Logo for University of Iowa Health Care This logo represents the University of Iowa Health Care
New Addition: Voice Rest - Vocal Conservation as a Management Strategy Non-Operative and PostopClick Here

Pharmacotherapy for Recurrent Respiratory Papillomatosis

last modified on: Fri, 08/24/2018 - 17:21

Pharmacotherapy for Recurrent Respiratory Papillomatosis (RRP) 
See also Recurrent Respiratory Papillomatosis (RRP) - General Information

Microdirect Laryngoscopy (Suspension Microlaryngoscopy or Direct Laryngoscopy)

and Voice Clinic Management Protocols and Specific Voice Disorders

and Microdebrider Suction Modulator for RRP; KTP Laser for the Larynx; KTP Laser for RRP local anesthesia case example


Caused most commonly by HPV type 6 and 11, less commonly subtypes 16 and 18. Affects squamous epithelium. Juvenile form thought to be from vertical transmission due to associations with maternal age, presence of maternal genital papillomas, and birth through vaginal delivery.

Incidence: 4.3/100,000 children and 1.8/100,000 adults.

  1. Symptoms include hoarseness, stridor, dyspnea or dysphagia.
  2. Risks factors vary depending on whether referring to juvenile or adult-onset forms but include oral sex, multiple sexual partners, low socioeconomic status, young first-time mothers.
  3. Gardasil is a quadrivalent vaccine (against HPV 6,11,16,18) that was licensed for use in the US in June 2006. It has been approved for use in 121 nations with approximately 74 million doses administered worldwide as of March 2011. The most significant risk factor for contracting juvenile RRP is a history of genital warts in the mother, thus the possibility of eventually reducing the incidence of RRP exists with vaccination against the HPV subtypes that cause over 90% of genital warts cases.
  4. Indication for pharmacotherapy
    1. Patient with moderate to severe recurrent respiratory papillomatosis requiring frequent excisions of papillomas (at least three annually)  agree to undergo direct laryngoscopy and bronchoscopy (DL/B) every 12 weeks for a minimal study time of 12 months
    2. Distal spread to the trachea or bronchopulmonary tree. Pulmonary involvement of disease can be fatal.
    3. Diindolymethane may be useful, including for patients with milder disease
    4. Several studies link EERD and RRP.  There are a number of case reports demonstrating improvement in RRP following adequate treatment of EERD.
  5. Contraindications
    1. By agent, as listed below
    2. Agents with less severe side effects preferable for milder disease
  1. Document Extent of Disease
    1. For adults
      1. Videostroboscopy on entry into study (prior to initiating adjuvant therapy)
      2. Repeat videostroboscopy every eight weeks
    2. For children
      1. Intraoperative videotape prior to initiating therapy
      2. Repeat videotape with each DL/B
  2. DL/B with complete but judicious laser excision of papillomas prior to adjuvant pharmacotherapy
    1. Microdirect Laryngoscopy (Suspension Microlaryngoscopy or Direct Laryngoscopy)
    2. Good example of positioning/setup: Microdirect Laryngoscopy case example
  3. Repeat DL/B with videorecording at least every eight to 12 weeks
  4. Baseline CXR, repeated annually
  5. Additional workup if distal tracheal or bronchopulmonary tree involved
    1. Chest CT
    2. Referral to pulmonologist
    3. Pulmonary function tests
  6. Additional Agent-Specific Laboratory Test (as detailed below)
PHARMACOTHERAPY AGENTS  -- Note: acyclovir as well as 13-Cis-Retinoic Acid (Accutane, Isotretinoin) are no longer actively employed in our current practice. Cidofovir use has been limited due to the concerns about malignant potential. DIM is used by many of our patients. Patients who qualify for the NIH study evaluating celebrex (400 mg/d) are offered enrollment on study. Access to trial: NIH Celebrex Clinical Trial
  1. Diindolylmethane (DIM): A naturally occurring derivative of cruciferous vegetables related to Indole 3 Carbinol, which alters peripheral estrogen levels
