ASCO 2014 dossiers 81-90/100 des tumeurs de cerveau CS256: Mobile Web development - structure
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ASCO 2014 dossiers 81-90/100 des tumeurs de cerveau

Asco 2014
2081-
Watts Colin.
Évaluation préliminaire de tolérance et de faisabilité de combiner 5 ALA avec les implants de carmustine (Gliadel) dans la gestion chirurgicale du glioblastome primaire. Lire Etats-Unis
Résumé :
Fluorescence-guided resection of glioblastoma improves surgical cytoreduction, which may improve therapeutic benefit from intra-operative carmustine wafers. The objective of this study was to establish the safety and tolerability of combining fluorescence‐guided surgical resection (5-ALA) with intra‐operative chemotherapy (carmustine wafers) in patients with primary glioblastoma (GBM) prior to standard treatment with radiotherapy and temozolomide.
Méthodes :
A single arm design with the following inclusion criteria: Age 18+ years; patient reviewed at a specialist neuro-oncology MDT; imaging evaluated by a neuro-radiologist and judged to be a GBM; radical resection judged to be realistic by the neurosurgeons (i.e. NICE criteria for the use of Carmustine wafers can be met); and WHO performance status 0 or 1 on clinical review
Résultats :
Seventy-two patients were recruited from 8 UK sites between July 2011 and May 2013; 64 patients received carmustine wafer implants and 59 patients were found to be eligible after surgery. Thirteen patients were ineligible due to wafers not inserted (n=8); GBM not diagnosed post-operatively (n=4); simultaneous diagnosis of cutaneous sebaceous carcinoma (n=1). There were 8 surgical complications reported in 6 patients: wound infections in 5 patients (8%) and cerebrospinal fluid leakage in 3 patients (5%). One patient was unable to begin chemoRT (1/33, 3%), and 4 patients (4/33, 12%) were not able to begin chemoRT within 6 weeks of surgery, due to surgical complications. After a median follow-up of 10.8 months, 25 patients (42%) are alive without progression, 16 patients (27%) are alive having progressed and 18 patients (31%) have died. Thirty-three patients (56%) have reported 68 adverse events of grade 3 or higher, 5 of these were reported as being ‘possibly’ related to the combination of 5-ALA and carmustine wafers: sepsis (n=2), wound infection (n=2), seizure (n=1). 
Conclusions :
The combination of 5-ALA and carmustine wafers is safe and tolerable in the surgical management of primary glioblastoma. A phase III randomised controlled trial is being designed to confirm efficacy Clinical trial information: 77105850.

Asco 2014
2082-
Henry S. Friedman.
Révision rétrospective dans notre centre sur glioblastome récemment diagnostiqué (GBM) soigné avec bevacizumab (BEV).
Original
Etats-Unis
Résumé :
Following the FDA approval of BEV for recurrent GBM pts, two multicenter phase III trials, RTOG0825 and AVAglio, evaluated the addition of BEV to radiation and temozolomide in newly diagnosed GBM. These trials failed to show statistically significant increased survival [median overall survival (OS) of 15.7 and 16.8 months for the BEV groups, respectively]. We performed a retrospective chart review of newly diagnosed GBM pts treated with BEV at Duke, with the goal to identify subgroups of pts who might benefit from BEV in the community. 
Méthodes :
Newly diagnosed adult GBM pts treated at Duke were identified through our “Primary and Recurrent Glioblastoma Registry”. We conducted a retrospective chart review of pts who initiated BEV off clinical trial between January 1, 2009 and May 14, 2012. Pts who participated in a clinical trial prior to receiving BEV were excluded from analysis. Pts alive on May 15, 2012 consented to the prospective collection of their data. Demographic, clinical, and outcome data were analyzed.
Résultats :
Thus far, a total of 181 pts have been identified. Median age at start of BEV was 57 years (range 20-80) and 66% were male. Gross total resection was obtained in 46%, biopsy in 20%, and subtotal resection in 34% of pts. At a median follow-up of 31.2 months, median OS from the time of GBM diagnosis was 26.2 months (95% Confidence Interval [CI], 23.3-32 months) and median progression-free survival (PFS) was 17.8 months (95%CI, 14.9-19.8 months). Grade 3 or higher proteinuria occurred in 6% of pts; grade 3 or higher thromboembolic events occurred in 9% of pts. Two grade 2 intracranial hemorrhages were observed. 
Conclusions :

