Recurrent Respiratory Papillomatosis: Pediatric Issues 2005

1. Recurrent Respiratory Papillomatosis: Pediatric Issues 2005 Seth M. Pransky, M.D. Director, Pediatric Otolaryngology Children’s Specialists San Diego Children’s Hospital & Health Center San Diego, CA.

2. Recurrent Respiratory Papillomatosis • Can be devastating with multiple surgical interventions necessary for airway control • Long term voice issues • Huge impact on patient, family and surgical team • NO predictive therapeutic intervention available

3. RRP: General Treatment Principles • Interval debulking for airway and voice • LASER, Forceps, Microdebrider • Conservative (Govenator) approach: “I’ll be back” • Protect anterior commissure • Avoid trach

4. RRP: Disease Severity • Age at diagnosis is the primary determinant of disease severity • Number of sites involved and tracheotomy • Cohort analysis indicates current age is major determinant of annual treatments

5. RRP: Disease Severity 2005 • HPV Type 11 appears to be predictor of more severe disease • Wiatrak:Recurrent Respiratory Papillomatosis: A Longitudinal Study Comparing Severity Associated with Human Papilloma Viral Types 6 and 11 and Other Risk Factors in a Large Pediatric Population Laryngoscope 2004: 114 (2); 1-23 (Supplement 104) • 10 yr prospective study; 58 typed pts-type 6=31;type 11=23 • Type 11 significantly more severe disease; 4/5 pts with HPV after c-section were type 11 • Reidy et al.:Integration of Human Papillomavirus Laryngoscope 2004: Type 11 in Recurrent Respiratory Papilloma-Associated Cancer114; 1906-1909 • 6 pts with early onset RRP who developed laryngeal or bronchogenic cancer had HPV-11 • HPV 11 not “low risk”. Integration of viral genome into host DNA can generate malignancy. Increases levels of E6 & E7. • Kiselev:ESPO 2004--HPV 11 pts younger at diagnosis and need more surgery • Gerein et al:2’5’-Oligoadenylate Synthetase Activity Analysis and HPV Typing as Prognostic Factors in Patients with Recurrent Respiratory Papillomatosis J Laryngol Otol 2004: 118;750-756

6. Pathogenesis Analysis • Molecular markers • Pou: Molecular Characterization of Mutations in Patients with Benign and Aggressive Recurrent Respiratory PapillomatosisAnn Otol Rhinol Laryngol 2004: 113; 180-186 • Sequence variations within upper regulatory region that affect E6/E7 regions (transforming capabilities) • Genetic basis for susceptibility to HPV infection • Buchinsky: Multicenter Initiative Seeking Critical Genes in Respiratory PapillomatosisLaryngoscope 2004: 114; 349-357 • Host genes that modulate immune response permit HPV infection • Assess integration of the HPV DNA into host DNA • Looking for participants for NIH supported multicenter study: fbuchins@wpahs.org www.centerforgenomicsciences.org/Buchinsky/RRP

7. Technique Issues 2005 • Microdebrider • Spontaneous ventilation

8. “New” Technologies • Pulsed dye laser • Penetrates epithelium and absorbed by underlying subepithelial microvasculature • Wavelength targets hemoglobin and destroys vessel walls while leaving surrounding tissue unaffected • Diseased tissue ablation and photothermal denaturing of basement membrane linking proteins • Good for “sensitive” areas (anterior commissure) • Not good for bulky lesions • Radiofrequency Coblation • Compared to conventional laser extended time between treatments

9. RRP Adjuvant Therapy Update 2005 • Cidofovir issues • Indole-3-carbinol • Mumps injection • Merck quadrivalent vaccine • HspE7 • Celebrex • Hamlet • Gefitinib • Artemesinin

10. Clinical Trial of Celebrex Therapy for Recurrent Respiratory Papillomatosis Mark J. Shikowitz, MD Allan L. Abramson, MD Bettie M. Steinberg, Ph.D. Department of Otolaryngology LIJ Medical Center The Long Island Campus for the Albert Einstein College of Medicine New Hyde Park, NY 11040

11. COX-2 * Neg control Relative COX-2 levels Papilloma Normal Normal Papilloma The Target of Celebrex, COX-2, is Expressed in Papillomas

12. * * * * Relative Cell Growth * Relative Cell Death Celecoxib (M) Celecoxib (M) Celebrex Alters Papilloma Cell Growthand Cell Survival

13. Celebrex PGE2 COX-2 HPV E7 Inhibit cell- mediated immunity Enhance Papilloma growth Celebrex COX-2 and RRP - A Positive Feed-Back Loop Disrupted by Celebrex

