode in the control arm., Conclusions: Neo-adjuvant and adjuvant BEV/IRI, combined with TMZ-radiation, is not recommended for further evaluation in the first-line treatment of unresectable GB., Clinical Trial Registration: Clinical trial registered under EUDRACT number 2008-002775-28 (NCT01022918)., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.

Purpose of this study was to determine the effect of waiting time for radiotherapy on overall survival of patients with glioblastoma treated in the EORTC-NCIC trial at 18 centers in France. A total of 400 adult patients with glioblastoma who were treated between January 1, 2006 and December 31, 2006 were included. There were 282 patients with "minimum criteria" according to the EORTC-NCIC trial: (i) concurrent chemotherapy with temozolomide; and (ii) age between 18 and 70 years old. Among these patients, 229 were treated with adjuvant temozolomide and were classified as "maximal criteria". One-hundred and eighteen patients were in the "without minimal criteria" group. Waiting time from the first symptom (FS-RT), pathology diagnosis (P-RT), multidisciplinary meeting (MM-RT), surgery (S-RT), and CT scan for delineation (CT-RT) until the start of radiotherapy were recorded. Median follow-up for all patients was 327 days. Overall, median FS-RT, P-RT, MM-RT, CT-RT, and S-RT times were 77, 36, 32, 12, and 41 days, respectively. Median, and 12 and 24-month overall survival were 409 days, and 56.3 ± 2.1 % and 27.6 ± 2.6 %, respectively. Univariate analysis failed to reveal a difference in survival, irrespective of the delay. In multivariate analysis, independent favorable prognostic factors for overall survival were age (p ≤ 0.0001) and type of surgery (p = 0.0006). In this large series treated during the EORTC-NCIC protocol period, waiting time until radiotherapy did not seem to affect patient outcome.

Background: In a previous phase I clinical trial of dietary methionine (MET) restriction with cystemustine treatment for melanoma or glioma, we determined the optimal MET-free diet duration to be 1 day. On this basis, a phase II clinical trial was initiated to evaluate safety and efficacy of this combination., Patients and Methods: Twenty-two patients (20 with metastatic melanoma and 2 with recurrent gloma) received a median of 4 cycles of the association of a 1-day MET-free diet with cystemustine (60 mg/m(2)) every two weeks., Results: This association was well tolerated (toxicity and nutritional status). Toxicity remained mainly hematological and consisted of WHO grade 3-4 thrombocytopenia, leucopenia and neutropenia in 36, 27 and 27% of patients respectively. The median disease-free survival was 1.8 months and the median survival was 4.6 months, with 2 long-duration stabilizations. The plasmatic MET depletion obtained was of 40 + or - 31%.

In animal models, methionine (MET) restriction in association with chloroethylnitrosoureas led to a substantial improvement. On this basis, we initiated a Phase I clinical trial of dietary MET restriction in association with chloroethylnitrosourea (cystemustine) treatment for patients with recurrent glioma or metastatic melanoma. Our purpose was 1) to determine the optimal MET-free diet duration for a maximum depletion of plasma MET and 2) to evaluate the feasibility of this association. A total of 10 patients received 4 cycles of 2 wk of an association of a MET-free diet of 1, 2, 3, or 4 consecutive days and cystemustine (60 mg/m(2)). For each cycle, plasma MET concentrations, nutritional status (weight, albumin, prealbumin) and toxicity were measured. Conversely, fed-state concentrations of plasma MET (12 AM) were reduced by dietary MET restriction, with an optimal depletion of 41% at the 1st day of MET-free diet without effect of the extending MET-free diet period. Indeed, we demonstrated the feasibility, that is, good diet acceptability and good tolerance (nutritional status and toxicity), of the association of a MET-free diet and cystemustine treatment. Based on these results, a Phase II clinical trial has been initiated to test the activity of the association of a 1-day MET-free diet with cystemustine treatment.

Background: Methionine (MET) depletion used in association with chemotherapy improves the therapeutic index in animal models. This potentiating effect may be due to tumor cell sensitization to chloroethylnitrosoureas through their MET dependency and the down-regulation of O6- methylguanine-DNA methyltransferase (MGMT). Our purpose was to evaluate the impact of the association of a dietary MET restriction with nitrosourea treatment on MGMT activity in peripheral blood mononuclear cells (PBMCs)., Patients and Methods: Six patients with metastatic cancer (melanoma and glioma) received 4 cycles of a MET-free diet with cystemustine (60 mg/m2)., Results: MGMT activity in PBMCs decreased by an average of 13% from 553+/-90 fnol/mg before the diet to 413+/-59 fmol/mg after the diet + chemotherapy period (p=0.029). The decrease of MGMT activity was not affected by the duration of the MET-free diet period but seems to be correlated to the plasma MET depletion induced by the MET-free diet.

In this study, we have assessed the efficacy of a nitrosourea, cystemustine, in treating patients with recurrent high grade glioma with overall survival analysis as primary end-point. Forty-eight patients with recurrent high grade glioma (24 glioblastomas, 17 astrocytomas and 5 oligodendrogliomas) were treated every 2 weeks with 60 mg/m2 cystemustine by a 15 min-infusion. The median number of treatment cycles was 4 (range 1-17). The median overall survival was 8.3 months (range 1-97) and the 6- and 12-month overall survival rates were 55.3% (95% CI, 41.3-68.6%) and 29.8% (95% CI, 18.6-44.0%), respectively. The objective response rate was 18.8% (95% CI, 7.7-29.9%), and 54.2% of patients had stable disease (95% CI, 40.1-68.3%). Multivariate analysis showed that WHO performance status, histology and response to cystemustine were significant prognostic factors for survival of patients with recurrent glioma. In conclusion, cystemustine has encouraging activity for patients with recurrent high grade glioma.