François Dubois

Lomustine and Bevacizumab in Progressive Glioblastoma

Background Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma. Methods We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive lomustine plus bevacizumab (combination group, 288 patients) or lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O6‐methylguanine–DNA methyltransferase (MGMT) was assessed. Health‐related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival. Results A total of 437 patients underwent randomization. The median number of 6‐week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression‐free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P<0.001). Grade 3 to 5 adverse events occurred in 63.6% of the patients in the combination group and 38.1% of the patients in the monotherapy group. The addition of bevacizumab to lomustine affected neither health‐related quality of life nor neurocognitive function. The MGMT status was prognostic. Conclusions Despite somewhat prolonged progression‐free survival, treatment with lomustine plus bevacizumab did not confer a survival advantage over treatment with lomustine alone in patients with progressive glioblastoma. (Funded by an unrestricted educational grant from F. Hoffmann–La Roche and by the EORTC Cancer Research Fund; EORTC 26101 ClinicalTrials.gov number, NCT01290939; Eudra‐CT number, 2010‐023218‐30.)

Contrast enhancement in 1p/19q-codeleted anaplastic oligodendrogliomas is associated with 9p loss, genomic instability, and angiogenic gene expression

BACKGROUNDnThe aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs).nnnMETHODSnThe MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays.nnnRESULTSnMost of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2.nnnCONCLUSIONnIn AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.

A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer

Approximately 2–5xa0% of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). 103 consecutive patients with BC were diagnosed with LM and initially treated with intra-CSF liposomal cytarabine from 2007 to 2011 at a single institution. Correlations were determined with respect to patient characteristics and BC subtype with regard to overall survival (OS). At LM diagnosis, 61xa0% of patients had a 0–2 performance status (PS), the remaining 39xa0% were severely neurologically impaired. Regardless of PS, all patients received intra-cerebrospinal fluid (CSF) liposomal cytarabine as first-line treatment. Systemic treatment and radiotherapy were also given in 58 and 17xa0% of patients respectively as clinically appropriate. Second- (intra-CSF thiotepa) and third-line (intra-CSF methotrexate) treatment was administered in 24 and 6 patients respectively. Median OS was 3.8xa0months (range 1xa0day–2.8xa0years). In multivariate analysis, an initial combined treatment, a second-line treatment with intra-CSF thiotepa, an initial clinical response, and a non-‘ER/PR/HER2 negative’ BC were significantly associated with a better OS. Median OS in this heterogeneous retrospective case series was similar to that of previously observed BC patients treated with intra-CSF methotrexate suggesting intra-CSF liposomal cytarabine is a reasonable first choice therapy of BC-related LM.

Loss of 1p, 19q, and 10q heterozygosity prospectively predicts prognosis of oligodendroglial tumors—towards individualized tumor treatment?

The purpose of this study was to determine whether chromosome 10q loss is a predictor of tumor aggressiveness and poor clinical outcome in patients with oligodendroglial tumors alone or together with loss of heterozygosity (LOH) on chromosomes 1p and 19q. A microsatellite analysis was performed on sections from 130 patients with grade II and grade III oligodendroglial tumors to assess the allelic status of chromosomes 1p, 19q, and 10q, plus detailed clinical and radiological information was taken prospectively. Median age at diagnosis was 45.5 years. Seventy-eight patients had disease progression after initial therapy; median progression-free survival (PFS) was 27.5 months. Age <47 years, postoperative Karnofsky performance score >65, no contrast enhancement on MRI, grade II, and complete removal on surgery were significantly correlated with a better PFS. Median overall survival (OS) was 40.5 months. Pure oligodendroglioma and temozolomide chemotherapy were correlated with better OS. 10q LOH was correlated with anaplastic grade and 1p19q LOH correlated with pure oligodendroglioma. There was a significant association between LOH status and the tumors response to chemotherapy: 92.3% with 1p19q LOH, 83.3% without allelic losses, 50% with 1p19q10q LOH, and 14.5% with 10q LOH. Patients with 10q LOH alone had PFS of 6 months and a 3-year survival rate of 1%, when compared with 36 months and 85%, respectively, in patients with 1p19q LOH but without 10q LOH. 1p loss was correlated with better PFS (P < .005) and OS (P = .0007), whereas 10q loss was correlated with decreased PFS (P < .0001) and OS (P < .0001). 10q LOH predicted a survival disadvantage in patients with oligodendroglial tumors irrespective of 1p/19q LOH status.

