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Background The World Health Organization (WHO) adult glioma grading system is questionable in pediatric high-grade gliomas (pHGGs), which are biologically distinct from adult HGGs. We took advantage of the neuropathological review data obtained during one of the largest prospective randomized pHGG trials, namely HERBY (NCT01390948), to address this issue in children with newly diagnosed non-brainstem HGG. Methods HGG diagnosis was confirmed by pre-randomization, real-time central pathology review using WHO 2007 criteria, followed by a consensus review blinded to clinical factors and outcomes. We evaluated association between WHO 2007 grade and other clinical/radiological/biological characteristics and the prognostic value of WHO 2007 grade, midline location, and selected biomarkers (Ki-67 index/Olig2/CD34/EGFR/p53/H3F3A K27M mutation) on overall survival. Results Real-time central neuropathological review was feasible in a multicenter study, with a mean time of 2.4 days, and led to the rejection of HGG diagnosis in 20 of 163 cases (12.3%). The different grading criteria and resulting WHO grade were not significantly associated with overall survival in the entire population (n = 118) or in midline and non-midline subgroups. H3F3A K27M mutation was significantly associated with poor outcome. No significant prognostic value was observed for grade, even after regrading H3F3A K27M-mutated midline glioma as grade IV (WHO 2016). Midline location and a high Ki-67 index (≥20%) were associated with poor outcome (P = 0.004 and P = 0.04, respectively). A 10% increase in Ki-67 index was associated with a hazard ratio of 1.53 (95% CI: 1.27–1.83; P < 0.0001). Conclusion Our findings suggest that WHO grade III versus IV has no prognostic value in pediatric HGG.

International audience; When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab's initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies. In the past 15 years, our understanding of VEGF's role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive. Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.

International audience; Background:Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI), portal hypertension, and splenic sequestration of platelets. Evidence suggests that bevacizumab may protect against HSI.Methods:Two cohorts of metastatic colorectal cancer (CRC) were analyzed: a nonrandomized exploratory cohort of 184 patients treated at a single institution from 2003 to 2010 and a confirmatory cohort of 200 patients from a multi-institutional randomized trial (NO16966). All patients were treated with frontline fluoropyrimidine and oxaliplatin with or without bevacizumab. Changes in splenic volumes and platelet counts were compared by treatment, two-sided log-rank test.Results:In the exploratory cohort, the bevacizumab-treated patients (n = 138) compared with the nonbevacizumab-treated patients (n = 46) demonstrated a longer median time to splenic enlargement (≥30%, P = .02) and reduced rate of thrombocytopenia (

Colorectal cancer is the third most common cancer worldwide. A significant proportion of patients presents with unresectable metastatic disease or develops metachronous metastases following surgical resection of the primary tumor. The prognosis of the disease has improved over the past two decades, with extended multimodality treatment options and the development of increasingly intensified chemotherapy regimens that now typically include targeted biologics. A recent advance in therapy is a treatment regimen composed of three chemotherapeutic agents (i.e., triplet chemotherapy: 5-fluorouracil [5-FU]/leucovorin [LV], oxaliplatin, and irinotecan; FOLFOXIRI) in combination with the vascular endothelial growth factor inhibitor bevacizumab. This regimen has been shown to elicit significantly improved objective response rates and median progression-free survival compared with 5-FU/LV and irinotecan in combination with bevacizumab. However, triplet chemotherapy has been associated with increased rates of chemotherapy-related adverse events, and treatment-emergent adverse events should be properly managed to minimize treatment interruption or discontinuation. We present herein a review of clinical studies evaluating the safety and efficacy of FOLFOXIRI with bevacizumab in metastatic colorectal cancer, and propose a practical guide for the management of adverse events associated with the regimen. Support for third-party medical writing assistance was provided by Genentech, Inc.

