Drs.Maguire,Patel,Smith - Recurrent Respiratory · PDF file$60000‐$470000 $150 million ... The virus shell or coat has 2 proteins L1 and L2 The Virus Particle The virus shell consists

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 

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

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

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

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

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

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

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)

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.

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

Pediatric Case A flexible laryngoscopy

was performed in the ED.

Decision was made to take the pt to the OR urgently.

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

Pediatric Case

Pediatric Case A microdebrider was

used to debulk the papilloma.

No adjuvant therapy was used during initial procedure

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.

Pediatric Case Lasers used in RRP

CO2 Largely absorbed by water Used more for cutting/ablation

PDL-585nm KTP-532nm

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

Peds Adult 16 yo AA female Dx @ age 10 45 sx from 2007‐2013

Adult 52 yoWM Dx @ age 25 Sx q 6‐12mo

Narrow Band Imaging Blood vessels

415 nm:  penetrate superficial mucosa.  Capillaries  brown color

540 nm:  penetrate deeper within mucosal layers.  “cyan”

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

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.

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??

KTP “Smart” laser Angiolytic Photothermolysis ablative

16 yo:  intra‐op

16 yo:  post‐op

52 yo: intra‐op

• Prospective open‐label study

• 33 patients

• 1/3 with complete response

• 1/3 with partial response

• 1/3 with no response

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

1/3 – 1/3 – 1/3

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

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

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

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

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)

Adult‐onset 33 yo AA female 6 mo hx progressive hoarseness

PMHx:  DM, HTN, AR HIV Researcher

RRP Sx ~q 6 mo x 3 years Low risk HPV Developed cough after 2nd surgery Subglottis “clean” Adjunctive treatment

I3C Cidofovir (spaced apart)

3 yrs later… Cough worsening During in‐office KTP procedure, bronch for cough  tracheal RRP

Now sx q4‐6weeks

Extra Case

Objectives Review Vaccine Adjuvant treatments Advances in technology Discussion

www.UPMC.com/voicecenterVoice Center

HPV, Vaccination, Head and Neck Neoplasms

Robert L. Ferris, MD, PhDRobert L. Ferris, MD, PhD

This image cannot currently be displayed.

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.

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)

HPV explains rising OP incidence

Chaturvedi AK et al, J Clin Oncology 2011.

Observed and projected incidence rates of OP and cervical cancers (US)

Chaturvedi AK et al, J Clin Oncology 2011.

Jemal A, et al. J Natl Cancer Inst. 2013; vol 105

Incidence of HPV‐associated cancers‐USA

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

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

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

Age‐specific prevalence of oral HPV infection

Prevalence = Incidence * Duration

Gillison ML et al. JAMA 2012.

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

HPV infection – preventative targeted therapy of SCCHN?

tibody vs ellcognition 

V ected s

Class I MHC HPV L1outer capsid

CD8+

T cell

CD8

Antibody

Shaum S. Sridharan, MD

University of Pittsburgh Medical CenterDepartment of Otolaryngology Grand RoundsMay 21, 2014

Indole ‐ 3 ‐ Carbinol Found in cruciferous vegetables (broccoli, cabbage, brussel sprouts, cauliflower)

Alters estrogen metabolism Blocks P450 Favors 2‐hydroxyestrone over 16a‐ hydroxyestrone

• Prospective open‐label study

• 33 patients

• 1/3 with complete response

• 1/3 with partial response

• 1/3 with no response

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

1/3 – 1/3 – 1/3

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

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

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

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

19 consecutive patients enrolled Improvement in Derkay Score overall though no difference amongst groups

Improvement in VHI score with cidofovir but not statistically significant

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.

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

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

Benjamin L. Hodnett, MD, PhD

University of Pittsburgh Medical CenterDepartment of Otolaryngology Grand RoundsMay 21, 2014

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

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)

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)

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

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

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

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

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

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

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)