Pathophysiology

Human papillomavirus infiltrates basal epithelial cells of the squamous epithelium through microtears in the overlying cell layers, activating the epidermal growth factor pathway and suppressing tumour-suppressor proteins.^{Reference Fortes, von Ranke, Escuissato, Araujo Neto, Zanetti and Hochhegger5} Specifically, the proteins encoded by the E6 and E7 regions of the HPV viral genome interfere with tumour suppressor proteins p53 and pRB, respectively.^{Reference Oh, Longworth and Laimins6} This results in cellular proliferation and epithelial differentiation that culminates in the development of papillomatous lesions that can be microscopic or macroscopic and exophytic. These lesions are typically benign, but depending on the specific subtype of HPV involved, they can have varying degrees of malignant potential. In recurrent respiratory papillomatosis these papillomata predominantly manifest at the junction between the stratified squamous epithelium in the larynx and the pseudostratified columnar epithelium of the respiratory tract distally.^{Reference Fortes, von Ranke, Escuissato, Araujo Neto, Zanetti and Hochhegger5}

Human papillomavirus infection is ubiquitous in the population. It is estimated that by the age of 50 years old, 80 per cent of women in the United States have serological evidence of previous infection.^{Reference Syrjänen, Hakama, Saarikoski, Väyrynen, Yliskoski and Syrjänen7} While in the majority of cases the virus is cleared by a host cell-mediated immune response, it is estimated that 5 per cent of the general population has HPV DNA detectable in their larynx suggesting persistent infection.^{Reference Sivasankar, Erickson, Rosenblatt and Branski8} It is unclear why a small number of these individuals go on to develop recurrent respiratory papillomatosis, but it is thought to be related to an ineffective immune response to the viral proteins. While the mechanism is unknown, there is evidence that the adaptive immune response becomes polarised toward a Th2-like or T-regulatory phenotype in these patients. This results in suppression of Th1 cells that would produce the inflammatory cytokines, such as interleukin-2 and tumour necrosis factor, responsible for clearing viral infections.^{Reference Bonagura, Hatam, Rosenthal, De Voti, Lam and Steinberg9}

Recurrent respiratory papillomatosis is predominantly associated with HPV sub-types 6 and 11, but can also be caused by other strains, including 16, 18, 31 and 33. Traditionally, HPV 11 has been linked to more severe recurrent respiratory papillomatosis disease.^{Reference Welschmeyer and Berke10} However, emerging evidence suggests that age at diagnosis may be a more consistent predictor of disease severity, with the probability of an aggressive disease course being higher in patients diagnosed under five years of age.^{Reference Tjon Pian Gi, San Giorgi, Slagter-Menkema, van Hemel, van der Laan and van den Heuvel11,Reference Buchinsky, Valentino, Ruszkay, Powell, Derkay and Seedat12}

Juvenile-onset recurrent respiratory papillomatosis is typically thought to be due to transmission of maternal HPV infection to the child at birth. Trans-placental transmission of HPV has been suggested to occur in 12 per cent of cases,^{Reference Rombaldi, Serafini, Mandelli, Zimmermann and Losquiavo13} and the presence of maternal anogenital papilloma increases the risk of developing juvenile-onset recurrent respiratory papillomatosis by 231 times.^{Reference Silverberg, Thorsen, Lindeberg, Grant and Shah14} First-born status, vaginal delivery, and being born to a teenage mother have also been reported to increase the risk of juvenile-onset recurrent respiratory papillomatosis.^{Reference Kashima, Shah, Lyles, Glackin, Muhammad and Turner15}