    1. Indication
      1. Recalcitrant papillomatosis
      2. May be useful for patients with mild disease
    2. Dosing (oral)
      1. For adults and children, 4 mg per kg per day orally as a single dose
    3. Side effects
      1. Dizziness, headache, or unsteady gait at excessive doses
      2. May be goitrogenic or cause bone loss
  2. Acyclovir: An acyclic purine nucleoside requiring thymidine kinase (co-viral infection necessary) that disrupts DNA synthesis
    1. Indication
      1. May be beneficial for patients with recalcitrant papillomatosis
    2. Dosing (oral)
      1. Adults and children, 10 mg per kg, five times per day by mouth for 10 days then twice per day for six weeks
    3. Side effects
      1. Vomiting, diarrhea, fatigue, dull headache, low-grade temperature
    4. Monitor liver function tests at the beginning of therapy and every eight weeks.
  3. Interferon Alfa-2b: Cloned protein naturally produced by leukocytes in response to viral infection; thought to act by stimulating existing host defenses into an antiviral state, modulating immune responses, inhibiting cell growth, and inducing several enzyme systems. Agent most proven to be effective against RRP but has several side effects and requires regular subcutaneous administration
    1. Indication
      1. Aggressive papillomatosis resistant to DIM/Acyclovir
      2. Aggressive papillomatosis possibly requiring tracheotomy
      3. Papillomatosis with distal tracheal or bronchopulmonary spread
    2. Dosing (subcutaneous)
      1. Initial teaching requires approximately three hours
      2. Initiate dosing at 1 million units m 2 per day QOD and escalate by 1 million units per m 2 per week up to 3 million units m 2 day QOD
      3. In children with a response at six months, taper dose slowly and reintroduce in those with recurrence
      4. In children without a response, stop administration
      5. Observe for rebound in RRP after discontinuation of alpha-interferon
    3. Side effects (frequent)
      1. Side effects frequently seen on initiation disappear with continued use (tachyphylaxis)
        1. Fatigue, malaise
        2. Anorexia
        3. Fever
      2. Long-term complications
        1. Liver dysfunction
        2. Coagulopathy
        3. Alopecia
        4. Growth retardation (rare)
        5. Leukopenia
        6. Elevated renal indices
        7. Spastic diplegia (rare)
    4. Monitor (medical oncology and neurology consultations may be helpful)
      1. LFTs at initiation and every two months
      2. CBC with platelets at initiation and every two months
      3. BUN/creatinine at initiation and every two months
      4. Routine neurology consult for patients under two years
  4. 13-Cis-Retinoic Acid (Accutane, Isotretinoin): Vitamin-A derivative that inhibits proliferation and regulates growth and differentiation of the epithelium
    1. Indication
      1. Used for distal tracheal or bronchopulmonary spread
      3. May be synergistic with alpha-interferon
    2. Dosing
      1. 1 mg per kg orally qd for six months
    3. Side effects
      1. Cheilitis (dose related)
      2. UV radiation sensitivity
      3. Arthralgia (rare, mild)
    4. Monitor
      1. Dry eyes, blurred vision, decreased night vision, vomiting
      2. Pregnancy test prior to initiation
      3. LFTs, CBC with differential, BUN, creatinine, coagulation profile at initiation and every two months
  5. Cidofovir: Metabolite (cidofovir diphosphate) is a nucleoside analogue inhibiting viral DNA polymerase at intracellular concentrations 50-fold to 1000-fold lower than those required to inhibit cellular DNA synthesis.  
    1. Efficacy
      1. Many case reports demonstrate efficacy, though frequently without control groups.
      2. A randomized double blind study (N=19) demonstrated a significant improvement in the Derkay severity score in the entire cohort of patients, but no difference between the treatment and control arm in terms of number of procedures performed.  There was a significant improvement in the voice handicap score at the 12 month followup.