This retrospective review suggests a median OS of 26.2 months and median PFS of 17.8 months in newly diagnosed GBM pts treated on BEV in clinical practice. One possible explanation for the long-term survival could be our practice of continuing BEV at progression. Further prospective and retrospective analyses to identify subgroups of pts who can benefit from the addition of BEV to the standard of care will be performed.

Asco 2014
2083- Ciprian Barlog. * Sauvetage bevacizumab néoadjuvant sur le glioblastome récemment diagnostiqué (GBM).
Original

Auteurs : Ciprian Barlog, Emeline Tabouret, Marc Sanson, Ahmed Idbaih, Caroline Houillier, Florence Laigle-Donadey, Agusti Alentorn; APHP Service de Neuro-Oncologie, Paris, France; Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Neurologie 2, Paris, France; Université Pierre et Marie Curie Paris VI, Paris, France; APHP-CHU Pitié-Salpêtrière, Paris, France
Résumé :
Quelques malades (pts) avec GBM sont dans une pauvre condition au début de la radiothérapie (RT), en particulier à cause
d'hypertension intracrânienne résistante aux stéroïdes (ICH), et RT est annulée. Notre objectif était d'évaluer si bevacizumab franc (BEV) pouvait aider dans ce cadre rare, en permettant à quelques malades de reprendre le traitement de radio-chimiothérapie standard.
Méthodes :
Nous avons analysé rétrospectivement tout les pts avec GBM récemment diagnostiqués qui ne pourrait pas commencer RT à cause d'ICH sévère ou statut neurologique incompatible avec les exigences pour administrer RT et qui ont reçu BEV comme thérapie néo-adjuvante. Les caractéristiques cliniques, radiologiques et les réponse à BEV ont été enregistrées. Il a été aussi noté que la radio chimiothérapie puisse être délivrée secondairement.
Résultats :
12 pts ont reçu BEV néo adjuvant à cause d'un grand volume tumoral (N=8) ou statut neurologique altéré (N=4). Tous avaient été diagnostiqué par biopsie. L'âge médian était de 60 ans (gamme 19-72). Tous les pts étaient sous stéroïdes à dose élevée. 7 pts (58%) pourrait recevoir RT standard après administration de BEV. Après BEV et avant RT, le statut neurologique a été amélioré chez 6 pts, et 8 étaient stable ou réponse partielle sur IRM. L'achèvement de RT a été correspondu avec l'âge, mais pas le volume de la tumeur ni le KPS. La survie sans progression (PFS) et la survie totale (OS) était de 3,7 mois (1,4-6,0) et 10,1 mois ( 0-20,4) respectivement. La PFS médiane pour les malades avec ou sans RT était de 8,2 mois ( 0,1-16,4) et 2,5 mois (2,2-2,9) respectivement.
Conclusions :

Le sauvetage néo adjuvant avec BEV peut aider quelques malades GBM dont la condition clinique est très pauvre, souvent un obstacle qui n'autorise pas le début sûr de RT. Une future évaluation est garantie.

