Bevacizumab (Avastin) Neus Spray voor Frequente Neusbloedingen bij ROW Proefbehandeling F.S. van der Meer, MD St Antonius hospital Nieuwegein,, The Netherlands

ROW en neusbloedingen (epistaxis) > 90% terugkerende epistaxis Frequent ijzer and bloedtransfusies Verstoort dagelijkse leven en werk Meeste behandelingen hebben tijdelijk effect of veel bijwerkingen Laser, embolisation, surgery: Saunders Estrogen (de pil), - Thalidomide |

Bevacizumab (Avastin) Eerder onderzoek: Patienten met ROW hebben verhoogde spiegels van VEGF (oa Saddic et al, 2005) Menselijk antilichaam Bind aan en remt VEGF activiteit Iremt vaatgroei |

Eerdere Bevacizumab publicaties, lokale toepassing Davidson TM, Olitsky SE, Wei JL. Hereditary hemorrhagic telangiectasia/avastin Laryngoscope 2010: Case report, male 45 yrs, HHT, recurrent epistaxis Injection submucosal 100mg Bevacizumab <1 wk epistaxis stopped effect: 3-4 months Nasal spray 10mg/ml, 2wk, total 50mg effect 3-4 months Nasal spray 25mg/ml, every 30min 1 spray till 25mg effect 2.5 months Promising effects |

Eerdere Bevacizumab publicaties, lokale toepassing Karnezis TT, Davidson TM. Efficacy of intranasal Bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis Laryngoscope 2011: 32 patients: 17 topical, spray, 50-100mg, 10 submucosal injection, 100mg (125mg), 5 topical spray and submucosal injection, 12/32 also KTP laser Follow-up: ESS before treatment and 2-18 (mean 4.1) months after treatment Results: ESS pre treatment 7.0, after treatment: 2.9 ( 17 topical: 6.6- 3.6, 10 submucosal 8.1- 2.1) Promising effects |

Eerdere Bevacizumab publicaties, lokale toepassing Veiligheid Chen S 4th, Karnezis T, Davidson TM. Safety of intranasal Bevacizumab (avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope 2010: 52 patients, treated with bevacizumab intranasally applied, some on mutiple occasions Topical spray, 50-100mg Bevacizumab (26) KTP 0 Submucosal injection, 25-100mg bevacizumab, (34), also KTP (30) Follow-up 1.5-46 months after treatment: 5 septal perforation (all combined submucosal injection and KTP laser) No other common or serious event |

Proefbehandeling Bevacizumab nasal spray Solution 25mg/ml, dose 0.1ml (2.5mg) Daily use: 2dd1 both sides (0.4ml=10mg) Treatment duration: 1 week (70mg) Inclusion of 8 HHT patients with recurrent epistaxis All signed informed consent Diary of epistaxis during 4 weeks before treatment and 4 weeks after treatment Validated in previous studies Hb, ferritin levels before and after treatment Video of nasal mucosa before and after treatment June and August 2011: 2 and 4 months after treatment evaluation 4 weeks diary, hb/iron/ferritine levels |

Pilot treatment Bevacizumab nasal spray Solution 25mg/ml, dose 0.1ml (2.5mg) Daily use: 2dd1 both sides (0.4ml=10mg) Treatment duration: 1 week (70mg) Inclusion of 8 HHT patients with recurrent epistaxis All signed informed consent Diary of epistaxis during 4 weeks before treatment and 4 weeks after treatment Validated in previous studies Hb, ferritin levels before and after treatment Video of nasal mucosa before and after treatment June and August 2011: 2 and 4 months after treatment evaluation 4 weeks diary, hb/iron/ferritine levels |

Pilot treatment Bevacizumab nasal spray Solution 25mg/ml, dose 0.1ml (2.5mg) Daily use: 2dd1 both sides (0.4ml=10mg) Treatment duration: 1 week (70mg) Inclusion of 8 HHT patients with recurrent epistaxis All signed informed consent Diary of epistaxis during 4 weeks before treatment and 4 weeks after treatment Validated in previous studies Hb, ferritin levels before and after treatment Video of nasal mucosa before and after treatment June and August 2011: 2 and 4 months after treatment evaluation 4 weeks diary, hb/iron/ferritine levels |

