Use of Bevacizumab in anticoagulated recurrent glioblastoma multiforme patients: An Australian experience Adrian Lee 1,2,3,4, Marina Kastelan 4,5, Helen Wheeler 2,4,5 1 Northern Cancer Institute, 2 Bill Walsh Cancer Research Laboratory, 3 Sydney Medical School, 4 Royal North Shore Hospital, Sydney, 5 Sydney Neuro-Oncology Group BACKGROUND Other adverse events (non clotting related) AIM & METHOD RESULTS Bleeding events 4 intracranial bleeding events were noted – 1 in the anticoagulated group and 3 in the non-anticoagulated group AnticoagulatedNon anticoagulated Grade 1 & 2Grade 3 & 4Grade 1 & 2Grade 3 & 4 Hypertension 6084 Proteinuria 1131 Bowel perforation 0300 Stroke (ischemic) 0100 Wound dehiscence 0020 Survival Length of survival post Bevacizumab commencement (months) Overall survival (months) Whole cohort (n=201) Anticoagulated (n=52) Anticoagulated prior to Bevacizumab (n=36) Anticoagulated post Bevacizumab (n=16) Not anticoagulated (n=149) DISCUSSION Overall, our retrospective data demonstrated that it is safe to add Bevacizumab to anticoagulated recurrent GBM cases, with NO increased risk of bleeding There were no significant correlation with other non clotting related adverse events There were 3 cases of bowel perforation when LMWH was used with Bevacizumab but it is unlikely anticoagulation would have contributed to these events and this is a known bevacizumab related adverse event Bevacizumab reduced dexamethasone dose in majority of cases by at least 50% - Minimising steroid induced side effects 26% of the cohort had VTE and were anticoagulated – consistent with historical data – not significantly increased despite the use of Bevacizumab Our data have also shown a survival difference of 1.8 months in favour of those who never clotted and never needed anticoagulation, however this was not statistically significant We also found those who developed VTE and started on anticoagulation prior to Bevacizumab did worse in survival compared to those who had clots after Bevacizumab was commenced (14.12 vs months) Our data is consistent with the accepted view that VTEs are associated with poorer survival in cancer patients and that early clotting events is possibly a marker for more aggressive disease This could ideally be correlated with molecular subtyping Prospective trials can be developed to examine if newer oral anticoagulants (NOACs) would be superior and safer than LMWH in targeting this population Translational research can expand on the interaction between clotting and angiogenesis and inflammation to determine the pathways involved in driving this malignant potential  High grade Gliomas affects approximately 1500 Australians per annum.  Following debulking surgery, most patients with grade IV Glioblastoma multiforme (GBM) are managed with 6 weeks concurrent Temozolomide (TMZ) and radiation followed by adjuvant TMZ  There is no formal consensus on management following progression.  High grade Gliomas (HGGs) are often complicated by the development of thromboembolic disease (VTE) with an incidence of up to 30% in some series.  The management of concurrent VTE and high GBM is medically challenging.  Perioperative prophylaxis remains highly variable with neurosurgeons concerned about the risk of intracranial haemorrhage.  GBM secrete high levels of vascular endothelial growth factor (VEGF) resulting in a network of unstable, leaky blood vessels that have a tendency to bleed.  In 2005, Bevacizumab (Bev)– a humanised monoclonal antibody against vascular epidermal growth factor (VEGF) – was found to have a major impact on GBM, and it was shown it could rapidly reduce cerebral oedema in many patients.  In Australia – Bevacizumab is approved for use in recurrent high grade Gliomas. Its use in the clinic is however constrained by high cost and lack of financial subsidy from insurers or government.  Previous experience in other tumour types identified VTE, haemorrhage, hypertension, proteinuria and would healing problems as known complications seen with Bevacizumab therapy  We undertook a retrospective chart analysis to evaluate the incidence and outcome VTE and haemorrhagic complications in patients with GBM receiving Bevacizumab for relapsed GBM  To document the safety and outcome of the use of concurrent low molecular weight heparin (LMWH) and bevacizumab in patients with relapsed GBM  We searched the RNSH neuro-oncology data base for patients who had received Bevacizumab for relapsed GBM. We included those treated from 2006 (when bevacizumab became available in Australia) to 2014  Inclusion criteria  Recurrent GBM patients (18 years old and over)  Bevacizumab used in 2 nd line (or later) setting We selected patients who were receiving LMWH concurrently with bevacizumab therapy. We reviewed medical records and imaging (CT and MRI) to document any evidence of hemorrhage during this period. Table 2 Patient characteristics – Anticoagulated vs Non anticoagulated AnticoagulatedNon anticoagulated Cases identified52149 Median age at start of Bevacizumab (yrs) 6157 Median time from end of radiation therapy to Bevacizumab commencement 7 months9.37months Median Bevacizumab dose used 9 mg/kg Median Dexamethasone dose at start of Bevacizumab 4 mg Median Dexamethasone dose at week 4 of Bevacizumab 2 mg1 mg Table 1 Patient characteristics Number of patients identified201 GenderMales 132 (66%) Females 69 (33%) Age (median)58 ECOG (median)2 Number of patients who were anticoagulated during Bevacizumab therapy 52 (26%) Venous thromboembolic events All 13 cases that recorded a VTE event post commencement of Bevacizumab did not have VTEs prior to starting Bevacizumab There were 3 cases of grade 3-4 VTE event 1 occurred prior to Bevacizumab commencement 2 occurred post Bevacizumab commencement Type of Venous thromboembolic events DVT36 PE5 DVT & PE11 Anticoagulated groupGrade 1-2Grade 3-4 Epistaxis30 Retroperitoneal haematoma01 Intracranial bleeding01