Asco 2014
2084-David A. Reardon. Blocus d'un contrôle immunitaire pour glioblastome, activité préclinique d'un agent seul et thérapie combinatoire.
Original
Auteurs : Dana-Farber Cancer Institute, Boston, Division of Hematopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Résumé :
Outcome for glioblastoma (GBM) remains dismal and innovative treatment strategies are desperately needed. Growing data support the contribution of local and systemic immune checkpoint molecules mediating immunosuppression by GBM tumors.
Méthodes :
Luciferized GL261 cells (GL261-Luc) were stereotactically implanted intracranially in albino C57BL/6 mice. Cohorts of mice with growing tumors (increasing bioluminescence) were treated with murine monoclonal antibodies (MAb) against PD-1, PD-L1, PD-L2, and CTLA-4 (single agent and combinations) every 3 days X 8 beginning 6 days following tumor implantation and were followed for overall survival. Subsets of mice underwent MRI as well as analysis of tumor infiltrating immune cells, and systemic immune cells and immunocytokines. Tumor re-challenge experiments were performed among long-term surviving mice. 
Résultats :
Immune checkpoint blockade was well tolerated with no apparent morbidity or mortality among treated animals. Improved survival was noted among mice treated with immune checkpoint blockade compared to appropriate controls. The most robust survival benefit was noted among mice treated with combinatorial therapy including 12/18 (75%) mice treated with anti-PD-1 + anti-CTLA-4 MAbs alive at 140 days with no evidence of residual tumor. MRI imaging among long-term surviving animals demonstrated clear evidence of initial tumor growth followed by regression and eradication of tumors.
Long-term surviving mice appeared fully intact neurologically and exhibited no evidence of tumor growth following re-challenge of GL261-Luc cells injected subcutaneously. Characterization of tumor infiltrating immune cells as well as systemic immune cells and immunocytokines is ongoing. 
Conclusions :

Immune checkpoint blockade provides significant survival benefit and appears safe in this immunocompetent, orthotopic syngeneic GBM model.
Re-challenge experiments demonstrate evidence of long-term immunologic memory and further elucidation of underlying mechanisms of immune-mediated anti-tumor activity is ongoing. These data strongly support the evaluation of immune checkpoint inhibitors among patients with GBM.

Asco 2014
2085- Andrea Pace.
Facteurs angiogéniques et procoagulant dans le plasma des malades avec tumeur de cerveau traitée avec bevacizumab.
Original

Auteurs : Cancer Institute, Rome, Italy; Clinical Pathology Service, Regina Elena National Cancer Institute, Rome, Italie
Résumé :
Glioblastoma (GBM) is one of the most vascularized human tumors and GBM cells produce proangiogenic factors, including vascular endothelial growth factor (VEGF). Bevacizumab (BV), a monoclonal antibody against VEGF, has shown antitumor activity, but so far no biomarkers have been identified to predict outcome. The purpose of the present study was to investigate the possible predictive value of circulating VEGF, von Willebrand factor (vWF) and procoagulant factors in patients with recurrent GBM
Méthodes :
 We conducted a prospective analysis of recurrent malignant gliomas (MG) patients treated with BV alone or in combination with chemotherapy performing serial evaluations of plasma VEGF levels, vWF antigen and procoagulant factors such as thrombin-antithrombin complex (TAT), prothrombin fragment F1+2 (F1+2), Factor VIII and D-Dimer. Baseline, and post-treatment samples were collected at each administration of BV.
Résultats :
Forty-nine recurrent MGs (glioblastoma=26, astrocytoma=17, oligodendroglioma=6) who received BV at 10 mg/kg intravenously every 3 weeks, of whom 26 in association with chemotherapy were included in the study. Median age was 45 years (22-73), median Karnofsky performance status was 80
(60-100). Out of the 48 evaluable, 17 partial responses (35%), 7 stable disease (15%) and 24 disease progressions (50%) were observed. At baseline all patients presented with laboratory signs of coagulation activation (i.e. high TAT and FVIII levels). Circulating plasma levels of VEGF and vWF antigen significantly increased in all patients post-treatment of BV (p=0.0001 and 0.009 respectively). No responder patients showed significantly higher vWF antigen levels than responders (p=0.01) after second administration of BV. 
Conclusions :

These preliminary data suggest that low vWF antigen levels might help predict response in recurrent MG patients treated with BV. This marker should help clinicians to decide the right therapy, advise them of the generation of mechanisms of drug resistance during antiangiogenic treatment.

