Post-surgical recurrence of lesions is common, but the frontiers of non-surgical RRP management are expanding. RRP treatment may look very different in the not-too-distant future.
Aaron D. Friedman, MD, on behalf of the Voice Committee
Aaron D. Friedman, MDRecurrent respiratory papillomatosis (RRP) is a chronic, incurable infection of the upper aerodigestive tract caused by infection with human papilloma virus (HPV) types 6 and 11. The disease results in exophytic, wart-like lesions that usually occur in a multifocal pattern and can affect mucosal surfaces of the larynx, tracheobronchial tree, pharynx, oral cavity, and/or esophagus. In advanced cases, even the lung parenchyma can be involved.
Surgical debridement (in the operating room under general anesthesia, and, more recently, as awake, angiolytic laser procedures in the office) has been the mainstay of management by otolaryngologists. Despite attempts at complete surgical extirpation, however, recurrence of the lesions is common, although the rate and aggressiveness are variable between patients and sometimes even within a patient.
Although many patients with RRP suffer from dysphonia and/or airway obstruction because of the disease, recent data have demonstrated what has been long suspected: iatrogenic laryngeal injury (which can also lead to these symptoms) increases with the lifetime total number of surgical procedures.1 This can lead to chronic, incurable hoarseness. As such, there has been renewed interest and progress in non-surgical options to manage this disease.
Bevacizumab
The use of bevacizumab, a vascular endothelial growth receptor (VEGF)-inhibiting antibody, was first described as an off-label localized injection in addition to surgery to help manage RRP 15 years ago.2 However, increasing evidence has been mounting as to the parenteral efficacy of this drug in significantly reducing surgical intervention frequency and improving voice in patients with advanced RRP.3 In some cases, the reduced need for surgical intervention has persisted (at least temporarily) even after discontinuing the drug.4 Catastrophic, irreversible side effects have not yet been reported to date, although some RRP patients receiving intravenous (but not local) bevacizumab experience renal dysfunction, hypertension, thrombocytopenia, epistaxis, headache, gastrointestinal distress, or impaired wound healing.4 Management of RRP with parenteral bevacizumab is best performed in collaboration with a medical oncologist familiar with this medication. Also, because the current use of bevacizumab in RRP is off-label, insurance hurdles can be significant.
Prophylactic HPV Vaccines
Some prophylactic HPV vaccines also include protection against types 6 and 11, including the current nonavalent vaccine, Gardasil 9® (FDA approved in 2014), as well as its quadrivalent predecessor, Gardasil® (FDA approved in 2006, but no longer available in the United States). Although the mechanism of efficacy remains unclear for those with RRP (who are already infected with HPV type 6 and/or 11), there are retrospective, meta-analysis data suggesting that RRP patients who subsequently received one of these vaccines had an increase in inter-surgical intervals.5 Less controversial is the fact that use of Gardasil 9® in a patient with RRP will provide protection against all other HPV serotypes covered by the vaccine, including HPV 16 and 18, which cause cervical and oropharyngeal cancers. Gardasil 9® is currently FDA approved in the United States for male and female patients from age 9 through 45. However, because the maximum age approved by the FDA only recently (2018) increased to 45 (from 26 years old), there may be a substantial number of adult-onset RRP patients who previously never received the vaccine but would benefit from doing so.
Therapeutic HPV Vaccines
Perhaps the most exciting advances in RRP management have come in the last few years, where there has been an acceleration in the development of therapeutic vaccines against HPV 6 and 11. Two recent phase 1/2 trials of different therapeutic HPV 6/11 vaccines in adult RRP patients have demonstrated minimal side effects. Although these trials are difficult to compare owing to design differences, 24% – 50% of participants formerly receiving at least two surgeries per year needed no additional surgical treatment during one year of post-vaccination follow up.6,7 Although additional studies are planned, FDA review of the results to date has been favorable enough that commercial development of both vaccines is currently being explored.
With the goals of maximally preserving voice and laryngeal function and more successfully dealing with the disease, particularly when it is surgically less accessible, the frontiers of non-surgical RRP management are expanding rapidly. Indeed, the way in which this disease is treated may be very different in the not-so-distant future.
World Voice Day Resources for You and Your Patients
For more information on maintaining vocal health, check out these other articles from the AAO-HNS Voice Committee in this issue of the Bulletin:
So RJ, Hillel AT, Motz KM, Akst LM, Best SR. Factors Associated with Iatrogenic Laryngeal Injury in Recurrent Respiratory Papillomatosis. Otolaryngol Head Neck Surg. 2023.
Zeitels SM, Lopez-Guerra G, Burns JA, Lutch M, Friedman AD, 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;201:1-13.
Pogoda L, Ziylan F, Smeeing DPJ, Dikkers FG, Rinkel R. Bevacizumab as treatment option for recurrent respiratory papillomatosis: a systematic review. Eur Arch Otorhinolaryngol. 2022;279(9):4229-4240.
Ballestas SA, Hidalgo Lopez J, Klein AM, et al. Long-Term Follow-up of Parenteral Bevacizumab In Patients with Recurrent Respiratory Papillomatosis. Laryngoscope. 2023;133(10):2725-2733.
Ponduri A, Azmy MC, Axler E, et al. The Efficacy of Human Papillomavirus Vaccination as an Adjuvant Therapy in Recurrent Respiratory Papillomatosis. Laryngoscope. 2023.
Mau T, Amin MR, Belafsky PC, et al. Interim Results of a Phase 1/2 Open-Label Study of INO-3107 for HPV-6 and/or HPV-11-Associated Recurrent Respiratory Papillomatosis. Laryngoscope. 2023;133(11):3087-3093.
Norberg SM, Bai K, Sievers C, et al. The tumor microenvironment state associates with response to HPV therapeutic vaccination in patients with respiratory papillomatosis. Sci Transl Med. 2023;15(719):eadj0740.
Aaron D. Friedman, MD
