O5/06/2014
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ASCO 2014 dossiers 91-100/100 et fin des tumeurs de cerveau

Asco 2014
2091-
Carmin Maria Carapella.
Le rôle potentiel des PET-SCAN 18F-FDOPA dans les gliomes de bas grade. Lire
Auteurs Rome, Italy; Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy; Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italie

Résumé :
Brain tumors have been widely evaluated with 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine (18F-FDOPA) PET examination, that demonstrated higher sensitivity and specificity for gliomas than 18F-FDG PET imaging. The aim of the present study is to evaluate the potential role of 18F-FDOPA PET in low grade glioma (LGG)
Méthodes :
We enrolled 56 patients (35 males and 21 females) affected by LGG; 23% were newly diagnosed, 45% were studied during chemotherapy, and 32% were observed out of treatment during a periodic follow-up. The mean age at diagnosis was 44.5 years. All patients underwent 18F-FDOPA PET and MRI examinations. Both FLAIR and contrast-enhanced T1 sequences were considered for the assessment of therapeutic response according to RANO criteria. PET images were considered as positive when the lesion definitely presented 18F-FDOPA accumulation taking into account background and controlateral site. The slices with a maximal 18F-FDOPA uptake in the ROI were chosen for quantitative measurement of metabolic activity of the tracer [standardized uptake value (SUV)]. In order to evaluate the concordance between diagnostic test 1 (MRI) and diagnostic test 2 (18F-FDOPA) we calculated the unweighted kappa statistic and its relative 95% Confidence Interval (CI). This value was interpreted in a qualitative manner on the basis of Landis and Koch criteria. 
Résultats :
The Kappa statistic for the whole sample was equal to 0.301 (95% CIs from 0.21 to 0.40) showing a fair concordance between the two tests in terms of diagnostic ability. We found a good correlation between residual volume and SUV max (r=0.435, p=0.002 by Spearman Rank Correlation Coefficient), indicating that greater the residual volume, higher is the SUV max. Also multivariate analysis showed that a SUV max greater than 1.65 was the only independent predictor of tumor progression (HR=4.59, 95% CIs from 0.99 to 21.31, p=0.054). This implies that a patient with a SUV max higher than 1.65 had an almost 5-fold increased risk of progressive disease, regardless of its clinical and MRI characteristics.
Conclusions :

Our results confirm that 18F-FDOPA PET imaging could assume a relevant role mainly in the prognostic assessment of patients affected with primary and recurrent LGG.

Asco 2014
2092-
Razelle Kurzrock.
Un essai de phase I de niraparib en combinaison avec temozolomide (TMZ) chez les malades avec cancer avancé. Lire
Auteurs University of California, San Diego, La Jolla, CA; Mayo Clinic, Rochester, MN; TESARO, Inc., Waltham, MA; Tesaro, Inc., Waltham, MA Etats-Unis

Résumé :
Niraparib (Np) is an oral, highly potent and selective PARP1/2 inhibitor. The hypothesis for this study is 1) PARP inhibition of DNA repair damage is potentiated with TMZ. 2) PARP inhibition restores sensitivity to TMZ mismatch repair-deficient tumors.
Méthodes :
This was a multi-center (3), open-label, non-randomized two-part study in patients with advanced cancers. Patients were treated with Np (once daily continuously) + TMZ (once daily for first five days) in 28-day treatment cycles. In Part A, the objective was to determine the preliminary MTD of the two drugs in combination. Part B was to explore the efficacy and tolerability of this combination in two cohorts (recurrent GBM and melanoma). The study was closed after defining MTD in Part A.
Résultats :
There were 19 patients treated in Part A with Np at 3 dose levels 30 mg (6 subjects), 40 mg (10 subjects), and 70 mg (3 subjects) and 150 mg/m2 TMZ once daily. The MTD and RP2D was determined to be 40 mg Np and 150 mg/m2 TMZ. The DLT of Grade 4 Thrombocytopenia occurred in 2/10 patients at the 40 mg dose level for Np. The DLT of Grade 4 neutropenia occurred in 1/3 patients at the 70 mg dose level for Np. At this dose level all 3 patients enrolled experienced Grade 4 thrombocytopenia with only one patient meeting protocol-specified DLT criteria. The most frequently reported AEs were thrombocytopenia (78.9%), anemia (68.4%), and leukopenia (57.9%). The most common ≥ grade 3 AEs were thrombocytopenia (52.6%), neutropenia (31.6%), and neoplasm progression (15.8%). Based on the in vitro metabolism data, the likelihood of a drug interaction between Np and TMZ is highly unlikely. Out of 16 evaluable subjects, 1 subject reported a PR (Glioblastoma), 2 subjects experienced SD (Malignant melonama and Serous ovarian carcinoma) and 13 subjects had PD. 
Conclusions :

