Pharmacotherapy for Recurrent Respiratory Papillomatosis - Update January 2023

last modified on: Tue, 02/27/2024 - 15:17

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

GENERAL CONSIDERATIONS (1-09-2023)

Background

Recurrent respiratory papillomatosis affects the airway (larynx and lungs) to cause speaking and breathing problems classically treated surgically by resection or laser vaporization (see links to procedures above). The prevalence of RRP has declined with introduction of the human papillomavirus (HPV) vaccine - but still is (as of 2019) the most common benign laryngeal neoplasm in children (Derkay 2019). Human papilloma virus strains 6 and 11 (HPV6 and HPV11) are implicated as most common - with variable presentation of the disease in both children and adults - characterized by recurrence that may be aggressive - but also cases with spontaneous remission.

Adjuvant (Non-Surgical) Therapy

As per Ruiz et al (2022) "for children with severe disease involving the trachea and lungs, there has been no reliably effective adjuvant medication to help reduce the need for repeated surgical debridements"

Despite the opening statement above, these investigators report enthusiasm for use of adjuvant therapy based on the favorable results they report with long-term treatment employing bevacizumab infusions for 7 patients with a median duration of treatment of 2.13 years (the longest at 5.5 years). Ruiz et al (2022) report this experiences as introducing a paradigm shift away from their traditional use of reserving adjuvant therapy for those requiring debridement more than four times per year (in the absence of lung disease). The paradigm shift they report is to consider bevacizumab (Avastin®, Genentech, Inc) as primary therapy and surgery as an adjuvant.

Derkay et al (2023) similarly identify the potential paradigm shift that has led some centers to use "intraveous bevacizumab as first-line of therapy". They advocate for addiational controlled studies in acknowleding a potential paradigm shift toward medical management of RRP.

a. Bevacizumab

Bevacizumab (Avastin ®, Genentech, Inc.) is a humanized monoclonal antibody that inhibits bascular endothelial growth factor (VEGF) to disrupt tumor angiogenesis (Sullivan 2010). Reports of response to both systemic (Mohr 2014) and intralesional (2013) bevacizumab therapy for RRP generated enthusiasm following the initial report in 2009 in the German literature (Nagel 2009 cited by Ruiz 2022).

A systematic literature review by Pogoda (2022) identified 15 studies including 64 patients with RRP treated with bevacizumab (95% systemic; remainder intralesional injection). They judged the overall quality of the articles to be 'moderate'. Although some benefit was identified with intralesional injection (interval between surgeries extended in 62% of patients), the systemic treatment was more effective wtih more than half of the patients avoiding the need for surgical intervention with a mean 21.6 months followup. These investigators reported that side effects were identified in 44% (19/43) cases and were considered mild and self-limiting: "proteninuria, epistaxis, hemoptysis, hypertension, elevated creatinine level, headache, thrombocytopenia, hyperthyroidism, dysgeusia, nausea and premature menopause".

Ruiz et al (2022) report their approach to treating children with infusions every 3 weeks to every 4-6 weeks to 6-8 week intervals with the 'sweet spot' for infusion often between 2 to 3 months with 5 of the 7 patients they reported ultimately maintained on an infusion schedule everey 3-4 months. They report finesse in administration is important and in their practice involved a medical oncologist and 'ideally' a 2-4 week delay prior to bevacizumab infusion following surgery to avoid major bleeding or hemoptysis. Other side effects from treatment have been chronicled.

b. Vaccination as therapy

A non-randomized clinical trial of HPV vaccination as adjuvant therapy for 50 patients with RRP by Smahelova et al (2022) resulted in seroconversion in patients with out previous HPV-specific antibodies and all patients developing a 100-fold higher level of HPV vaccine type-specific antibodies compared to pre-vaccination. The frequency of RRP recurrence was found to be significantly lowerafter HPV vaccination resulting in their conclusion: "the earlier that patients with RRP receive HPV vaccine, the sooner they may show reduced burden of disease".

A systemic review published by Park et al (2022) concluded that "therapeutic use of HPV vacciantion has shown promise for some JoRRP [Juvenile-onset RRP] patients, it remains uncertain with the currently available data".