14. Clinical Trial of Celecoxib • Design: • Multicentered randomized placebo controlled clinical trial • Participating sites: New York, Pittsburgh, Virginia, Alabama, Iowa, San Francisco • Goals: • Determine whether celecoxib is a good adjunctive therapy for RRP • Determine which patients will benefit • Determine mechanism of effect

15. Celebrex Placebo Pre Treat Placebo Celebrex Celebrex Study Design • Patients: Age 18 or older, with 3 or more surgeries in past year, or tracheal/bronchial involvement • Randomized: two start times, 6 and 18 months after enrollment - late group is “control” group, all receive celebrex • Celebrex dose: 200 mg BID – ½ max FDA approved dose • Score disease at endoscopy every 3 months for total of 2.5 yr • Blood and biopsy studies: celebrex levels in blood, COX-2, latent HPV persistence, change in immune response to HPV proteins

16. Preliminary Data • 3 patients completed more than 1 year in study so far • Do not know which group they are in • Double blind – neither doctor nor patient will know until total study complete • 1 patient free of disease • 1 patient with rate of regrowth only 20% of rate at entry • 1 patient no change so far

17. Cidofovir • (S)-1-(3-hydroxy-2-phosphonylmethoxpropyl) cytosine • Cytosine Nucleotide Analog • Active against DNA virus family (HPV) • Inhibits viral DNA polymerase • Long intracellular 1/2-life • FDA approved for CMV retinitis in HIV Pt’s • ? Reduces viral E6 and E7 protein expression • Van Custem et al. and Snoeck et al. described intralesional use among adult RRP patients. • Van Custem et al. J Med Virol 1995; 45:230-5. • Snoeck et al. J Med Virol 1998; 54:219-25. • In 1996, we began to utilize intralesional cidofovir in children

18. Cidofovir Experience • 1996-1998: First Series: Clinical Response to Intralesional Cidofovir for Severe Recurrent Respiratory Papillomatosis in ChildrenPransky et al. Arch Otolaryngol 1999; 125:1143-48. • Five “severe RRP” pts requiring operative procedures every 4 weeks or less • Patients received between 8 and 13 injections at 2-week intervals • Impressive results • 1998-2000: Second Series: Clinical and Histological Update on 10 Children Treated with Intralesional Injections for Severe Recurrent Respiratory PapillomatosisPransky et al. Arch Otolaryngol 2000; 129:1239-43. • Assessed long-term response to cidofovir using 4 injections only • Initial response quite good, but only 1 patient cleared fully • 1996-2003: Long term Follow Up of Pediatric Recurrent Respiratory Papillomatosis Managed with Intralesional Cidofovir Pransky et al Laryngoscope 2003; 113:1583-1587 • Prolonged follow-up with 50% “durable and lasting remission”

19. Cidofovir Recent Reports • Pransky:Long term Follow Up of Pediatric Recurrent Respiratory Papillomatosis Managed with Intralesional CidofovirLaryngoscope 2003; 113:1583-1587 • Prolonged follow-up with 5/11 lasting remission; 5/11 significant improvement • 5mg/ml, varying number of injections; f/u 22-60 months • Froehlich:Intralesional Cidofovir and Surgical Excision for Laryngeal Papillomatosis Laryngoscope 2003:113;2174-2181 ESPO 2004, Athens, Greece • 19 adults-17/19 with lasting remission; 2/19 with significant improvement (f/u 6 months-4 yrs) • 8 peds -4/8 with lasting remission; 4/8 with significant improvement (f/u 4 months-4 years) • 5 mg/ml , 3 injections q 4wks • Then 7.5 mg/ml, 3 injections q 2 wks • If no remission, then repeat q 3 months

20. Cidofovir Recent Reports • Koltai:Stepped-dose Protocol of Cidofovir Therapy in Recurrent Respiratory Papillomatosis in Children Arch Otolaryngol 2003: 129; 841-846 AAO New York Sept 2004 • 4/11 durable remission; 2/11 significant improvement; f/u 14-42 mos • 4 injections q 4 wks with 5mg/ml; repeat if still disease with 10mg/ml • Increasing from 5mg/ml to 10 mg/ml had mixed response (3/5 improved while receiving the cidofovir injections) • Shapiro:A Scheduled Protocol for the Treatment of Juvenile Recurrent Respiratory Papillomatosis with Intralesional CidofovirArch Otolaryngol Head Neck Surg 2003: 129; 1081-1085 • 2/5 lasting remission; 3/5 mild residual disease • 5mg/ml; Used increasing treatment intervals with varying number of total injections