 Niraparib, dosed at 40 mg continuously in combination with 150mg/m2 TMZ was tolerable and demonstrated antitumor activity. 40 mg Np and150 mg/m2 TMZ was considered an MTD and RP2D. A future study will evaluate full dose, 300 mg daily Np in combination with escalating TMZ dose levels. Clinical trial information: NCT01294735.

Asco 2014
2093-Miriam Dorta. La fréquence et l'impact du nouvel arrangement ROS1 sur les résultats cliniques dans le GBM. Lire
Auteurs : Universitary Hospital, Madrid, Spain; Madrid, Spain; Biochemistry and Biology Department, Universidad Complutense de Madrid, Madrid,
Espagne 

Résumé :
The tirosine kinase (TK) receptor ROS1 is described in several preclinical analysis of glioblastoma (GBM) cells and its role in gliomagenesis has been reported as well. Since TK inhibitors has changed clinical response of ROS1 rearranged lung cancer, new therapeutic approach has emerged for GBM. However its rearrangement in GBM human tissue still has not been explored and it should be defined to check if those are relevant to assess ROS1 inhibitors in these neoplasms. We performed ROS1 FISH in human GBM tissue and correlates molecular alterations with overall survival (OS) and progression free survival (PFS) in a cohort of uniformly treated GBMs.
Méthodes :
Clinical history of 54 patients treated from GBM at Doce de Octubre Spanish Hospital, between 2008 and 2010, were reviewed. Only 33 patients had accessible data, tumor specimen, received treatment out of any other clinical trial and had an adequate follow-up. To better analyze the series of 33 cases, a tissue array paraffin platform was performed, and we disposed probes for ROS1 split. 30 samples from 33 from tissue array keeped enough quality to ROS1 microscope analysis. Results were sorted and pooled in non-mutated and mutated, including deletions and rearrangements in mutated group. 
Résultats :
Mutations were found in 51,5% of samples. Deletion was the most common mutation (48,5%). Only 1 sample showed rearrangement (3%). 39,4% was not mutated, and 3 patients were not evaluable for ROS1 (9.1%). The median overall survival (OS) and progression-free survival (PFS) of the whole series (33 samples) was 19 months (CI 95 %: 13.66-24.34) and 8 months (95 % CI: 6.47 to 9.53), respectively. For ROS1 subgroup, median OS resulted in 19 versus 11 months for non-mutated and mutated cases, respectively, with statistical signification (p = 0.005). ROS1 median PFS was 9 versus 6 months for non-mutated and mutated respectively, also with statistical significance (p = 0.044).
Conclusions :
In our series of human GBM tissues treated uniformly, a high frequency of genetic splits is estimated, with just 3% of rearrangements. These findings have prognostic relevance by the relation resulted between ROS1 status and patients survival, being significantly worse for those with ROS1 rearrangements or deletions.

