Annual Clinic Assembly May 6, 2016

Transcription

1 Annual Clinic Assembly May 6, 2016 Raymond Maguire DO Assistant Professor of Otolaryngology Childrens Hospital of Pittsburgh of UPMC Libby Smith DO Associate Professor of Otolaryngology University of Pittsburgh Voice Center Ankur Patel DO, MPH Assistant Professor of Otolarygology Childrens Hopsital of Los Angeles

2 Recurrent Respiratory Prevalence 1 4 per 100,000 Juvenile vs adult (age 12) Cost Lifetime cost for 1 pt: $60000 $ $150 million annual cost for care in US Impact 10,000 15,000 procedures per year in US Avg 4.4 procedure per pt annually Papillomatosis

3 Virology 10 20% of US population aged yrs are DNA positive 60% women of child bearing age are antibody positive and DNA negative Limited to basal cells of stratified epithelium only place the virus may replicate Papillomas occur in areas of transitional mucosa Vestibula nasi Distal soft palate True vocal folds Tracheostomy stoma

4 The Virus Particle The virus shell or coat has 2 proteins L1 and L2 The virus shell consists of 72 pentamers each of 5 molecules of L1 that stud the surface of the particle L2 sits deep in the dimple in the centre of the rosette Virus neutralizing antibodies recognize conformational epitopes in L1 Neutralizing antibodies to L2 are not made in natural infections

5 Transmission Pediatric Vertical transmission mother to child 231 fold increased risk of developing RRP when children born to mothers with active condylomata. 2 fold higher risk with 10+ labor secondary factors: patient immunity; timing, length, and volume of virus exposure; and local traumas (intubation, extra esophageal reflux Adult Sexual contact Higher number of sexual partners Increased frequency of oral sex? reactivation of HPV vs de novo exposure

6 Staging System Derkay Derkay C, Malis D, Zalzal G, Wiatrak B, Kashima H, Coltrera M. A staging system for assessing severity of disease and response to therapy in recurrent respiratory papillomatosis. Laryngoscope. 1998;108:

7 FDA approved HPV vaccines Manufacturer (Trade name) Vaccine types Cervical vaccine efficacy Merck (Gardasil) GlaxoSmithKline (Cervarix) HPV16 and 18 HPV6 and 11 quadrivalent 90% of Genital Warts HPV16 and 18 bivalent >95% >95% Both vaccines were tested and approved using a 3-dose regimen

8 Vaccination Gardasil tm Quadrivalent HPV vaccine Serotypes 6,11,16,18 Indications: CDC recommends routine boys and girls age Offer for females aged Offer for males aged Approved for use in children age 9 (boys and girls) 3 injections over 6 months New one in the works (8 9 valent)

9 Pediatric Case 3 yr old boy presents to the ED with worsening stridor and retraction over the past several days. No recent illnesses He is a child born term with no significant past medical or surgical history. Mom states that ever since he started to speak he had a hoarse voice.

10 Pediatric Case Office Work up Any child that presents to the office with prolonged dysphonia, stridor, and chronic cough get a flexible laryngoscopy. OR or observation depends on amount of obstruction and airway symptoms

11 Pediatric Case A flexible laryngoscopy was performed in the ED. Decision was made to take the pt to the OR urgently.

12 Pediatric Case OR Set up Parsons vs Lindholm laryngoscopy in suspension Pt spontaneously breathing with ETT in hypopharynx Depending on pt, the modality in which the papilloma is removed is chosen.

13 Pediatric Case

14 Pediatric Case A microdebrider was used to debulk the papilloma. No adjuvant therapy was used during initial procedure

15 Pediatric Case Microdebrider vs cold knife vs coblator Laryngeal skimmer 2.9 and 3.5, 500 osc Limited literature on coblator in pediatric popultion, mostly case reports/series. Use technique which is you are most comfotable with.

16 Pediatric Case Lasers used in RRP CO2 Largely absorbed by water Used more for cutting/ablation PDL-585nm KTP-532nm

17 Clark A. Rosen MD, FACS Director and Professor University of Pittsburgh Voice Center Department of Otolaryngology Voicecenter.upmc.com Annual Clinical Assembly RRP panel, 5/6/2016

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19 Peds Adult 16 yo AA female age sx from

20 Adult 52 yo WM age 25 Sx q 6 12mo

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22 Narrow Band Imaging Blood vessels 415 nm: penetrate superficial mucosa. Capillaries brown color 540 nm: penetrate deeper within mucosal layers. cyan

23 Technology Cold knife CO2 Microdebrider KTP (in office?)

24 Is it a good idea?? Ease for patient/surgeon Tolerated RRP Location Young VN, Smith LJ, Sulica L, Krishna P, Rosen CA. Patient tolerance of awake, in office laryngeal procedures: a multiinstitutional perspective. Laryngoscope Feb;122(2): Centric A, Hu A, Heman Ackah YD, Divi V, Sataloff RT. Office based pulsed dye laser surgery for laryngeal lesions: a retrospective review. J Voice Mar;28(2):262.e9 262.e12.

