drs.maguire,patel,smith - recurrent respiratory · pdf file$60000‐$470000 $150 million ......
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Raymond Maguire DOAssistant Professor of OtolaryngologyChildrens Hospital of Pittsburgh of UPMC
Libby Smith DOAssociate Professor of OtolaryngologyUniversity of Pittsburgh Voice Center
Ankur Patel DO, MPHAssistant Professor of OtolarygologyChildrens Hopsital of Los Angeles
Annual Clinic Assembly May 6, 2016
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Recurrent Respiratory Papillomatosis
Prevalence 1‐4 per 100,000
Juvenile vs adult (age 12) Cost
Lifetime cost for 1 pt:$60000‐$470000 $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
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Virology 10‐20% of US population aged 15‐49 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
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Virus neutralizing antibodies recognize conformational epitopes in L1
Neutralizing antibodies to L2 are not made in natural infections
The virus shell or coat has 2 proteins L1 and L2
The Virus Particle
The virus shell consists of 72pentamers each of 5 moleculesof L1 that stud the surface of the particle
L2 sits deep in the dimple in the centre of the rosette
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TransmissionPediatric Adult 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
Sexual contact Higher number of sexual
partners Increased frequency of oral
sex ? reactivation of HPV vs de
novo exposure
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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;108:935‐937
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FDA‐approved HPV vaccines
90% of Genital Warts
Manufacturer(Trade name) Vaccine types Cervical vaccine
efficacy
Merck(Gardasil)
HPV16 and 18HPV6 and 11‘quadrivalent’
>95%
GlaxoSmithKline(Cervarix)
HPV16 and 18‘bivalent’ >95%
Both vaccines were tested and approved using a 3-dose regimen
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Vaccination Gardasiltm
Quadrivalent HPV vaccine Serotypes 6,11,16,18 Indications:
CDC recommends routine boys and girls age 11‐12 Offer for females aged 13‐26 Offer for males aged 13‐21 Approved for use in children age 9 (boys and girls)
3 injections over 6 months New one in the works (8‐9 valent)
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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.
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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
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Pediatric Case A flexible laryngoscopy
was performed in the ED.
Decision was made to take the pt to the OR urgently.
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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.
Pediatric Case
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Pediatric Case
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Pediatric Case A microdebrider was
used to debulk the papilloma.
No adjuvant therapy was used during initial procedure
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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.
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Pediatric Case Lasers used in RRP
CO2 Largely absorbed by water Used more for cutting/ablation
PDL-585nm KTP-532nm
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Clark A. Rosen MD, FACSDirector and Professor
University of Pittsburgh Voice CenterDepartment of Otolaryngology
Voicecenter.upmc.com
Annual Clinical Assembly – RRP panel, 5/6/2016
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Peds Adult 16 yo AA female Dx @ age 10 45 sx from 2007‐2013
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Adult 52 yoWM Dx @ age 25 Sx q 6‐12mo
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Narrow Band Imaging Blood vessels
415 nm: penetrate superficial mucosa. Capillaries brown color
540 nm: penetrate deeper within mucosal layers. “cyan”
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Technology Cold knife CO2 Microdebrider KTP (in‐office?)
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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 multi‐institutional perspective. Laryngoscope. 2012 Feb;122(2):315‐21.
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. 2014 Mar;28(2):262.e9‐262.e12.
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OR in‐office $5000+
Rees CJ, Postma GN, Koufman JA. Cost savings of unsedated office‐based laser surgery for laryngeal papillomas. Ann Otol RhinolLaryngol. 2007 Jan;116(1):45‐8.
Insurance reimbursement??
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KTP “Smart” laser Angiolytic Photothermolysis ablative
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16 yo: intra‐op
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16 yo: post‐op
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52 yo: intra‐op
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• Prospective open‐label study
• 33 patients
• 1/3 with complete response
• 1/3 with partial response
• 1/3 with no response
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Indol‐3‐Carbinol (I3C) Found in cruciferous vegetables Alters estrogen metabolism Blocks P450 slow growth
1/3 – 1/3 – 1/3
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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 DerkayScore? and longer surgical intervals
OR – office
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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
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Does it work? 25mg/cc, q6wks x 4+
Avastin + KTP Zeitels 2009, 2011 Ann Otol Rhinol Laryngol
15 – 88 mg total Best 2012 Ann Otol Rhinol Laryngol
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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
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Celecoxib and RRP 2/3 patients in pilot study (200 mg BID for 6 months) followed for 5 years had extended remission time, 3rd patient disease free at 4.5 years (Lucs 2012 Mol Med)
TH2 cytokines increased in papilloma and TH1 cytokine decreased in papilloma suggesting active HPV infection shifts TH1/ TH2 profile to TH2 state (Rosenthal 2012 Mol Med)
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Adult‐onset 33 yo AA female 6 mo hx progressive hoarseness
PMHx: DM, HTN, AR HIV Researcher
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RRP Sx ~q 6 mo x 3 years Low risk HPV Developed cough after 2nd surgery Subglottis “clean” Adjunctive treatment
I3C Cidofovir (spaced apart)
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3 yrs later… Cough worsening During in‐office KTP procedure, bronch for cough tracheal RRP
Now sx q4‐6weeks
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Extra Case
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Objectives Review Vaccine Adjuvant treatments Advances in technology Discussion
www.UPMC.com/voicecenterVoice Center
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HPV, Vaccination, Head and Neck Neoplasms
Robert L. Ferris, MD, PhDRobert L. Ferris, MD, PhD
This image cannot currently be displayed.
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Efficacy: 100% Efficacious Against HPV 16‐ and 18‐Related Cervical Cancer Precursors
93–100100%538,46008,48
7CIN 2/3 or AIS
88–100100%328,46008,48
7CIN 3 or AIS†‡
95% CI
Vaccine Efficacy
PlaceboCasesn
GARDASIL® or HPV 16
L1 VLP Cases*n
End Point:HPV 16/18-related
*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.