    2. Dosing
      1. Intralesional cidofovir, 1 mg/kg (other studies report using 5mg/ml) at the following interval: first four treatments were at two-week intervals (week 0, 2, 4, and 6). Subsequent treatment intervals were each increased by one week (treatments took place at week 9, 13, 18, 24) for 66 weeks.
    3. Side effects
      1. Nephrotoxic: causing renal problems in approximately 29% of patients when used at IV doses of 5mg/kg.
      2. Intralesional doses of Cidofovir have been shown to have plasma levels below toxic levels. 
      3. Malignant potential: 
        1. Pathologic data collected over 10 years in 13 patients with serial excisions at the University of Iowa Hospitals showed no clear-cut pattern between the use of cidofovir and the degree of dysplasia over time. The results strongly suggested that intralesional cidofovir therapy does not correlate with worsening dysplastic progression. Also, the prognostic significance of dysplasia in the setting of RRP is unknown. (Gupta, Hoffman, et al. 2010)
        2. In studies to evaluate the nephrotoxicity of the drug, 22 of 37 female rats developed adenocarcinoma of the mammary tissue.  Even at lower doses such as 1/25th of the dose for CMV retinitis, 20% of rats still developed tumors.  The lower doses used in this last study may be comparable to the blood levels detected in humans following intralesional injections of cidofovir. There has been no clearly demonstrated causative relationship in humans.. 
  6.  Bevacizumab (Avastin): Monoclonal antibody to the VEGF which prevents its interaction with the VEGF receptor.  Basic science studies showed that the VEGF-receptor was present on papillomas examined after resection.  It has shown some efficacy in adults (x) and even in a few refractory pediatric cases (y).  A current NIH trial has been established for adults with advanced RRP for treatment with bevacizumab (https://clinicaltrials.gov/).  We have implemented it for selected cases as of 2016. Avastin (Bevacizumab) at 25m/cc has been reported for use in the pediatric population by way of subepithelial injection ranging from 5 to 45 mg (Sidell 2014).
  1. TRACHEOSTOMY SHOULD BE AVOIDED as it is associated with distal airway involvement; Likely secondary to seeding of HPV virus
  2. Techniques include microdebrider, cold resection and CO2 laser; in office or in OR
  3. Goals of surgical care is to remove symptomatic lesions and maximize amount of time patient is symptom free between procedures.
  4. Pathologic examination of resected tissue should be done regularly
  1. Alberts DS, Coulthard SW, Meyskens FL Jr. Regression of aggressive laryngeal papillomatosis with 13-cis-retinoic acid (Accutane). J Biol Response Mod. 1986;5:124-128.
  2. Bell R, Hong WK, Itri LM, McDonald G, Strong MS. The use of cis-etinoic acid in recurrent respiratory papillomatosis of the larynx: a randomized pilot study. Am J Otolaryngol. 1988;9:161-164.
  3. Benjamin BN, Gatenby PA, Kitchen R, Harrison H, Cameron K, Basten A. Alphainterferon (Wellferon) as an adjunct to standard surgical therapy in the management of recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 1988;97:376-380.
  4. Blumin JH, Handler EB, Simpson, CB, Osipov V, Merati AL. Dysplasia in adults with Recurrent Respiratory Papillomatosis: Incidence and Risk Factors. Ann Otol Laryngol Rhinol. 2009 Jul; 118 (7): 481-5.
  5. Chhetri DK, Shapiro NL. A scheduled protocol for the treatment of juvenile recurrent respiratory papillomatosis with intralesional cidofovir. Arch Otolaryngol Head Neck Surg. 2003 Oct;129(10):1081-5.
  6. Derkay CS, Malis DJ, Zalzal G, Wiatrak BJ, Kashima HK, Coltrera MD. A staging system for assessing severity of disease and response to therapy in recurrent respiratory papillomatosis. Laryngoscope. 1998;108:935-937.