Nyirjesy et al (2022) contend that "HPV vaccination for all patients with RRP, even over the age of 45 years, may decrease treatment costs" - based on their literature review associated with their single case report of complete resolution of RRP after vaccination.

c. Metformin

Din-Lovinescu and Blitzer (2022) studied 5 non-diabetic patients with adult-onset RRP treated wtih 500 mg twice daily dosing of metformin with reduced progression and burden of disease identified in all five patients, two showing spontaneous resolution independent of surgical procedures. The investigators suggested further study and offered conjecture regarding several mechanisms to explain metformin's antiproliferative effects.

d. Active Hexose Correlated Coumpound (AHCC)

AHCC was proposed by Gau and Benninger (2022) as a possible immunity strengthening oral over-the-counter supplement derived from shiitake muschrooms that may have benefit. They cited a phase II ongoing study evaluating its use for clearance of cervical HPV - but no data addressing RRP.

e. Cidofovir

Ablanedo-Terrazas et al (2020) performed a randomized placebo-controled study comparing adjuvant intralesional cidofovir with bevacizumab and placebo. 5 children and 11 adults were enrolled with no difference between treatment arms observed in the annular surgery rate- with their conclusion that in this small study they observed a signficant decrease in RRP severity with intralesional cidofovir but not intralesional bevacizumab.

f. Indole-3-Carbinol

Rosen and Bryson (2003) evaluated 45 patients with RRP treated with indole-3-carbinol following complete surgical resection over a 5 years period. 12 patients were lost to followup. The dose was "I3C PO BID with the adult dose as 200 mg and pediatric dosages determined by weight." (citing Derkay et al 1998). 11/33 (33%) 'experienced remission of papillomatous growth and did not require surgery while on I3C - with no immediate or long-term side effects related to I3C were found - leading to their interpretation that "Our results indicate that I3C can be a safe and efficacious chemopreventative agent for patients with RRP" - and - "efficacy in pediatric population merits further study".

References (1-09-2023)

Derkay CS, Bluher AE. Update on Recurrent Respiratory Papillomatosis. Otolaryngol Clin North Am. 2019 Aug;52(4):669-679. doi: 10.1016/j.otc.2019.03.011. Epub 2019 May 8. PMID: 31078306.

Ruiz R, Balamuth N, Javia LR, Zur KB. Systemic Bevacizumab Treatment for Recurrent Respiratory Papillomatosis: Long-Term Follow-Up. Laryngoscope. 2022 Oct;132(10):2071-2075. doi: 10.1002/lary.30021. Epub 2022 Jan 19. PMID: 35043981.

Pogoda L, Ziylan F, Smeeing DPJ, Dikkers FG, Rinkel RNPM. Bevacizumab as treatment option for recurrent respiratory papillomatosis: a systematic review. Eur Arch Otorhinolaryngol. 2022 Sep;279(9):4229-4240. doi: 10.1007/s00405-022-07388-6. Epub 2022 Apr 24. PMID: 35462578; PMCID: PMC9363326.

Derkay CS, Wikner EE, Pransky S, Best SR, Zur K, Sidell DR, Klein A, Rosen C, Dikkers FG, Johnson R. Systemic Use of Bevacizumab for Recurrent Respiratory Papillomatosis: Who, What, Where, When, and Why? Laryngoscope. 2023 Jan;133(1):2-3. doi: 10.1002/lary.30180. Epub 2022 May 11. PMID: 35543118.

Din-Lovinescu C, Blitzer A. Metformin for the Treatment of Recurrent Respiratory Papillomatosis. Ann Otol Rhinol Laryngol. 2022 Sep 21:34894221125002. doi: 10.1177/00034894221125002. Epub ahead of print. PMID: 36131550.

Yeung V, Sackstein P, Grant NN, Krochmal R, Gandhi N, Aggarwal C, Halmos B, Reuss JE, Liu SV, Kim C. Use of Erdafitinib in FGFR3-Mutated Recurrent Respiratory Papillomatosis. JCO Precis Oncol. 2022 Nov;6:e2200435. doi: 10.1200/PO.22.00435. PMID: 36455194.

Gau VL, Benninger MS. Potential Role for Active Hexose Correlated Compound (AHCC) in Treatment of Recurrent Respiratory Papillomatosis. J Voice. 2022 Jul;36(4):441-442. doi: 10.1016/j.jvoice.2022.05.004. Epub 2022 Jun 27. PMID: 35773058.

Nyirjesy S, Osmundson P, Matrka L. Spontaneous Regression of Recurrent Respiratory Papillomatosis with HPV Vaccination: A Case Study. J Voice. 2022 Jul;36(4):587.e21-587.e25. doi: 10.1016/j.jvoice.2020.08.013. Epub 2020 Sep 3. PMID: 32891477.