PPE; subjects were naïve to HPV Types 6, 11, 16, and/or 18
Combined Analysis
Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package 20651083(1)-GRD.
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Immunogenicity of Quadrivalent HPV Vaccine: 5‐Year Follow‐up
0
10
100
1000
10000
7 12 18 24 30 36 54 60
HPV 6/11/16/18 vaccine: (Sero (-) at Day 1 and PCR (-)to HPV 16 through Month 60)
Placebo: (Sero (+) at Day 1 and PCR (-)to HPV 16 through Day 1)Vaccination* * *G
MT
Wit
h 95
% C
I, m
MU
/mL
(Log
Sca
le)
Time Since Vaccination 1 (months)
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HPV explains rising OP incidence
Chaturvedi AK et al, J Clin Oncology 2011.
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Observed and projected incidence rates of OP and cervical cancers (US)
Chaturvedi AK et al, J Clin Oncology 2011.
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Jemal A, et al. J Natl Cancer Inst. 2013; vol 105
Incidence of HPV‐associated cancers‐USA
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7,466 Women 18-25 years old
2004- 2005
Control vaccineHepatitis A Vaccine
CervarixHPV-16/18 Vaccine
Costa Rica Vaccine Trial
Herrero R et al Cancer Discovery 2011;1:408Herrero R et al Vaccine 2008;26:4795
Aimee Kreimer, PhD
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7,466 Women 18-25 years old
2004- 2005
Control vaccineHepatitis A Vaccine
CervarixHPV-16/18 Vaccine
• Annual follow-up for 4 years
• Cervical samples collected at all visits
• Oral specimens collected at 4 year visit
Costa Rica Vaccine Trial
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Arm # Women
# HPV16/18 Infections
HPV16/18 VE (95%CI)
HPV 2910 193% (63% to 100%)
Control 2924 15
Herrero R et al PLOS ONE 2013
Vaccine efficacy against oral HPV 16/18 infections‐4 years of protection
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Age‐specific prevalence of oral HPV infection
Prevalence = Incidence * Duration
Gillison ML et al. JAMA 2012.
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Duration of vaccine protection at different anatomic sites
Non‐cervical sites
Cervix
Years of follow‐up 4 >8
Long-term follow-up studies are required
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HPV infection – preventative targeted therapy of SCCHN?
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tibody vs ellcognition
V ected s
Class I MHC HPV L1outer capsid
CD8+
T cell
CD8
Antibody
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Shaum S. Sridharan, MD
University of Pittsburgh Medical CenterDepartment of Otolaryngology Grand RoundsMay 21, 2014
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Indole ‐ 3 ‐ Carbinol Found in cruciferous vegetables (broccoli, cabbage, brussel sprouts, cauliflower)
Alters estrogen metabolism Blocks P450 Favors 2‐hydroxyestrone over 16a‐ hydroxyestrone
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• Prospective open‐label study
• 33 patients
• 1/3 with complete response
• 1/3 with partial response
• 1/3 with no response
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Indol‐3‐Carbinol (I3C) Found in cruciferous vegetables Alters estrogen metabolism Blocks P450 slow growth
1/3 – 1/3 – 1/3
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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
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Dosing Dose should remain below 3 mg/kg Different concentrations are used from 2.5 – 15 mg/ml Most common concentration 7.5 mg/ml Most common volume 5 mL
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Clinical SuccessMultiple 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
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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
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19 consecutive patients enrolled Improvement in Derkay Score overall though no difference amongst groups
Improvement in VHI score with cidofovir but not statistically significant
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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‐lesionalinjection 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 VilàF, 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.
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13 patients reviewed Biopsy before and after treatment Varying pathology results‐ 57% with mild dysplasia‐ 28% with moderate dysplasia‐ 8% with severe
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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 DerkayScore? and longer surgical intervals
OR – office
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Benjamin L. Hodnett, MD, PhD
University of Pittsburgh Medical CenterDepartment of Otolaryngology Grand RoundsMay 21, 2014
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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
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Drug Administration Cancer: IV every 14 days
Investigational: intra‐arterial for brain tumors
Eye disease: intravitreously (dosage 1.25 – 2.5 mg, 0.05 – 0.1 ml of 25 mg/ml solution)
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Side Effects Systemic
Hypertension Increased risk of bleeding Bowel perforation Nasal septum perforation Renal thrombotic microangiopathy Necrotizing fasciitis (52 cases from 1997‐2012, 17 deaths)
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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
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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 (7.5 – 12.5 mg)
Improved vocal parameters No local/systemic complications 15% no disease, 80% less disease, 5% more disease
Zeitels 2011 Ann Otol Rhinol Laryngol
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Safety and Dosing of Bevacizumab (Avastin) for the Treatment of Recurrent Respiratory Papillomatosis
Ranges from 15 – 88 mg total No clinical complications (local or systemic) No local wound problems
Best 2012 Ann Otol Rhinol Laryngol
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Does it work? 25mg/cc, q6wks x 4+
Avastin + KTP Zeitels 2009, 2011 Ann Otol Rhinol Laryngol
15 – 88 mg total Best 2012 Ann Otol Rhinol Laryngol
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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
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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
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Celecoxib and RRP 2/3 patients in pilot study (200 mg BID for 6 months) followed for 5 years had extended remission time, 3rd patient disease free at 4.5 years (Lucs 2012 Mol Med)
TH2 cytokines increased in papilloma and TH1 cytokine decreased in papilloma suggesting active HPV infection shifts TH1/ TH2 profile to TH2 state (Rosenthal 2012 Mol Med)
TH2 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)