25 OR in office $5000+ Rees CJ, Postma GN, Koufman JA. Cost savings of unsedated officebased laser surgery for laryngeal papillomas. Ann Otol Rhinol Laryngol Jan;116(1):45 8. Insurance reimbursement??

26 KTP Smart laser Angiolytic Photothermolysis ablative

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29 16 yo: intra op

30 16 yo: post op

31 52 yo: intra op

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33 Prospective open label study 33 patients 1/3 with complete response 1/3 with partial response 1/3 with no response

34 Indol 3 Carbinol (I3C) Found in cruciferous vegetables Alters estrogen metabolism Blocks P450 slow growth 1/3 1/3 1/3

35 Cidofovir Anti viral, cytotoxic Off label use Controversy: Malignant transformation? AdenoCA in rats IV: nephrotoxicity, neutropenia, ocular toxicity Intralesional: scarring? But SAFE < 3mg/kg, 7.5mg/ml, q2 4 wks x 3+ Studies: improved Derkay Score? and longer surgical intervals OR office

36 Bevacizumab (Avastin) FDA Approval 2004 Humanized monoclonal antibody Inhibits vascular endothelial growth factor A (VEGF A) angiogenesis inhibitor Half life 20 days Systemic (CA): bleeding, HTN, bowel perf, nasal septal perf, renal thrombotic microangiopathy, necrotizing fasciitis

37 Does it work? 25mg/cc, q6wks x 4+ Avastin + KTP Zeitels 2009, 2011 Ann Otol Rhinol Laryngol mg total Best 2012 Ann Otol Rhinol Laryngol

38 Celecoxib (Celebrex) Selective COX 2 inhibitor Sulfonamide Indications: OA, RA, dysmenorrhea, AS, FAP 50, 100, 200 or 400 mg Black box warnings for CV risk and GI complications Drug Interactions: Metabolized by P450 2C9 (caution with other 2C9 inhibitors such as fluconazole. May increase risk of renal failure with ACEI and diuretics

39 Celecoxib and RRP 2/3 patients in pilot study (200 mg BID for 6 months) followed for 5 years had extended remission time, 3 rd patient disease free at 4.5 years (Lucs 2012 Mol Med) T H 2 cytokines increased in papilloma and T H 1 cytokine decreased in papilloma suggesting active HPV infection shifts T H 1/ T H 2 profile to T H 2 state (Rosenthal 2012 Mol Med)

40 Adult onset 33 yo AA female 6 mo hx progressive hoarseness PMHx: DM, HTN, AR HIV Researcher

41 RRP Sx ~q 6 mo x 3 years Low risk HPV Developed cough after 2 nd surgery Subglottis clean Adjunctive treatment I3C Cidofovir (spaced apart)

42 3 yrs later Cough worsening During in office KTP procedure, bronch for cough tracheal RRP Now sxq4 6weeks

43 Extra Case

44 Voice Center Objectives Review Vaccine Adjuvant treatments Advances in technology Discussion

45 This image cannot currently be displayed. HPV, Vaccination, Head and Neck Neoplasms Robert L. Ferris, MD, PhD

46 Efficacy: 100% Efficacious Against HPV 16 and 18 Related Cervical Cancer Precursors PPE; subjects were naïve to HPV Types 6, 11, 16, and/or 18 End Point: HPV 16/18- related CIN 2/3 or AIS CIN 3 or AIS n 8,48 7 8,48 7 GARDASIL or HPV 16 L1 VLP Cases* 0 0 n 8,460 8,460 Placebo Cases Combined Analysis Vaccine Efficacy 100% 100% 95% CI *Analysis of CIN 2/3 and AIS end points included protocol 005. Defined by FIGO as Stage 0 cervical cancers; FIGO = International Federation of Gynecology and Obstetrics. CIN 3 or AIS analysis was a secondary end point. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA Please specify information package (1)-GRD.