Asco 2014
2086-Rajappa Kenchappa.
Effet de l'inhibition de l'alpha secretase sur le récepteur de neurotrophine p75 (p75NTR) et prolifération des cellules initiatrices de tumeurs (BTICs) des gliomes malins (Mg).
Original

Auteurs : . Lee Moffitt Cancer Center & Research Institute, Tampa, FL
Résumé :
MGs are highly invasive, proliferative, and are resistant to treatment. The identification of Glioma Stem Cells (GSCs a.k.a. BTICs) suggests MGs may arise from these cells. By using an unbiased strategy of serial in vivo selection, we identified p75NTR as a novel mediator of invasion of MGs/BTICs, and p75NTR proteolysis by γ-Secretase was required for glioma invasion (Johnston et al., 2007; Wang et al., 2008). However, p75NTR’s role in glioma proliferation is unknown. We hypothesized that p75NTR also mediates BTICs proliferation via proteolysis by γ-Secretase
Méthodes :
We used frozen human MG tissues and BTICs isolated from fresh human MGs, examined the expression of neurotrophin receptors and their ligands, and studied their role in proliferation. Gene expression data from TCGA and a validation set from the Moffitt Cancer Center MG datasets were also used.
Résultats :
We show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB and TrkC), their ligands (NGF, BDNF and NT3), and predominantly secrete NGF. Down regulation of p75NTR significantly decreased BTICs proliferation. Conversely, exogenouous NGF, stimulated BTIC proliferation through γ-secretase mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR-ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF stimulated p75NTR cleavage and BTIC proliferation; suggesting the Trk receptors role in p75NTR signaling and BTIC proliferation. Further, knockdown of p75NTR or pharmacologic inhibition of cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR mediated proliferation. We also found that p75NTR, Trk receptors, α-secretase and the γ-secretase enzymes were elevated in GBM patients. Importantly, the ICD of p75NTR was commonly found in MG patient specimens suggesting that the receptor is activated and cleaved in patient tumors. 
Conclusions :

These results show that p75NTR proteolysis is required for BTIC proliferation and is a novel clinical target.

Asco 2014
2087-Marica Eoli.
Association de la survie sans progression augmentée dans le glioblastome primaire avec lymphopénie au départ et activation des cellules NK et NKT par immunothérapie cellulaire dendritique.
Original

Auteurs : Istituto Neurologico Carlo Besta, Milan, Italy; Fondazione IRCCS Istituto Neurologico, Milan, Italy; Neurological Institute C. Besta, milan, Italy; Neurological Institute C. Besta, Milan, Italie
Résumé :
DENDR1 is a phase I-II phase study aimed at evaluating dendritic cell (DC) immunotherapy in patients with first diagnosis of glioblastoma multiforme (GBM). Here we provide results of the interim analysis on 22 patients
Méthodes :
Patients with post-surgery volume ≤10 cc underwent leukapheresis before radiotherapy and chemotherapy with temozolomide (TMZ) (Stupp et al, 2005). DC prepared under GMP procedures were loaded with whole tumor lysate (Nava et al, 2012). Three intradermal injections of mature DC were done before adjuvant chemotherapy. The subsequent 4 injections were performed 17 ±3 days after adjuvant TMZ. MRI, clinical and immunological
follow-up were performed every 2 months