Asco 2014
2094-Jian Li Campian. Faisabilité de la récolte et de la réinjection des lymphocytes chez les malades avec gliomes de haut grade récemment diagnostiqués. Lire
Auteurs
Washington University in St. Louis, St. Louis, The Johns Hopkins University School of Medicine, Baltimore, MD; Stony Brook Medicine, Stony Brook, NY; The Johns Hopkins Hospital, Baltimore, MD; The Johns Hopkins Hospital and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD Etats-Unis

Résumé :
Standard radiation (RT), temozolomide (TMZ), and dexamethasone cause severe treatment-related lymphopenia (TRL) (total lymphocyte counts (TLC) <500 cells/mm3) two months after initiating therapy in patients with newly diagnosed high grade gliomas (HGG). Published studies suggest that severe TRL is related to radiation of circulating lymphocytes and is associated with shorter survival due to tumor progression. This study was designed to evaluate the feasibility of harvesting lymphocytes before radiation and reinfusing them after radiation is completed.
Méthodes :
Ten patients with newly diagnosed HGGs and baseline TLC >1000 cells/mm3 were enrolled. Lymphocytes were harvested with a single 120 minute apheresis procedure via peripheral veins, cryopreserved, and reinfused immediately after RT was complete. Weekly blood counts were followed for 20 weeks. A post-reinfusion TLC rise of >300 cells/mm3was desired. 
Résultats :
10 patients were harvested and 8 received lymphocyte reinfusion. Median age was 55.5 years (range 40-67); median dexamethasone dose was 3 mg/day (range 0-4mg/day), and 70% was glioblastoma multiforme. Their baseline median TLC was 1980 cells/mm3 (range: 1060-2290) and a median of 8.9x107 lymphocytes/Kg (range 3.4-11.1x107) were harvested. After 6 weeks of therapy, the TLC fell 63% (median 605 cells/mm3, p<0.0001). A median of 7.0x107 lymphocytes/Kg (range: 2.7–9.5x107) were reinfused. Four weeks after reinfusion the average increase in TLC was 274 cells/mm3 (STD: ± 298, p=0.045). Overall, 7 of 8 patients (88%; 90%CI: 53-99%) had an absolute increase in TLC >300 cell/mm3in the 14 weeks following reinfusion and this persisted in 4 of 7 (57%) patients. No adverse events occurred related to harvest or reinfusion.
Conclusions :
Lymphocyte harvest and reinfusion is feasible in HGG patients on dexamethasone and no toxicities were noted. An increase in TLC >300 cells/mm3 was seen in 88% of reinfused patients during the 14-week observation period post reinfusion. Future studies are being designed to document the role of lymphocyte reinfusion in the increase in TLC. Clinical trial information: NCT01653834.

Asco 2014
2095- John E. Schmidt.
Fonction cognitive et symptômes dépressifs chez les malades avec des tumeurs primaires de cerveau récemment diagnostiquées.. Lire
Auteurs
University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA Etats-Unis

Résumé :
Primary Brain Tumor (PBT) and its treatment result in reduced cognitive function which significantly interferes with work, personal, and social activities. Depression is also a clinically significant problem in patients with PBT at diagnosis, during and post-treatment. Recent research in non-cancer patients with mild-cognitive impairment has found strong associations between reduced cognitive function and depression; however this association has been little researched in PBT patients. The goal of the present study was to explore the potential interactive relationship between cognitive function (psychometrically assessed) and depression in patients undergoing primary adjuvant treatment for newly diagnosed PBT.
Méthodes :
Participants included 49 patients (51% male, mean age 48.0) with glioblastoma (n=18), oligodendroglioma (n=17), and astrocytoma (n=14). All completed a pre-treatment psychological and cognitive assessment. The assessment was repeated twelve months later. Assessments included depression (CES-D), physical symptoms and interference (MDASI-BT), and cognitive function (STROOP, Digit Symbol Coding).
Résultats :
At both assessments, mean scores on Digit Symbol Coding were in the low-average to borderline range compared to WAIS-IV norms. Mean STROOP T-scores fell in the average to low-average range. No significant differences were found in physical symptom severity or interference between assessments (p’s>.05). Performance on the STROOP and Digit Symbol Coding declined significantly (rANOVA, p’s<.05). Depression scores did not change (p’s>.05). When pretreatment depression scores were included as a covariate, changes in cognitive function were no longer significant. The majority of the participants were working or in school at baseline (n=34, 70%), but were on disability or unemployed at second assessment (n=33, 67%).
Conclusions :
The results suggest that depressive symptoms may contribute to declines in cognitive function over time in PBT patients. It is tempting to speculate that interventions focused on improving cognitive function in these patients might be enhanced by early intervention to reduce depressive symptoms.