47 Immunogenicity of Quadrivalent HPV Vaccine: 5 Year Follow up GMT With 95% CI, mmu/ml (Log Scale) ** * 0 HPV 6/11/16/18 vaccine: (Sero (-) at Day 1 and PCR (-) to HPV 16 through Month 60) Vaccination Placebo: (Sero (+) at Day 1 and PCR (-) to HPV 16 through Day 1) Time Since Vaccination 1 (months)

48 HPV explains rising OP incidence Chaturvedi AK et al, J Clin Oncology 2011.

49 Observed and projected incidence rates of OP and cervical cancers (US) Chaturvedi AK et al, J Clin Oncology 2011.

50 Incidence of HPV associated cancers USA Jemal A, et al. J Natl Cancer Inst. 2013; vol 105

51 Costa Rica Vaccine Trial 7,466 Women years old Control vaccine Hepatitis A Vaccine Cervarix HPV-16/18 Vaccine Aimee Kreimer, PhD Herrero R et al Cancer Discovery 2011;1:408 Herrero R et al Vaccine 2008;26:4795

52 Costa Rica Vaccine Trial 7,466 Women years old Control vaccine Hepatitis A Vaccine Cervarix HPV-16/18 Vaccine Annual follow-up for 4 years Cervical samples collected at all visits Oral specimens collected at 4 year visit

53 Vaccine efficacy against oral HPV 16/18 infections 4 years of protection Arm # Women # HPV16/18 Infections HPV16/18 VE (95%CI) HPV Control % (63% to 100%) Herrero R et al PLOS ONE 2013

54 Age specific prevalence of oral HPV infection Prevalence = Incidence * Duration Gillison ML et al. JAMA 2012.

55 Duration of vaccine protection at different anatomic sites Noncervical sites Cervix Years of follow up 4 >8 Long-term follow-up studies are required

56 HPV infection preventative targeted therapy of SCCHN?

57 CD8 + T cell Antibody CD8 tibody vs ell cognition V ected s Class I MHC HPV L1 outer capsid

58 Shaum S. Sridharan, MD University of Pittsburgh Medical Center Department of Otolaryngology Grand Rounds May 21, 2014

59 Indole 3 Carbinol Found in cruciferous vegetables (broccoli, cabbage, brussel sprouts, cauliflower) Alters estrogen metabolism Blocks P450 Favors 2 hydroxyestrone over 16a hydroxyestrone

60 Prospective open label study 33 patients 1/3 with complete response 1/3 with partial response 1/3 with no response

61 Indol 3 Carbinol (I3C) Found in cruciferous vegetables Alters estrogen metabolism Blocks P450 slow growth 1/3 1/3 1/3

62 Cidofovir & RRP Anti viral medication, cytotoxic effect First used 1995 as an adjuvant treatment Off label use (controversy) Intravenous use associated with nephrotoxicity hematopoietic dysfunction (neutropenia) ocular toxicity Theoretical concern for scarring with intralesional use

63 Dosing Dose should remain below 3 mg/kg Different concentrations are used from mg/ml Most common concentration 7.5 mg/ml Most common volume 5 ml

64 Clinical Success Multiple retrospective studies demonstrate improved Derkay Scores and longer intervals between surgery Can be used as an adjuvant treatment or as a primary modality Can be administered in the operating room or in the office

65 Prospective enrollment of 19 adults patients Patients treated q4 weeks at 5 mg/ml Protocol changed to q2 weeks at 7.5 mg/ml Complete remission in 17 pts (89%) Better results with higher dosage 24 month follow up

66 19 consecutive patients enrolled Improvement in Derkay Score overall though no difference amongst groups Improvement in VHI score with cidofovir but not statistically significant

67 Cidofovir & Tumorigenicity Evidence of adenoca in rats Could not be replicated in primates Phase 1 and 2 human trials could not show increased CA risk with intravenous cidofovir Numerous clinical publications with intra lesional injection demonstrating safety Safety of intralesional cidofovir in patients with recurrent respiratory papillomatosis: an international retrospective study on 635 RRP patients. Tjon Pian Gi RE1, Ilmarinen T, van den Heuvel ER, Aaltonen LM, Andersen J, Brunings JW, Chirila M, Dietz A, Ferran Vilà F, Friedrich G, de Gier HH, Golusinski W, Graupp M, Hantzakos A, Horcasitas R, Jackowska J, Koelmel JC, Lawson G, Lindner F, Remacle M, Sittel C, Weichbold V, Wierzbicka M, Dikkers FG.