Adult-onset recurrent respiratory papillomatosis has historically been thought to potentially be a sexually transmitted infection and linked to the practice of oral sex. Studies have found higher sexual partner counts, oral sex prevalence, and increased number of lifetime sexual partners to be associated with adult-onset recurrent respiratory papillomatosis. However, they also reported no significant difference in the number of lifetime oral sex partners when compared to controls, and instances where no prior oral sex or sexual partners were noted.^{Reference Buchinsky, Valentino, Ruszkay, Powell, Derkay and Seedat12,Reference Ruiz, Achlatis, Verma, Born, Kapadia and Fang16} An alternative hypothesis is that adult-onset recurrent respiratory papillomatosis may represent the reactivation of latent infection acquired at the time of birth. However, juvenile-onset recurrent respiratory papillomatosis and adult-onset recurrent respiratory papillomatosis patients have been demonstrated to have different exposures to the proposed birth risk factors^{Reference Buchinsky, Valentino, Ruszkay, Powell, Derkay and Seedat12} as well as no discernible difference in birth history between adult-onset recurrent respiratory papillomatosis patients and healthy controls.^{Reference Ruiz, Achlatis, Verma, Born, Kapadia and Fang16}

Surgical treatment

In adult-onset recurrent respiratory papillomatosis, the clinical course of the disease is highly variable but typically requires frequent surgical interventions. The average rate of surgeries is 4.4 per year and, although spontaneous remission can occur, chronic disease is the norm.^{Reference Rasmussen, Schnack, Jørkov, Raja, Olsen and Homøe17} Paediatric patients with juvenile-onset recurrent respiratory papillomatosis typically require an average of 5.1 surgeries per year, with a mean duration of disease of 4.4 years. Remission can occur at any age but is most likely in cases where the disease presents at 6–10 years of age and is confined to the larynx, with younger age of diagnosis (< 5 years old) being associated with more aggressive disease.^{Reference Armstrong, Derkay and Reeves18,Reference Reeves, Ruparelia, Swanson, Derkay, Marcus and Unger19}

Multiple modalities are available to surgically treat recurrent respiratory papillomatosis under general anaesthesia. These include cold steel, microdebrider, coblation, CO₂ laser (10 600 nm), pulsed dye laser (585 nm) and potassium titanyl phosphate (KTP) (532 nm), and blue-light laser (445 nm). There is growing evidence for the use of blue-light laser (445 nm) in an office-based laser treatment setting.^{Reference Hess, Fleischer and Ernstberger20,Reference Hamdan and Ghanem21} In terms of efficacy, a retrospective study of 112 adult-onset recurrent respiratory papillomatosis patients treated with KTP laser, CO₂ laser, or microdebrider found no significant difference in mean surgical intervals among the three treatment groups.^{Reference Hock, Kennedy, Howell, Friedman, de Alarcon and Khosla22} A further retrospective study of 194 adult-onset recurrent respiratory papillomatosis patients treated with either CO₂ laser or cold steel resection found the method of treatment did not affect the rate of recurrence.^{Reference Preuss, Klussmann, Jungehulsing, Eckel, Guntinas-Lichius and Damm23} The UK recurrent respiratory papillomatosis registry of 1208 procedures performed April 2018 to August 2022 demonstrated that a wide variety of surgical approaches are used across the UK. Analysis from the registry regarding which surgical modalities are most effective in recurrent respiratory papillomatosis has not yet been published, but the most common techniques employed were microdebrider, CO₂ laser, and radiofrequency ablation.²⁴

Repeated surgery at the same anatomic site carries a risk of complications such as mucosal scarring, webbing, impaired vocal cord mobility, and subglottic and glottic stenosis. A recent systematic review and meta-analysis of 20 studies reported a complication rate of 0–44.9 per cent.^{Reference Liu, Wang and Shao25} The weighted average complication rate for CO₂ laser treatment was 0.16, for KTP laser was 0.04, and for microdebrider was 0.03.^{Reference Liu, Wang and Shao25}

Quality of life and economic burden

Recurrent respiratory papillomatosis imposes a substantial QoL burden and economic strain. In the USA, the economic impact linked to non-cervical HPV types 6, 11, 16 and 18 was estimated to be $418 million annually.^{Reference Hu and Goldie26} The annual cost of treating a single case of juvenile-onset recurrent respiratory papillomatosis has been estimated to range from $58,000 to $76,115, and for adult-onset recurrent respiratory papillomatosis to range from $5000 to $11,000.^{Reference Bishai, Kashima and Shah27,Reference Tam, Wu, Peng, Dahlstrom, Sturgis and Lairson28} A UK-based single-centre study reported an annual expenditure of £7677 per adult-onset recurrent respiratory papillomatosis patient.^{Reference Harrison, Montgomery and Macgregor29}