Correlation between magnetic resonance imaging findings and histological diagnosis of intrinsic brainstem lesions in adults

Management of brainstem mass lesions remains a controversial issue, especially when the lesion cannot be excised and when infiltration occurs; moreover, the benefits of a stereotactic procedure are still under debate. In most studies, treatment decisions are based solely on MRI features and do not include a histopathological diagnosis. In the current study, we compared MRI characteristics with histopathological findings of intrinsic brainstem lesions and identified the characteristics associated with the diagnosis of pathologies other than diffuse glioma. From February 1988 through August 2007, 96 brainstem biopsies were performed at the Roger Salengro Hospital in Lille, France, on adult patients with intrinsic brainstem lesions not amenable to excision. Of the 96 patients, 42 were women and 54 were men, with a mean age of 41 years (range, 18-75 years). Data analysis of the MRI findings revealed focal (P < .05) and contrast enhancing lesions (P < .05), and these lesions were significant factors associated with the diagnosis of pathologies other than diffuse glioma. Focal lesions were a significant factor associated with a diagnosis of nontumor lesions (P < .05). In conclusion, the diagnostic effect of stereotactic biopsy on intrinsic brainstem lesions was greater in patients with focal or enhancing lesions shown by MRI, in whom the diagnosis of diffuse glioma was less frequent.

Stereotactic biopsy for brainstem tumors: comparison of transcerebellar with transfrontal approach.

Background: An important aspect of evaluating patients submitted to stereotactic biopsy of the brainstem is the trajectory used. The literature describes two principal approaches: the suboccipital transcerebellar and the transfrontal; however, no studies exist comparing these two techniques. Objective: The purpose of this study was to compare diagnosis success rates and complications between the suboccipital transcerebellar and transfrontal trajectories. Methods: The study evaluated 142 patients submitted to stereotactic biopsy. The patients presented brainstem tumors in the following areas: pons (n = 31), midbrain (n = 36), medulla (n = 2), pons-medulla (n = 30), pons-midbrain (n = 33), and midbrain-pons-medulla (n = 10). On 123 patients, the transfrontal approach was used, and on 19 the suboccipital transcerebellar approach. Results: Comparing success rates between the two approaches, it was observed that in the group of patients submitted to the transfrontal approach, 95.1% (117 cases) were successful, while in those submitted to the suboccipital transcerebellar approach, 84.2% (16 cases) were successful. Despite a higher success rate among patients in the first group, the difference was not statistically significant. Regarding complications, in patients who were biopsied via the transfrontal trajectory, the morbidity rate was 9.8% (12 cases), while in patients submitted to the suboccipital transcerebellar approach, the morbidity rate was 5.3% (1 case) and the mortality rate 5.3% (1 case). Conclusions: This study verified a higher diagnosis rate in patients submitted to the transfrontal approach than in those submitted to the suboccipital transcerebellar approach (95.1 vs. 84.2%); however, the difference was not statistically significant. Regarding complications, the rate was similar in both groups of patients.

Diffuse brainstem glioma: prognostic factors

OBJECTnBrainstem gliomas were regarded as a single entity prior to the advent of MRI; however, several studies investigating MRI have recognized that these lesions are a heterogeneous group, and certain subgroups have a better prognosis for long-term survival. The aim of this study was to conduct a retrospective analysis of prognostic factors of patients with brainstem gliomas confirmed by histopathological diagnosis, particularly regarding assessment of whether histological grade, age, and MRI findings are prognostic factors for patient survival.nnnMETHODSnThe study evaluated 100 patients diagnosed with brainstem glioma. There were 63 adults (40 men and 23 women; age range 18-75 years, mean 41 years) and 37 children (19 boys and 18 girls; age range 2-12 years, mean 6.9 years).nnnRESULTSnThe mean overall survival of this population, measured from the date of biopsy, was 57 months for diffuse low-grade glioma and 13.8 months for diffuse high-grade glioma (p < 0.001). The mean survival among patients with nonenhancing contrast lesions on MRI was 54.2 months, whereas for patients with enhancing lesions, it was 21.7 months (p < 0.001). Comparisons between the Kaplan-Meier survival curves of adults and children revealed similar median survival periods of 25 and 16 months, respectively (p > 0.05). The multivariate analysis (Cox proportional hazards regression) revealed that only histological grade was a significant prognostic factor (p < 0.001).nnnCONCLUSIONSnThe study revealed that histological grade and MRI features were significant prognostic factors for survival in these patients, but in multivariate analysis, only histological grade remained a significant factor.