Résultats :
Median age at surgery was 54.5 years (28-69). After a median follow up of 14 months (6-27), the median progression-free survival (PFS) was 9 mo, with PFS6 90% (C. I. 0.78-1.029%) and PFS12 42% (C. I: 0.20-0.64) at Kaplan Meier analysis. Median overall survival (OS) was 22 mo with OS 12 70%. (C. I. 0.50-0.9). RT-TMZ induced significant lymphopenia (<1000 lymphocytes/microl) in 17/22 patients (77.2%). Patients with >1000 lymphocytes/microl (5/22) before first vaccination had shorter PFS than others (p<0.005). Peripheral Blood Lymphocytes (PBLs) were analyzed by flow cytometry to identify CD8+ T cells, NK and NKT cells before and after DC vaccines. The ratio of vaccination/baseline cell frequencies (V/B ratio) was calculated for each patient and the median of all values used as the cut off value to separate patients. Increased V/B ratio for NK cells and NKT cells, but not for CD8 T lymphocytes, was significantly associated with prolonged PFS (median PFS 14 vs 8.0 mo, p=0.01; 15.0 vs 8.0 mo). 2/4 patients with MGMT methylation were in the group of high V/B ratio. Interferon-gamma in peripheral blood was significantly higher in patients with PFS12 (p<0.02).
Conclusions :

The results show significant positive association between PFS and increased peripheral levels of NK and NKT cells, encouraging the expansion of this study to a larger number of primary GBM. Clinical trial information: 2008-005035-15.

Asco 2014
2088-
Ariz Akhter.
Analyse génétique de l'expression des récepteurs des cellules B-Cellule récepteurs (BCR) chemin pour l'identification du gène PDE4B comme une cible thérapeutique potentielle pour vaincre la résistance aux glucocorticoides dans les lymphomes primaires du SNC.
Original

Auteurs : University of Calgary, Calgary, University of Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia; Prince Sultan Military Medical City, Riyadh, Saudi Arabia; Tom Baker Cancer Centre, Canada
Résumé :
Gene expression profile (GEP) and supervised learning has identified effective targeted therapies and B-cell receptors (BCR) pathway inhibitors have improved outcomes in refractory Diffuse Large B-cell lymphoma (DLBCL) patients (pts). Primary lymphoma of the central nervous system (PCNSL) is a specific DLBCL entity arising in and confined to the CNS. BCR pathway is frequently dysregulated in PCNSL due to mutations affecting CD79B, CARD11, and MYD88 genes. Studies focusing on GEP in PCNSL; thus providing clinical tool for selection of novel targeted therapies is lacking. 
Méthodes :
Here, we report GEP data on BCR related genes and associated downstream pathways (154 gene-probeset) in a cohort (n=21) of PCNSL pts, utilizing mRNA from diagnostic tissue, assessed by Nano string technology.
Résultats :
Hierarchical clustering (based on BCR genes) revealed two distinct clusters (A, n=15 and B, n=6) with differential expression of CD79a, CD79b, Bcl10 and CARD-11 (p<0.002). Cell of origin signatures were not distinct between two clusters (p=0.825). However, MAP kinase pathway (MEK1/ERK2) (p<0.018); TAB2/TAB3 (p<0.05); CCDN1 (p<0.05); TLRs (p<0.02) genes were differentially expressed. PDE4B gene, that regulates responses to BCR signaling and apoptosis, exhibited higher (1.5 x) expression in cluster A vs. cluster B (0.004). PDE4B expression correlated well with mTOR expression (p=0.018).
Conclusions :

BCR activity defines two distinct sub-groups within PCNSL with distinct signatures including expression ofPDE4B. PCNSL ptsmay benefitfrom PDE4B inhibitors, through improving glucocorticoid sensitivity. It also demonstrates that insights into disease pathogenesis can be exploited to rationally overcome drug resistance.

