Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial.

Background: The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT â†’ TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population. Patients and methods: ARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses. Results: Median PFS was longer in arm A than in arm B (7.6 and 4.8 months, P = 0.003), but OS was similar (12.1 and 12.2 months, P = 0.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, P = 0.014) and proneural gene expression (HR 0.29, P = 0.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for age <70 years (HR 0.52, P = 0.018) and Karnofsky performance score 90%-100% (HR 0.51, P = 0.026). Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS (HR 1.73, P = 0.076). Conclusion: Efficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients. Molecular biomarkers may identify patients with preferential benefit from bevacizumab. Clinical trial registration number: NCT01443676.

Deep vein thrombosis and heterotopic ossification in spinal cord injury: a 3 year experience at the Swiss Paraplegic Centre Nottwil.

STUDY DESIGN: Retrospective review of patient data. OBJECTIVES: (i) To determine the incidence and time of deep vein thrombosis (DVT) under low molecular weight heparin (LMWH) prophylaxis in spinal cord injury (SCI), (ii) to determine the incidence and time of heterotopic ossification (HO) and (iii) to assess a possible aetiologic relationship in the pathogenesis of DVT and HO. SETTING: Swiss Paraplegic Centre, Nottwil. METHODS: We analyzed the incidence of DVT and HO in 1209 SCI patients (275 first rehabilitations) at the Swiss Paraplegic Centre Nottwil from 1998 to 2000. Clinical files and laboratory data were scrutinised for particularities preceding DVT and HO. RESULTS: The incidence of DVT was 6.55% for first rehabilitation compared to only 1.59% in all patients hospitalised. DVT was complicated by pulmonary embolism (PE) in 1.45% and 0.47% respectively. Incidence of HO was 8% for first rehabilitation and 1.82% for all patients hospitalised. In first rehabilitation patients the peak for DVT occurred around day 30 contrary to HO with a peak around day 120. In single patients HO was identified by MRI as a rapidly progressing process. Laboratory profiles were inflammatory in both HO and DVT. Increased physical activity preceding HO was observed in four patients. In two patients acute HO was complicated by ipsilateral DVT. CONCLUSION: Prophylaxis with LMWH and elastic stockings significantly reduces the frequency of DVT during first rehabilitation in SCI. DVT and HO are both associated with laboratory parameters of non-infectious inflammation. The later onset of HO coinciding with ongoing mobilisation, argues for a different pathogenetic mechanism. Acute HO of the hip region appears to favour ipsilateral DVT by well known thrombogenic mechanisms.