Correlation among magnetic resonance imaging findings, prognostic factors for survival, and histological diagnosis of intrinsic brainstem lesions in children.

OBJECTnThe aim of this study was to compare MR imaging characteristics with histopathological findings of intrinsic brainstem lesions and also to show the prognostic factors in patients with diffuse brainstem glioma.nnnMETHODSnBetween February 1988 and August 2007, 44 brainstem biopsies were performed at the Roger Salengro Hospital in Lille, France, in children with intrinsic brainstem lesions not amenable to excision. Twenty-six were female and 18 male, and the mean age was 6 years.nnnRESULTSnHistological evaluation revealed diffuse brainstem glioma in all patients with diffuse nonenhancing brainstem lesions. Diffuse brainstem glioma was found in 18 patients (90%) with diffuse enhancing brainstem lesions. Pathological entities different from diffuse glioma were verified in 2 patients (10%)-1 with ependymoma and 1 with ganglioglioma. In 4 of 5 patients with a focal nonenhancing brainstem lesion, the histopathological diagnosis was diffuse low-grade glioma. In 6 of 10 patients with focal enhancing brainstem lesion, the diagnosis was diffuse brainstem glioma, and pathological entities different from diffuse brainstem glioma were verified in 2 (20%), both with pilocytic astrocytoma. The mean 1-year actuarial survival rates for patients classified with low-grade and high-grade glioma were 80.4% ± 0.08% and 48.6% ± 0.14%, respectively.nnnCONCLUSIONSnThe impact of stereotactic biopsy on intrinsic brainstem lesions was greater in patients with MR imaging-documented enhancing lesions in whom the diagnosis of diffuse glioma was less frequent. Patients with low-grade glioma seem to have longer survival than those with high-grade glioma.

H - 12 Étude préliminaire des troubles cognitifs dans les tumeurs gliales

Introduction Les troubles cognitifs sont importants a prendre en compte lors du suivi des tumeurs gliales de grade II et III en raison des progres therapeutiques permettant une amelioration de la survie. Objectifs L’objectif etait de definir un protocole de tests neuropsychologiques adapte (tests valides, reproductibles, realisables en un temps approprie, etc.) afin de caracteriser les difficultes les plus frequentes de ces patients. Methodes Des patients presentant une tumeur gliale de grade II ou III, confirmee par un examen anatomopathologique, ont realise un bilan neuropsychologique (evaluant notamment les fonctions necessitant des reseaux largement distribues), des echelles de qualite de vie avant traitement, 3 semaines apres chirurgie, 2 mois apres arret de la radiotherapie, 6 mois apres debut d’une chimiotherapie puis tous les 6 mois. Des analyses descriptives, des tests non parametriques (correlations bilan cognitif — qualite de vie) ont ete realises. Resultats Seize patients (âge moyen : 39,69 ± 13,79), ont ete suivis en moyenne 8 ± 4 mois. Au premier bilan, les troubles cognitifs les plus souvent observes etaient des difficultes en attention divisee, memoire episodique et fluence non verbale. Tous les patients avaient au moins un domaine cognitif perturbe. La qualite de vie etait associee au nombre de domaines cognitifs atteints. Aucun changement significatif n’etait observe a 6 mois sur les bilans cognitifs et la qualite de vie. Discussion Certains troubles etaient communs malgre des topographies lesionnelles et des grades differents. Des tests rapides d’evaluation globale ne suffisaient pas a les mettre en evidence. Il est important d’utiliser des tests adaptes puisqu’il existe des relations entre troubles cognitifs, evolution clinique et qualite de vie. Les traitements n’avaient pas d’effets deleteres a six mois. Conclusion Les troubles cognitifs, touchant notamment la memoire, l’attention et les fonctions executives sont frequents dans cette population. Il est necessaire de les rechercher systematiquement par des tests adaptes.