  7. Donne, A.J., M.P. Rothera, and J.J. Homer, Scientific and clinical aspects of the use of cidofovir in recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol, 2008. 72(7): p. 939-44.
  8. Eicher SA, Taylor-Cooley LD, Donovan DT. Isotretinoin therapy for recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg. 1994;120:405-409.
  9. Endres DR, Bauman NM, Burke D, Smith RJ. Acyclovir in the treatment of recurrent respiratory papillomatosis. A pilot study. Ann Otol Rhinol Laryngol 1994;103:301-305.
  10. Gupta HT, Robinson RA, Murray RC, Karnell LH, Smith RJ, Hoffman HT. Degrees of dysplasia and the use of cidofovir in patients with recurrent respiratory papillomatosis. Laryngoscope. 2010 Apr;120(4):698-702.
  11. Healy GB, Gelber RD, Trowbridge AL, Grundfast KM, Ruben RJ, Price KN Treatment of recurrent respiratory papillomatosis with human leukocyte interferon. Results of a multicenter randomized clinical trial. N Engl J Med. 1988;319:401-407.
  12. Kiroglu M, Cetik F, Soylu L, et al. Acyclovir in the treatment of recurrent respiratory papillomatosis: a preliminary report. Am J Otolaryngol. 1994;15:212-214.
  13. Leventhal BG, Kashima HK, Mounts P, et al. Long-term response of recurrent respiratory papillomatosis to treatment with lymphob~lastoid interferon alfa-N1. N Engl J Med. 1991;325:613-617.
  14. Lippman SM, Donovan DT, Frankenthaler RA, et al. 13-Cis-retinoic acid plus interferon-alpha 2a in recurrent respiratory papilloma~tosis. J Natl Cancer Inst. 1994;86:859-861.
  15. Lopez Aguado D, Perez Pinero B, Betancor L, Mendez A, Campos Banales E. Acyclovir in the treatment of laryngeal papillomatosis. Int J Pediatr Otorhinolaryngol. 1991;21:269-274.
  16. Lott, D.G. and P.R. Krakovitz, Squamous cell carcinoma associated with intralesional injection of cidofovir for recurrent respiratory papillomatosis. Laryngoscope, 2009. 119(3): p. 567-70.
  17. McCabe BF, Clark KF. Interferon and laryngeal papillomatosis. The Iowa experience. Ann Otol Rhinol Laryngol. 1983;92:2-7.
  18. McMurray, J.S., N. Connor, and C.N. Ford, Cidofovir efficacy in recurrent respiratory papillomatosis: a randomized, double-blind, placebo-controlled study. Ann Otol Rhinol Laryngol, 2008. 117(7): p. 477-83.
  19. Morrison GA, Evans JN. Juvenile respiratory papillomatosis: Acyclovir reassessed. Int J Pediatr Otorhinolaryngol. 1993;26:193-197.
  20. Mullooly VM, Abramson AL, Steinberg BM, Horowitz MS. Clinical effects of alpha-interferon dose variation on laryngeal papillomas. Laryngoscope. 1988;98:1324-1329.
  21. Nieman, AN, et. all. Cidofovir plasma assays after local injection in respiratory papillomatosis. Laryngoscope 2004 Jul; 114(7): 1151-6
  22. Rosen CA, Woodson GE, Thompson JW, Hengesteg AP, Bradlow HL. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg. 1998;118:810-815.
  23. Sessions RB, Goepfert H, Donovan DT, Dichtel WJ, Gutterman JU. Further observations on the treatment of recurrent respiratory papillomatosis with interferon: a comparison of sources. Ann Otol Rhinol Laryngol. 1983;92:456-461
  24. Zeitels SM, Lopez-Guerra G, Burns JA, Lutch M, Friedman AM, Hillman RE. Microlaryngoscopic and office-based injection of bevacizumab (Avastin) to enhance 532-nm pulsed KTP laser treatment of glottal papillomatosis Ann Otol Rhinol Laryngol Suppl. 2009 Sep;201:1-13.
  25. Maturo S, Hartnick CJ. Use of 532-nm pulsed potassium titanyl phosphate laser and adjuvant intralesional bevacizumab for aggressive respiratory papillomatosis in children: initial experience. Arch Otolaryngol Head Neck Surg. 2010 Jun;136(6):561-5.
  26. Haupt RM, Sings HL. The Efficacy and Safety of the Quadrivalent Human Papillomavirus 6/11/16/18 Vaccine Gardasil. Journal of Adolescent Health. 49 (2011) 467-475.

  27. Motz KM and Hillel AT. Office-based Management of Recurrent Respiratory Papilloma Otorhinolaryngol Rep (2016)4:90 (only pub March 31, 2016)

  28.  Sidell DR, Nassar M, Cotton RT, Zeitels SM and de Alarcon A: High-dose sublesional bevacizumab (avastin) for pediatric recurrent respoiratory papillomatosis. Ann Otol rhinol Laryngol. 2014 Mar; 123 (3): 214-21