21. Cidofovir Recent Reports • Rosen:Efficacy of Cidofovir Injection for the Treatment of Recurrent Respiratory PapillomatosisJ Voice 2004: 18;551 • 13 pts; all failed I3C; 5mg/cc; q 3 wk interval; f/u 13-48 months • 10 adults-8/10 with full remission; 1/10 retreat with full remission; 1/10 ongoing disease but improved • 3 peds-2/3 with full remission; 1/3 non-responder • Vocal fold scarring issues raised • Wiatrak:Is Cidofovir a Useful Adjunctive Therapy for RRP in Children IJPO 2004: 68; 413-418 • 11 peds pts (10/11 type 11); 5mg/cc; q 2wks with varying number of injections • 3 responders; 2 partial responders; 6 no response • Now using 7.5 mg/cc to assess response

22. Cidofovir Technique • Severe RRP that required intervention every 2-6 weeks for airway control. • Bulky disease removed with laser (earlier patients) or microdebrider. • 1-2 ml of 5 mg/ml cidofovir injected with laryngeal or GI needle. • At least four injections delivered at 2-3 week intervals.

23. Cidofovir Safety Concerns • Toxicity and Carcinogenesis • Animal studies • Rat data; Monkey data (IV cidofovir) • Pransky: Histological Review of Cidofovir Treated Recurrent Respiratory Papillomatosis ABEA May 2004 (submitted Annals) • Froehlich: Cidofovir Plasma Assays after Local Injection in Respiratory Papillomatosis Laryngoscope 2004: 114; 1151-1156 • Plasma levels of intralesional injections well below IV levels • Use 3mg/kg; probenecid not necessary • Case reports of scc conversion in pts who received cidofovir • Use of cidofovir to treat EBV-related cancer • Antiviral Agent Cidofovir Decreases Epstein-Barr Virus Oncoproteins and Enhances the Radiosensitivity in EBV-Related Malignancies • Abdulkarim et al Oncogene 2003: 22;2260-2271

24. Cidofovir Safety Issues • Toxicity • Renal does not seem to be a problem • Carcinogenicity of concern, but no clear evidence • Severe pts. vs. casual use debate • RRP Task Force Recommendations: Caution • Treatment option only in severe cases • Appropriate informed consent (including discussion of carcinogenic potential) • Consent form • Voluntary reporting of adverse events, including evidence for dysplasia or malignant transformation

25. Benefits of Cidofovir • The profound impact of cidofovir treatment on these patients cannot be understated • Reduce fears of distal spread • Maintain airway • Improved voice • Improved emotional well-being • Decrease in potential iatrogenic damage to the larynx from repetitive debulking • (Ultimately) Reduce frequency of surgical intervention

26. Cidofovir Thoughts • Dosage-5mg/ml seems to work for most; higher dose may be helpful given volume restrictions • Interval- 2-4 weeks seems to be acceptable • # of treatments-looks like need 4-5 to bring about remission; probably need more for partial responders • Impact of associated surgery (laser, debrider) - unclear. • Some have seen effect of cidofovir without concomitant debulking • Multiple prior procedures could even decrease effect secondary to fibrosis • Seems to be 3 distinct subsets-responders with durable remission (45-50%); good response without full clearing (30%)-significantly increases surgical interval; non responders (20%) • Question if get prolonged effect after injections discontinued

27. Cidofovir-Lessons Learned • Often see dramatic initial response • Disease that persists/recurs after cessation of cidofovir often is less extensive and easier to control with some individuals progressing to lasting remission • Can achieve long term “cure”, but lasting remissions were not universal and we do not believe cidofovir represents the “miracle cure” for everyone. • Major benefit is control of “severe disease” • Long term follow-up critical

28. RRP management thoughts • Variable disease • Must approach individually • Multiple therapies • No single modality proven to be appropriate and effective for a specific patient • How manage your child?

29. RRP management thoughts • Education re: alternatives • Beware the pitfalls of well intentioned recommendations based on individual case reports • Beware the misinformation of chat room “chatter” • Clear communication with MD • Arrange time beyond routine office visit • Prepare the doc • Interact, discuss, listen, analyze

30. RRP management thoughts • Plan of action • Frequency/interval of intervention • Technique • Adjuvant therapy • Dosing • Flexibility • Consider new approach if required • Experimental protocols

31. Thank you

32. GERD • Long standing relationship between GERD and laryngeal disease • Recent retrospective study showed increased development of webs if not treated for reflux

33. ALDERA