Smahelova J, Hamsikova E, Ludvikova V, Vydrova J, Traboulsi J, Vencalek O, Lukeš P, Tachezy R. Outcomes After Human Papillomavirus Vaccination in Patients With Recurrent Respiratory Papillomatosis: A Nonrandomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2022 Jul 1;148(7):654-661. doi: 10.1001/jamaoto.2022.1190. PMID: 35653138; PMCID: PMC9164118.

Ablanedo-Terrazas Y, Estrada-Camacho O, Alvarado-de la Barrera C, Ramírez-García A, Tona-Acedo G, Bross-Soriano D, Schimelmitz-Idi J. Efficacy of cidofovir versus bevacizumab in recurrent respiratory papillomatosis: A randomized, double-blind, placebo-controlled pilot study. Acta Otorrinolaringol Esp (Engl Ed). 2022 Mar-Apr;73(2):82-88. doi: 10.1016/j.otoeng.2020.12.001. PMID: 35397828.

Park I, Carbone S, Preciado D. Systematic review of the use of human papillomavirus vaccine as adjuvant therapy for juvenile-onset recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol. 2022 Nov;162:111314. doi: 10.1016/j.ijporl.2022.111314. Epub 2022 Sep 13. PMID: 36116179.

Rosen CA, Bryson PC. Indole-3-carbinol for recurrent respiratory papillomatosis: long-term results. J Voice. 2004 Jun;18(2):248-53. doi: 10.1016/j.jvoice.2003.05.005. PMID: 15193659.

Derkay CS, Malis JM, Zalzal G, Wiatrak BJ, Kashima HK, Coltera MD. A staging system for assessing severity of disease and response to therapy in recurrent respiratory papillomatosis. Laryngoscope. 1998;108:935–937.

Sidell DR, Balakrishnan K, Best SR et al (2021) Systemic bevacizumab for treatment of respiratory papillomatosis: international consensus statement. Laryngoscope 131:1–9

Sullivan LA, Brekken RA. The VEGF family in cancer and antibody-based strategies for their inhibition. MAbs 2010;2:165–175.

Mohr M, Schliemann C, Biermann C, et al. Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis. Oncol Lett 2014;8:1912–1918.

Rogers DJ, Ojha S, Maurer R, Hartnick CJ. Use of adjuvant intralesional bevacizumab for aggressive respiratory papillomatosis in children. JAMA Otolaryngol Head Neck Surg 2013;139:496–501

Nagel S, Busch C, Blankenburg T, Schutte W. Treatment of respiratory papillomatosis—a case report on systemic treatment with bevacizumab. Pneumologie 2009;63:387–389.

Ryan MA, Leu GR, Upchurch PA, Tunkel DE, Walsh JM, Boss EF (2021) Systemic bevacizumab (Avastin) for juvenile-onset recurrent respiratory papillomatosis: a systematic review. Laryngoscope 131(5):1138–1146

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Updated Site As Per Above 1-09-2023

Historical Perspective Maintained Below (contains some outdated material)

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.

Symptoms include hoarseness, stridor, dyspnea or dysphagia.
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.
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.
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.
Contraindications
1. By agent, as listed below
2. Agents with less severe side effects preferable for milder disease

PRETHERAPEUTIC EVALUATION

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
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
Repeat DL/B with videorecording at least every eight to 12 weeks
Baseline CXR, repeated annually
Additional workup if distal tracheal or bronchopulmonary tree involved
1. Chest CT
2. Referral to pulmonologist
3. Pulmonary function tests
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

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
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.
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 NOTE: Derkay et al (2023) identify "contemporary use of interferon-α has been curtailed due to serious side effects including neurologic disorders, leukopenia, and thrombocytopenia"
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
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
  2. CONTRAINDICATED IN A PATIENT WHO MAY BECOME PREGNANT
  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. FETAL ABNORMALITIES
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
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..
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).

SURGICAL MANAGEMENT

TRACHEOSTOMY SHOULD BE AVOIDED as it is associated with distal airway involvement; Likely secondary to seeding of HPV virus
Techniques include microdebrider, cold resection and CO2 laser; in office or in OR
Goals of surgical care is to remove symptomatic lesions and maximize amount of time patient is symptom free between procedures.
Pathologic examination of resected tissue should be done regularly

Iowa Head and Neck Protocols