68 13 patients reviewed Biopsy before and after treatment Varying pathology results 57% with mild dysplasia 28% with moderate dysplasia 8% with severe

69 Cidofovir Anti viral, cytotoxic Off label use Controversy: Malignant transformation? AdenoCA in rats IV: nephrotoxicity, neutropenia, ocular toxicity Intralesional: scarring? But SAFE < 3mg/kg, 7.5mg/ml, q2 4 wks x 3+ Studies: improved Derkay Score? and longer surgical intervals OR office

70 Benjamin L. Hodnett, MD, PhD University of Pittsburgh Medical Center Department of Otolaryngology Grand Rounds May 21, 2014

71 Bevacizumab Trade Name: Avastin FDA Approval 2004 Humanized monoclonal antibody First clinically available angiogenesis inhibitor in US Inhibits vascular endothelial growth factor A (VEGF A) Half life 20 days Oncology: Colon, lung, renal, brain Ophthalmology: MD, DR

72 Drug Administration Cancer: IV every 14 days Investigational: intraarterial for brain tumors Eye disease: intravitreously (dosage mg, ml of 25 mg/ml solution)

73 Side Effects Systemic Hypertension Increased risk of bleeding Bowel perforation Nasal septum perforation Renal thrombotic microangiopathy Necrotizing fasciitis (52 cases from , 17 deaths)

74 Microlaryngoscopic and Office Based Injection of Bevacizumab (Avastin) to Enhance 532 nm Pulsed KTP Laser Treatment of Glottal Papillomatosis Pilot study of 1o adult patients with recalcitrant glottal RRP and prior angiolytic laser treatment Supepithelial injections of 5 10 mg bevacizumab along with pulsed KTP 4 6 weeks apart until optimal voice function obtained (laser discontinued) 90% reduction in recurrence and improvement in vocal function 40% resolution, 40% limited recurrence (injections alone), 20% required periodic injections/ktp Zeitels 2009 Ann Otol Rhinol Laryngol

75 Local Injection of Bevacizumab (Avastin) and Angiolytic KTP Laser Treatment of Recurrent Respiratory Papillomatosis of the Vocal Folds: A Prospective Study Prospective study of 20 adult patients with bilateral vocal fold RRP KTP treatments 4 times at least 6 week intervals (total 6 months) Vocal fold with greater volume disease initially injected with 4 serial bevacizumab injections ( mg) Improved vocal parameters No local/systemic complications 15% no disease, 80% less disease, 5% more disease Zeitels 2011 Ann Otol Rhinol Laryngol

76 Safety and Dosing of Bevacizumab (Avastin) for the Treatment of Recurrent Respiratory Papillomatosis Ranges from mg total No clinical complications (local or systemic) No local wound problems Best 2012 Ann Otol Rhinol Laryngol

77 Does it work? 25mg/cc, q6wks x 4+ Avastin + KTP Zeitels 2009, 2011 Ann Otol Rhinol Laryngol mg total Best 2012 Ann Otol Rhinol Laryngol

78 Celecoxib Trade Name: Celebrex, Celebra, Onsenal FDA Approval 1998 NSAID Selective COX 2 inhibitor Sulfonamide Indications: OA, RA, dysmenorrhea, AS, FAP 50, 100, 200 or 400 mg Dosage varies by indication Black box warnings for CV risk and GI complications

79 Side Effects Anaphylactoid Reactions (controversial) Appears to be safe in patients with NSAID induced anaphylactoid reactions (Quiralte 2004 Ann Allergy Asthma Immunol) Appears to be safe in patients with syndrome of asthma and aspirin intolerance (Dahlén 2001 N Engl J Med) Reported 4% incidence of cutaneous reactions in persons who have similar reactions to aspirin or nonselective NSAIDs May cause allergic reaction in patients allergic to sulfonamides Drug Interactions: Metabolized by P450 2C9 (caution with other 2C9 inhibitors such as fluconazole. May increase risk of renal failure with ACEI and diuretics Pregnancy: Category C prior to 30 weeks gestation, Category D afterwards

80 Celecoxib and RRP 2/3 patients in pilot study (200 mg BID for 6 months) followed for 5 years had extended remission time, 3 rd patient disease free at 4.5 years (Lucs 2012 Mol Med) T H 2 cytokines increased in papilloma and T H 1 cytokine decreased in papilloma suggesting active HPV infection shifts T H 1/ T H 2 profile to T H 2 state (Rosenthal 2012 Mol Med) T H 2 cytokines overexpressed in plasma of patients with RRP and plasma CCL18 levels decrease in correlation with disease severity with celecoxib treatment (Rosenthal 2012 Mol Med)