Pilot treatment Bevacizumab nasal spray Solution 25mg/ml, dose 0.1ml (2.5mg) Daily use: 2dd1 both sides (0.4ml=10mg) Treatment duration: 1 week (70mg) Inclusion of 8 HHT patients with recurrent epistaxis All signed informed consent Diary of epistaxis during 4 weeks before treatment and 4 weeks after treatment Validated in previous studies Hb, ferritin levels before and after treatment Video of nasal mucosa before and after treatment June and August 2011: 2 and 4 months after treatment evaluation 4 weeks diary, hb/iron/ferritine levels |

Inclusion Patients (8) Age (yrs) Sex (m/f) Type HHT Previous treatments Iron/bloodtransfusions 1 68 m HHT-1 Laser Argonlaser Iron and blood iv every 3wks 2 f Septumbutton Oral iron 3 Saunders Thalidomide stopped 2009 Sitaglyptine 4 60 HHT-2 Estrogen 5 Embolisation Thalidomide stopped 2-25-2011 Iron iv every week 6 51 Weekly visit ENT - 7 72 8 septumbutton Mean 64.4 50% male 50% HHT-1 Sitagliptine: |

Results Freq epistaxis/day Duration of epistaxis min/day Severity of epistaxis 1-2-3 Patients opinion of bleeding before after diff Before During treatment After treatment 1 2.9 2.6 -0.3 9.6 13 +3.4 1.3 1.6 +0.3 = Shorter 2 1.5 0.6 -0.9 77.0 33.9 -43.1 2.7 Heavy bleeding Less freq 3 3.0 2.1 30.1 15.1 -15 2.4 -0.2 More bleeding Less freq less severe 4 1.0 15.6 8.8 -6.8 1.1 +0.1 5 0.9 12.6 80 +67.4 Severe bleeding Less severe, wholeday bleeding 6 3.7 -2.8 6.1 -3.1 Less 7 0.5 0.2 7.4 2.5 -4.9 -0.1 Some bleeding 8 -0.5 42.0 14.6 -27.4 1.2 Median 1.55 0.95 14.1 13.0 1.64 1.63 -56% -50% +500% -52% -66% -65% p 0.757 / 0.065 p 0.049 Paired samples T-test |

Results Hb level Ferritin Patients opinion of bleeding patients before after Before During treatment After 1 7.2 6.8 23 34 = shorter 2 6.7 6.6 27 21 Heavy bleeding Less freq 3 7.0 7.6 14 25 More bleeding Less freq en severe 4 8.8 7.9 16 9.7 5 5.1 4.5 30 Severe bleeding, transfusion Less severe, wholeday bleeding 6 9.1 9.0 163 less Iron IV before last Hb/ferritin 7 7.8 15 13 Some bleeding Less 8 6.9 12 5.3 Mean 7.55 7.25 19.5 23 (21) |

Video before and after treatment No 4-5-8 |

Bijwerkingen Ernstige bijwerkingen Meer bloedneuzen tijdens gebruik neusspray(7) Misselijkheid tijdens gebruik neusspray(1) Moeheid(1) Ernstige bijwerkingen Ernstige bloeding warvoor opname en bloedtransfusie (1) |

Conclusies Mening van de patiënt: Tijdens de behandeling ervaarden 7/8 patienten meer bloedingen Na behandeling ervaarden 6/8 patientsen minder of minder ernstige bloedneuzen Dagboek evaluatie: Overall minder vaak en kortere duur bloedneuzen Geen verschil in ernst bloedarmoede en ijzervoorraad Geen relatie tussen behandelresultaat en mutatie HHT1 of HHT2 |

Discussion Application of bevacizumab: Dose of Bevacizumab Follow up Competence/execution of spray Spray type: lesions? Dose of Bevacizumab Previous reports: 25-100mg This report 70mg Follow up Previous effects: after one week (case report), evaluation after 2-18 months Extra follow-up planned after 2 and 4 months use Adverse events: Patient 5 stopped using thalidomide 5 weeks before treatment |

Bevacizumab Nasal Spray for Frequent Epistaxis in HHT, a pilot treatment Previous reports: positive effect Our treatment: Some positive signs Problems during application More research needed Study group size Effective dose Application RCT Long term effects NOSE: - Efficacy and safety |

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