Asco 2014
2096-
Seema Nagpal. Pegol Etirinotecan (EP, NKTR-102) dans le traitement des gliomes de haut grade (HGG), essai de phase II. Lire
Auteurs Stanford Cancer Institute, Stanford, CA; Stanford University School of Medicine, Stanford, CA Etats-Unis

Résumé :
Patients with recurrence of HGG after bevacizumab (BEV) have an extremely poor prognosis and generally do not respond to further treatment. EP is the first long-acting topoisomerase-I inhibitor designed to concentrate in and provide continuous tumor exposure throughout the entire chemotherapy cycle. Becasue irinotecan has demonstrated activity against HGG, we conducted a Phase 2, single arm, open label trial to evaluate EP in HGG patients who progressed after BEV
Méthodes :
Patients age >18 with histologically proven anaplastic astrocytoma (AA) or glioblastoma (GB) who previously received standard chemo-radiation and recurred after BEV were eligible. A predicted life expectancy > 6 weeks, KPS ≥ 50 and adequate organ and bone marrow functions were required for entry. Primary endpoint was PFS at 6-week, secondary endpoints were survival from first EP infusion, overall survival from date of pathologic diagnosis of HGG, and safety profile of EP. Response was assessed by RANO criteria. EP as a single agent is administered IV every 3 weeks at 145mg/m2. Patients did not receive BEV while on EP. 
Résultats :
Between August 2012-May 2013, 20 patients were enrolled. Median age was 50 years, median KPS was 70%. 90% of patients had GB with a median time of 1 year from a diagnosis of HGG to study entry with a median of 3 prior lines of therapy. Patients received a median of 3 cycles (1-19) of EP. All patients were evaluable for PFS and toxicity. 2 patients (both with GB) had partial MRI responses. 10 patients had stable disease. 2 patients are still on treatment after receiving 19 and 9 treatment cycles. 6-week PFS was 55%. Median and 6-month PFS were 1.9 mos and 10%, respectively. Median overall survival from first EP infusion was 4.1 months. Only one patient (5%) had a Grade 3 toxicity (diarrhea with dehydration) attributable to EP. Hematologic toxicity was mild.
Conclusions :

 Despite discontinuing BEV prior to starting EP, 2 patients had confirmed partial responses (10%) according to RANO criteria and an additional six patients had stable disease at their 1st and 2nd imaging assessment. These encouraging clinical data combined with a favorable safety profile warrant further clinical investigation of this agent in GB. Clinical trial information: NCT01663012.

Asco 2014
2097-Kim Edelstein.
Fonction neurocognitive chez les adultes traités avec radiothérapie pour des tumeurs primaires de cerveau. Lire
Auteurs Princess Margaret Cancer Centre, Toronto, ON, Canada