The objective of the study was to describe the effect of adjuvant bevacizumab on symptomatic lymphoceles in advanced ovarian cancer after optimal surgery. The effect of bevacizumab on survival was also studied in this cohort. This retrospectivestudy included patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics FIGO 1988 stages IIIB, IIIC, IV) and who had cytoreductive surgery with pelvic and lombo-aortic lymphadenectomy in Gustave Roussy Institute from 2005 to 2014. 255 patients were included. The rate of symptomatic lymphocele was 33.6% (85 out of 253). 61 patients (24.5%) received adjuvant bevacizumab. In multivariate analysis, bevacizumab wasn’t associated with the risk of symptomatic lymphocele wtih hazard ratio at 1.62 (IC95%= 0.87-3.01, p=0.12). The bevacizumab had an impact on disease free survival (DFS) with hazard ratio at 0.6 (IC95%= 0.41-0.91, p=0.01) and the median DFS was 31.7 months in bevacizumab group and 23 months in the control group. In conclusion, bevacizumab wasn’t associated with the risk of symptomatic lymphocele in our study but it had an impact on DFS in patients and prolonged the median DFS by about 9 months in patients with advanced ovarian cancer and complete surgery. Further studies are needed to confirm this result.; L’objectif de cette étude est d’évaluer l’impact du bevacizumab adjuvant sur la lymphocèle symptomatique chez des patientes atteintes d’un cancer de l’ovaire de stade avancé ayant eu une chirurgie complète. L’impact du bevacizumab sur la survie sera ensuite étudié chez ces mêmes patientes. Cette étude rétrospective incluait des patientes atteintes d’un cancer de l’ovaire de stades FIGO (Fédération Internationale de Gynécologie Obstétrique) 1988 IIIB, IIIC et IV ayant été opérées d’une cytoréduction complète avec curages pelviens et lombo-aortique à l’Institut Gustave Roussy entre 2005 et 2014. 255 patientes ont été incluses dans l’étude. Le taux de lymphocèle symptomatique était de 33,6% (85/253). 61 patientes ont été traitées par bevacizumab adjuvant, soit 24,5% des patientes. En analyse multivariée, le traitement par bevacizumab n’était pas significativement associé à la présence d’une lymphocèle symptomatique avec un hazard ratio (HR) à 1,62 (IC95%=0,87-3,01) p=0,12). Le bevacizumab adjuvant avait un impact significatif sur la survie sans récidive avec un HR à 0,6 (IC95%=0,41-0,91 et p=0,01) et la survie médiane sans récidive passait de 23 à 31,7 mois. En conclusion, le bevacizumab n’a pas d’impact sur la survenue de la lymphocèle postopératoire mais a un impact sur la survie sans récidive avec un gain de 8,7 mois dans cette cohorte de patientes de stade avancé et opérées d’une chirurgie complète, ce qui nécessite une confirmation par des essais thérapeutiques.

International audience; BACKGROUND:The combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC.PATIENTS AND METHODS:Patients received bevacizumab 7.5mg/kg on day 1 plus XELIRI (irinotecan 200mg/m(2) on day 1 and oral capecitabine 1,000 mg/m(2) bid on days 1-14) every 3 weeks or bevacizumab 5mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400mg/m(2) on day 1 plus 2,400 mg/m(2) as a 46-h infusion, leucovorin 400mg/m(2) on day 1, and irinotecan 180 mg/m(2) on day 1) every 2 weeks. Patients aged ≥ 65 years received a lower dose of capecitabine (800 mg/m(2) twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate.RESULTS:A total of 145 patients were enrolled (bevacizumab-XELIRI, n=72; bevacizumab-FOLFIRI, n=73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71-90%) in the bevacizumab-XELIRI arm and 85% (95% CI 75-92%) in the bevacizumab-FOLFIRI arm. In both the bevacizumab-XELIRI and bevacizumab-FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab-XELIRI 18%; bevacizumab-FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively).CONCLUSIONS:This randomised non-comparative study demonstrates that bevacizumab-XELIRI and bevacizumab-FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles.