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MUSC Otolaryngology - Head & Neck Surgery E-Update                 July 2016 
 Greetings Colleagues!

Recurrent respiratory papillomatosis (RRP) is a disease for which there is no known cure. However, advances in adjuvant therapy and vaccination have played a large role in increasing remission rates and the interval between surgeries. This July ENT E-Update is brought to you by Lucinda A. Halstead, M.D., Medical Director, Evelyn Trammell Institute for Voice and Swallowing. 

These newsletters are designed to provide brief, practical, clinical updates in areas where we all struggle in managing our patients. Your feedback or questions about the E-Update articles, your patients, or any other ENT issue are always welcome. Write to us at [email protected] - And please forward this E-Update to your colleagues who may also benefit from sharing the latest ENT topics. As always, your support is deeply appreciated.

Yours sincerely,
Paul R. Lambert, M.D.
Professor and Department Chair

Contemporary Management of Recurrent Respiratory Papilloma - Addition of Gardasil to Adjuvant Therapies
Lucinda A. Halstead, M.D.
Figure 1. The overall change in intersurgical interval (ISI) is plotted for all patients before and after receiving the Gardasil vaccine.
Recurrent respiratory papillomatosis (RRP) is characterized by benign wart-like growths within the aerodigestive tract. It affects both children and adults, with a reported incidence in children of 4.3 cases per 100,000 and an incidence in adults of 1.8 cases per 100,000. These lesions occur primarily in the larynx, causing dysphonia, respiratory distress, and ultimately airway obstruction if left untreated. These growths are overwhelmingly caused by the Human Papillomavirus (HPV) with over 90% of lesions attributed to serotypes 6 and 11. The course of the disease is extremely variable between patients. Some children diagnosed with the disease will eventually outgrow it, but a substantial number require lifelong treatment. Additionally, adult onset RRP appears to be increasing in frequency. Surgical intervention can maintain airway patency and improve voice, but it cannot cure the disease. Consequently, adjuvant therapies have been used for years to attempt to increase the interval between surgical interventions and to induce disease remission. A brief review of these adjuvant therapies and the positive addition of Gardasil to this management will be presented.
 
Early attempts at adjuvant therapy included interferon and methotrexate, but these have been largely abandoned in favor of safer alternatives due to hepatotoxicity and rebound effect. Current adjuvant therapies commonly used in RRP include cidofovir (Vistide) and bevacizumab (Avastin) injected intraoperatively directly into the lesion. The effectiveness of cidofovir for RRP has been controversial. The only randomized controlled trial in the literature found no significant difference between cidofovir and placebo at 12 months; however, the sample size was small and there were problems with the dosing regimen. Other papers have consisted of retrospective case series and case reports. Graup et al found remission in 25 of 34 patients (74%). Tanna et al found a 46% remission rate with cidofovir therapy. Wierzbicka et also showed a 56% remission rate. In 2003, Naiman et al demonstrated a remission rate of 31% and a final result of only slight or mild disease in 65% of patients.   Bevacizumab, one of the newest adjuvant treatments of RRP, was shown by Sidell et al to have a 25% complete remission rate, and a doubling of the time interval between treatments. Rogers et al found an increase in the time between interventions of 5.9 weeks after a series of 3 bevacizumab injections. Other adjuvant therapies, with much lower remission rates, have included high dose cimetidine, mumps vaccine, photodynamic therapy (PDT), ribavirin, acyclovir, indole-3-carbinol and most recently, propranolol.
Figure 2. Dramatic improvement in laryngeal papilloma in a patient receiving cidofovir adjuvant therapy before and after receiving the Gardasil vaccine series.  A. Larynx before Gardasil vaccine.  B. Larynx at completion of Gardasil vaccine series. 
The development of the Gardasil vaccine has stimulated interest within the otolaryngology community as to its potential to modulate the RRP disease course and perhaps induce remission. Originally a quadrivalent vaccine, Gardasil is currently active against nine HPV types, including types 6, 11, 16, 18, 31, 33, 45, 52 & 58, and has been shown to prevent disease transmission in those vaccinated prior to exposure. The vaccine was engineered to increase the immunogenicity of the viral capsid L1 protein by synthesizing it as a large polymer in yeast cells and then pairing it with adjuvants such as aluminum. Serology has demonstrated that the antibody titers after vaccination are much higher than after a natural infection. Recently, increased HPV titers after Gardasil vaccination have been documented in males with active laryngeal RRP, suggesting that vaccination may be able to influence the immune response in actively infected patients. A retrospective study of my patients has shown that the addition of Gardasil to the patient's previous regimen of surgery with adjuvant cidofovir or bevacizumab injection was associated with a significant increase in the intersurgical interval. (Figure 1)  Additionally, there were 8 cases of complete sustained remission. Figure 2 shows the benefit of the addition of Gardasil to the conventional surgical and adjuvant therapy. Men were more likely than women to achieve remission with the addition of Gardasil. The decreased efficacy in women appears to be related to the tumorigenic metabolites of estrogen. Of the two women achieving remission, one was postmenopausal and the other in a low estrogen state after total abdominal hysterectomy and oophorectomy. (Figure 3)  Our results show that the addition of Gardasil to established therapies allowed patients with continued active disease to achieve remission at rates comparable to those reported by previous investigators for the combination of surgery with cidofovir or bevacizumab injection. Therefore, patients failing that treatment are given an additional chance to achieve remission. 40% of our patients failing the combination of surgery with cidofovir or bevacizumab experienced remission and 25% experienced a partial remission. Thus, it appears that adding the vaccine as a therapeutic agent was enough to push many into remission and to decrease the severity of the disease. Vaccination should be considered an essential part of treatment for all patients with active RRP.
Figure 3. A. The overall change in intersurgical interval (ISI) is plotted for male patients before and after receiving the Gardasil vaccine.  B. The overall change in intersurgical interval (ISI) is plotted for female patients before and after receiving the Gardasil vaccine.
References
  1. Young DL, Moore MM, Halstead LA. The use of the quadrivalent human papillomavirus vaccine (Gardasil) as adjuvant therapy in the treatment of recurrent respiratory papilloma. J Voice. 2015 Mar;29(2):223-9. doi: 10.1016/j.jvoice.2014.08.003. Epub 2015 Jan 22. PMID: 25619468.
  2. Zeitels, S. M. et al. Microlaryngoscopic and office-based injection of bevacizumab (Avastin) to enhance 532-nm pulsed KTP laser treatment of glottal papillomatosis. Ann Otol Rhinol Laryngol Suppl. 201, 1-13 (2009)
  3. Makiyama K, Hirai R, Matsuzaki H. Gardasil Vaccination for Recurrent Laryngeal Papillomatosis in Adult Men: First Report: Changes in HPV Antibody Titer. Journal of Voice. http://dx.doi.org/10.1016/j.jvoice.2016.01.008. Epub 2016
Dr. Lucinda A. Halstead
Lucinda A. Halstead, M.D.

Associate Professor
Medical Director, MUSC Evelyn Trammell Institute for Voice and Swallowing 
M.D.: The George Washington University School of Medicine and Health Sciences
Residency: Tufts/Boston University Program - Otolaryngology Head & Neck Surgery
Special Interests: ENT - Voice & Swallowing
Email: [email protected]

E-Update Articles 
Look for these articles in upcoming issues!
   
August: The Effect of USP 797 Compounding Guidelines and The Compounding Bill on the Administration of Allergen Immunotherapy 
   
September: Endoscopic Sinus Surgery: When and how much?

October:
Balancing Function and Aesthetics in Nasal Surgery 


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August 5 - 7, 2016

November 11, 2016
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4th Annual Pediatric ENT Update
February 2017

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March 28-31, 2017

Temporal Bone Dissection Course
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The Charleston Course: 7th Annual Otolaryngology Literature Update
July 14-16, 2017 
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