Résumé :
Cranial radiation is associated with progressive declines in processing speed, attention, memory and executive functions, presumably due to deleterious effects on white matter growth in children and accelerated cognitive aging in older adults. However, little is known about the longitudinal effects of radiation in the adult brain tumor population.
Méthodes :
In this retrospective cohort study, we conducted neurocognitive assessments in 21 adults diagnosed with a primary brain tumor (12 male; mean age 44 years, range 21-66) within a year of radiation (baseline mean ± SD: 0.17 ± 0.36 years, range -0.15 to 1.1 years), and 3.05 ± 1.83 years later (range 0.51 to 6.77 years). Patients who required additional surgery, or developed tumor progression prior to neurocognitive follow up were excluded from analyses. Neurocognitive test scores were converted to scaled scores according to published criteria, and transformed to z-scores (mean 0, SD 15). Tests measuring the same construct were averaged to provide 4 cognitive domains: Speed, Attention, Memory, and Executive Functions. 
Résultats :
At baseline, Memory, Attention, and Executive Function were below population norms, and Speed was within normal limits (one-sample t-tests, respective means ±SD: -0.66±0.84;-0.40±0.74; -0.70±1.12; -0.30±0.94; all p<0.05). At follow-up, only Attention was below average (-0.40±0.81). Moreover, there was no difference in performance at baseline compared to follow-up across domains, nor was there an interaction between time and domain (time x domain repeated measures ANOVA, all p>0.1). There was also no difference in the number of tests that were impaired (defined as one standard deviation below the population mean) at baseline compared to follow up.
Conclusions :
Adult brain tumor patients showed deficits in cognitive functions that did not appear to decline over time after radiation in the absence of tumor progression. Longitudinal assessments of neurocognitive functions following radiation treatment in a larger sample is warranted to identify factors contributing to neurocognitive decline across the lifespan in this population.

Asco 2014

2098-Amol Narang. L'utilité de la prise de contraste IRM prophétique d'une histologie de haut grade chez les malades avec gliomes de bas grade progressifs. Lire
Auteurs
The Johns Hopkins Department of Radiation Oncology, Department of Neurosurgery, Baltimore, MD; The Johns Hopkins Hospital, Baltimore, MD; The Johns Hopkins University School of Medicine, Baltimore, MD Etats-Unis

Résumé :
In patients with low-grade gliomas, pathologic grade at time of progression has important therapeutic and prognostic implications. Whether surrogate radiographic variables such as new MR contrast enhancement can be used with high accuracy to predict malignant degeneration is uncertain.
Méthodes :
Patients with a pathologic diagnosis of low-grade glioma (WHO grade I or II) who underwent biopsy or resection at time of progression from 1995-2010 were retrospectively reviewed. Radiologic studies were examined to determine the presence of new MR contrast enhancement, which was analyzed as a predictor of high-grade transformation. 
Résultats :
One hundred and eight patients underwent biopsy or resection for progressive low-grade gliomas, with 19 patients undergoing multiple repeat resections, allowing a total of 127 evaluable records. Median age at initial diagnosis was 36.2 years, while 10% of patients were under the age of 18. Initial pathology consisted of astrocytoma (43%), oligodendroglioma (39%), oligoastrocytoma (11%), and pilocytic astrocytoma (11%). Of the 127 instances of progression, malignant degeneration was present in 74 specimens (58%). Sensitivity (sens) and specificity (spec) of MR contrast enhancement for high-grade transformation were 89% and 57% respectively, while positive (PPV) and negative predictive values (NPV) were 74% and 79%. Values were similar when patients under 18 or with pilocytic astrocytoma were excluded (sens 89%, spec 57%, PPV 71%, NPV 81%), or when patients who only underwent biopsy at time of progression were excluded (sens 91%, spec 64%, PPV 79%, NPV 83%). 
Conclusions :
Radiographic enhancement and pathologic grade were discordant in greater than 20% of cases, largely due to the lack of specificity of new MR enhancement for predicting malignant degeneration. As such, additional radiographic or clinical predictors are needed to better non-invasively identify tumors that have undergone malignant degeneration. Meanwhile, pathologic
confirmation of grade at time of progression should be considered when safe.

