Efficacy of Chemotherapy Plus Bevacizumab in Recurrent Glioblastoma Multiform: A Real-life Study.

BACKGROUND/AIM: Bevacizumab and chemotherapy are used in glioblastoma multiforme (GBM) relapse. However, the choice of chemotherapeutic agent remains an open question and this study aimed to evaluate the efficacy and safety of different combinations. PATIENTS AND METHODS: Between June 2005 and August 2020, all patients treated with chemotherapy plus bevacizumab (BVZ) for recurrent glioblastoma in the Georges-François Leclerc Cancer Center, Dijon, France were included in this retrospective comparative study. The primary objective was progression-free survival (PFS) and as secondary objectives, overall survival (OS), disease control rate (DCR), and safety were investigated. Factors associated with response were also analyzed. RESULTS: A total of 160 patients were screened: 100 received fotemustine plus BVZ (62%) and 62 (38%) received another cytotoxic agent plus BVZ: 35 (22%) irinotecan (IRI), 18 (11%) temozolomide (TEM), and 7 (4%) lomustine (LOM). In the whole population, median PFS was 4.47 months, median OS was 9 months, and 3-month DCR was 51%. Regarding survival according to treatment, median OS was significantly lower in the fotemustine group compared to that in other cytotoxic agents: 7.3 vs. 19.9 months. In the fotemustine group, steroids use at baseline and low Karnofsky performance status were associated with poor median OS. Grade 3-4 adverse events were found in 21.9%, with no difference between groups, but 7 patients had grade 5 adverse events in the fotemustine group. CONCLUSION: Using real-life data, this study showed lower efficacy of fotemustine and bevacizumab, as compared to IRI or TEM or LOM-BVZ combinations.

The molecular landscape of glioma in patients with Neurofibromatosis 1.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.

Hypofractionated Stereotactic Radiotherapy as a Salvage Therapy for Recurrent High-Grade Gliomas: Single-Center Experience.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the survival outcomes and safety of hypofractioned stereotactic radiotherapy as a salvage treatment for recurrent high-grade glioma. PATIENTS AND METHODS: Between March 2012 and March 2017, 32 consecutive patients (12 women, 20 men) treated in a single center were retrospectively included in this study. Grade III gliomas were diagnosed in 14 patients and grade IV in 18 patients. Thirty-four lesions were treated with hypofractionated stereotactic radiotherapy on a linear accelerator. Hypofractionated stereotactic radiotherapy delivered a median dose of 30 Gy (27-30) in 6 fractions (3-6) of 5 Gy (5-9). The treatment plans were normalized to 100% at the isocenter and prescribed to the 80% isodose line. Clinical outcomes and prognostic factors were analyzed. RESULTS: Median follow-up was 20.9 months. Median overall survival following hypofractionated stereotactic radiotherapy was 15.6 months (median overall survival for patients with glioblastoma and grade III glioma was 8.2 and 19.5 months, respectively; P = .0496) and progression-free survival was 3.7 months (median progression-free survival for patients with glioblastoma and grade III glioma was 3.6 and 4.5 months, respectively; P = .2424). In multivariate analysis, tumor grade III ( P = .0027), an Eastern Cooperative Oncology Group status <2 at the time of reirradiation ( P = .0023), and a mean dose >35 Gy ( P = .0055) significantly improved overall survival. A maximum reirradiation dose above 38 Gy ( P = .0179) was significantly associated with longer progression-free survival. CONCLUSION: Hypofractionated stereotactic radiotherapy is well tolerated and offers an effective salvage option for the treatment of recurrent high-grade gliomas with encouraging overall survival. Our results suggest that the dose distribution had an impact on survival.

Immune classifications with cytotoxic CD8+ and Th17 infiltrates are predictors of clinical prognosis in glioblastoma.

BACKGROUND: Interest is growing on immune cells involvement in central nervous system tumors such as glioblastoma. Even if a few reports highlighted that immune classifications could have a prognostic value, no paradigm has been clearly yet established on large and homogeneous cohorts. The aim of our study was to analyze the prognostic role of the in situ immune response of cytotoxic T cells (i.e., CD8+), Foxp3 cells, Th17 and tumor-associated macrophages in glioblastoma on two independent large and homogeneous cohorts. METHODS: We worked on two large homogenous cohorts of patients having glioblastoma who underwent standard radiochemotherapy. The first cohort of 186 patients was analyzed using IHC procedures (CD8+, IL-17A, FoxP3 and CD163) of surgery pieces. We next worked with transcriptomic data available online and used metagene strategy analysis for the second cohort of 525 patients. RESULTS: Cytotoxic CD8+ lymphocytes and Foxp3 cells were associated with a good prognosis, while Th17 were associated with a poor clinical outcome. These data were confirmed with transcriptomic analysis. Moreover, we showed for the first time a strong link between angiogenesis and Th17 metagenes expressions in glioblastoma. CONCLUSIONS: Our study shows that glioblastoma bearing patients can be classified on the immune infiltrate aspects. Beyond this prognostic role of immune biomarkers, subsequent classifications could definitely help clinicians to handle targeted therapy administration and immunotherapeutic interventions.

Natural course and prognosis of anaplastic gangliogliomas: a multicenter retrospective study of 43 cases from the French Brain Tumor Database.

Background: Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Methods: Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Results: Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. Conclusions: We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

[Place of surgery in brain metastases]. / Place de la chirurgie dans les métastases cérébrales.

Surgical excision in brain metastases has been well evaluated in unique metastases. Two randomized phase III trials have shown that combined with adjuvant whole brain radiotherapy, it significantly improves overall survival. However, even in the presence of multiple brain metastases, surgery may be useful in large, symptomatic or life-threatening lesions (posterior fossa tumor with mass effect). Also, even in lesions amenable to radiosurgery, surgical resection is preferred when tumors displayed cystic or necrotic aspect with important edema or when located in highly eloquent areas or cortico-subcortically. Furthermore, surgery may have a diagnostic role, in the absence of histological documentation of the primary disease, if the radiological aspect is atypical to rule out differential diagnosis (brain abscess, lymphoma, primary tumor of the central nervous system) or in case of suspicion of progression after irradiation to differentiate radionecrosis from a genuine progression of brain disease. Finally, the issue of biological documentation of brain disease may arise in situations where a specific targeted therapy can be proposed. If the surgical indications are relatively well defined, the selection of patients who will really benefit from surgery should take into account three factors, clinical and functional status of the patient, systemic disease status and characteristics of intracranial metastases. Given the improved survival of cancer patients due to the advent of effective targeted therapies on systemic disease, a renewed interest has been given to local therapy (surgery or radiosurgery) in brain metastases. Surgical resection currently represents a valuable tool in the armamentarium of brain metastases but has also become a diagnostic and decision tool that can affect therapeutic strategies in these patients.