Asco 2014
2089-Mélisse Azoulay.
Comparaison de la radiothérapie hypofractionnée avec temozolomide avec le traitement standard dans le traitement du glioblastome, résultats dans notre centre.
Original

Auteurs : University Health Centre, Montreal, QC, Canada; McGill University Health Centre, Research Institute, Montreal, QC,
Canada
Résumé :
The multimodality treatment of patients with glioblastoma (GBM) includes adjuvant radiation with concomitant chemotherapy. At this time the optimal radiation fractionation is yet to be determined. In this retrospective study, we compared different fractionation regimens and identified independent prognostic variables associated with outcome.
Méthodes :
457 underwent surgery for GBM between January 2005 and December 2012. Data related to clinical information, extent of surgery and adjuvant treatment was collected using electronic records and patient charts. Patients excluded were those who did not receive or complete adjuvant radiation and patients with infra-tentorial lesions. Univariate and multivariate analysis was performed using Cox model in order to identify variables associated with the primary endpoint, overall survival (OS). 
Résultats :
276 patients with a median follow-up of 13.4 months were included in this analysis. There were 147 patients in the conventional fractionation (CF) group of 60 Gy/30 fractions, 86 patients in the hypofractionation group of 60 G/20 fractions (HF60), and 43 patients in the 40 Gy/15 fractions group (HF40). Ninety-five percent of patients in both the CF and HF60 group received concomitant temozolomide, while 49% in HF40 group of patients received it. The median survival (MS) was 15.7 months for the CF group with a 2 year OS of 30.6%. MS was 13.8 months and 7 months in the HF60 and HF40 groups with a 2-year OS of 26.2% and 5.3%, respectively. Cox analysis showed no significant difference in terms of OS between the CF and HF60 group (HR1.22, P=0.20) but worse outcome in the HF40 group (HR 2.09, P=0.004). Multivariate analysis showed age, performance status, extent of surgery, repeat surgery, concomitant chemotherapy and methylation status to be significant factors associated with survival.
Conclusions :

HF60 shows OS comparable to CF while allowing for a shorter treatment time and potential radiobiological benefit without added toxicity. Our data also confirms that HF40 should be reserved for the palliative setting. There is a need for a prospective trial comparing the HF60 regimen to the current standard of care.

 Asco 2014
2090-Lingling Du.
Estimation pronostique révisée (GPA) pour le cancer du poumon (SCLC) avec métastases de cerveau (BM).
Original

Auteurs : Cleveland Clinic, Cleveland, OH; Cleveland Clinic, Cleveland, OH
Résumé :
Pts with SCLC commonly develop BM and the GPA is frequently used as a prognostic index for overall survival (OS). GPA includes 4 groups
(GPA scores 0-1.0 (worst), 1.5-2.0, 2.5-3.0, and 3.5-4.0 (best)). The purpose of this study is to develop a revised GPA in this population using a contemporary pt cohort. 
Méthodes :
With IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify SCLC BM pts treated between 2000 and 2013. OS from the diagnosis (dx) of SCLC BM was the primary endpoint. Cox proportional hazards models with stepwise variable selection were used to identify independent prognostic factors.
Résultats :
197 pts (52% male) with BM from SCLC were included for analysis. Median age at dx of BM was 64 yrs (range 36-85). 41% had BM at the initial dx of SCLC. Median number (No.) of BM was 2 (Range 1-25). 6% had leptomeningeal disease. Median OS after the dx of BM was 9.5 months (m) (95%C.I. 7.8-10.1 m). Conventional GPA for lung cancer is derived from KPS, No. of BM, presence of extracranial mets, and age. Overall GPA was prognostic of OS (p<.0001) but the categorizations of the factors comprising it were not optimal. A revised set of factors was identified (Table): the 4 original factors, but with different characterizations and weights, and control of the primary tumor. The revised GPA index categorizes pts into 3 groups - unfavorable (total score <8; 27% of pts), intermediate (8-13; 43% of pts), and favorable (>13; 30% of pts); with OS of 3.0m (vs 6.4m for pts with GPA <1.0; 36% of pts), 9.6m, and 15.8m (vs 13.3 for pts with GPA>2.5; 29% of pts) respectively (p<.0001).
Conclusions :

 A revised prognostic index consisting of modified versions of the factors comprising the GPA and primary controlled/uncontrolled in pts with BM from SCLC is proposed.
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