Asco 2014
2099-Tareq A. Juratli.
Méningiomes malins primaires et secondaires, comparaison clinique et histologique. Lire
Auteurs
Department of Neurosurgery, Dresden, Allemagne; Carl Gustav Carus University Hospital Dresden - Institute for Neuropathology., Dresden, Germany; Department of Radiation Medicine, The Ohio State University,  Etats-Unis

Résumé :
Malignant meningiomas WHO Grade III (MM °III) represent the most rare but aggressive subtype of all meningioma. They may progress from low- grade meningiomas °I or °II (secondary MM) or develop as de novo primary MM. In this study, we compared clinical and histological factors influencing outcome and survival of primary and secondary MM
Méthodes :
The dataset of over 1200 patients with intracranial meningiomas was used toidentify patients with histological proven MM. Of those patients clinical, histological, radiological, tumor- and treatment-related data were evaluated and analyzed.
Résultats :
 We identified 22 MM patients (median follow-up of 8 years); 12 patients with a secondary MM and 10 patients with a primary MM. Histologically, primary and secondary MM were largely indistinguishable. Even the immunohistochemistry including proliferation index (MIB-1), vascular density as well as PDGFR-/ EGFR- and VEGFR-expression failed to show significant differences between either groups or a significant influence on the overall survival. A typical feature of secondary MM were that they are preferentially located at the skull base, whereas primary MM aroused at the convexity (p=0.049). Patients with secondary MM underwent in average 4 surgeries, in opposite to patients with primary MM who had in average a single operation (p=0.002). 8 patients with secondary MM and all patients with primary MM received radiotherapy; whereas only 3 patients in each group underwent adjuvant chemotherapy. Repeated operations demonstrated a marked survival benefit in both groups in respect to the extent of resection (p=0.025). The median overall survival rate for secondary MM following the confirmation of malignant histology was 2.2 years; whereas this wasn’t reached yet in the patients group with primary MM at follow-up after 10 years (p<0.05). 
Conclusions :

Secondary MM seem to be of more aggressive nature than primary ones with a higher risk toward recurrence and with a significantly reduced survival time. Surgery is an effective treatment for secondary and primary MM WHO °III at initial presentation and recurrence. In addition, repeated surgery was the only identified significant prognostic factor for improved PFS and OS in both groupes.

 Asco 2014
2100-Thérèse A. Dolecek.
Analyse démographique complète et survie du médulloblastome pédiatrique. Lire
Auteurs
University of Illinois at Chicago, Chicago, IL; University of Kentucky, Lexington, KY Etats-Unis

Résumé :
We evaluated the American College of Surgeon’s National Cancer Data Base (NCDB) to describe current hospital-based epidemiologic frequency and survival patterns of pediatric medulloblastoma.
Méthodes :
We analyzed NCDB 1998-2010 data on medulloblastoma defined as ICD-0-3 histology codes 9470, 9471, 9474 diagnosed in primary site brain codes C71.0-C71.9 for children ages 0-19 years. Demographic variables analyzed were age, gender, race and Hispanic origin. Comparisons were also made among histologic subtypes and primary site. Frequencies and Kaplan-Meier relative survival estimates were generated using SEER*Stat software version 8.1.2. 
Résultats :
A total of 3,067 cases of medulloblastoma were identified. Among pediatric age groups, frequency was highest for 5-9 years and lowest in infants. Males were observed to have higher incidence than females. Whites had highest counts among race groups and non-Hispanics were observed to have more frequent diagnoses than Hispanics. The most common histologic subtype was classic medulloblastoma (9470), accounting for 88.2% cases. More than 75% of cases occurred in infratentorial sites C71.6 (cerebellum) or C71.7 (brain stem). Better relative survival was observed as age at diagnosis increased. Females were observed to have better survival than males. No significant differences in survival were observed among race or origin groups. Statistically significantly better 5-year relative survival was observed for cases diagnosed with histologic subtypes 9470 (75.5%) and 9471 (desmoplastic, 79.6%) than 9474 (anaplastic/large cell, 50.6%). Site at diagnosis did not appear to influence survival time for medulloblastoma.
Conclusions :
We report an extensive demographic and survival analysis of pediatric medulloblastoma. Observed differences likely reflect biology across age, gender, race and origin groups.
FIN

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