Recurrent respiratory papillomatosis can also have a significant effect on a patient's QoL. A recent study by So et al. found that 65.7 per cent of patients miss at least five workdays monthly, 79.5 per cent reported social anxiety, and the average lifetime number of surgeries was 20.^{Reference So, McClellan and Best30} The financial strain on patients is also evident, with over half allocating at least 5 per cent of their annual income towards recurrent respiratory papillomatosis-related medical care. This economic burden on healthcare systems and the considerable effect on patients’ QoL emphasizes the pressing need for effective management strategies for recurrent respiratory papillomatosis.

Malignant transformation and surveillance

While recurrent respiratory papillomatosis is clinically a benign disease, the development of dysplasia and transformation to malignancy can occur. The rates of dysplasia reported in the literature are 10–55 per cent in adult-onset recurrent respiratory papillomatosis and 0–10 per cent in juvenile-onset recurrent respiratory papillomatosis.^{Reference Karatayli-Ozgursoy, Bishop, Hillel, Akst and Best31} However, it is unclear if there is a typical progression from dysplasia to invasive malignancy in recurrent respiratory papillomatosis. Factors that are thought to increase the risk for malignant transformation include previous radiotherapy, smoking, older age at diagnosis in adult-onset recurrent respiratory papillomatosis, younger age at diagnosis in juvenile-onset recurrent respiratory papillomatosis, and the HPV subtype.^{Reference Karatayli-Ozgursoy, Bishop, Hillel, Akst and Best31–Reference Donne, Hampson, Homer and Hampson33}

Human papillomavirus subtypes 11, 16 and 18 are considered higher risk for malignant transformation,^{Reference Karatayli-Ozgursoy, Bishop, Hillel, Akst and Best31} although it has still been reported to occur with HPV 6 infection.^{Reference Zarod, Rutherford and Corbitt34} With this in mind, there is evidence from case reports that the HPV subtypes present in the papilloma of an individual can change during the lifetime of their recurrent respiratory papillomatosis disease. Doyle et al. reported a case of juvenile-onset recurrent respiratory papillomatosis where HPV 6 and 11 subtypes were detected initially, but with repeated biopsy over an 8-year period there was subsequent detection of HPV 16.^{Reference Doyle, Henderson, LeJeune and Miller35} Fancello et al. reported a case of adult-onset recurrent respiratory papillomatosis where only HPV 6 was detected on biopsy at the three initial surgeries, but upon repeat surgery and biopsy 3 years later both HPV 6 and HPV 18 subtypes were detected.^{Reference Fancello, Melis, Piana, Castiglia, Cossu and Sotgiu36} This would suggest that repeat biopsies should be performed in patients when there is clinical suspicion of progression or spread of disease, as well as at regular intervals as part of routine surveillance to detect any change in HPV subtype.

While the exact pathogenesis remains unclear, the risk of malignant transformation in laryngeal recurrent respiratory papillomatosis is estimated to be 3–7 per cent in adults and less than 1 per cent in children.^{Reference Alanazi, Karas and Husain37} However, up to 8.9 per cent of patients with recurrent respiratory papillomatosis will have pulmonary involvement, which carries a 32-fold increased lifetime risk of malignant transformation (range 11.7–16 per cent) compared with the overall recurrent respiratory papillomatosis population.^{Reference Pai, Wasserman, Ji, Gilman, Hung and Faquin38}

A clinical algorithm for screening and surveillance of pulmonary involvement in recurrent respiratory papillomatosis, based on known risk factors, was developed by Pai et al. and published in 2022.^{Reference Pai, Wasserman, Ji, Gilman, Hung and Faquin38} The algorithm proposes performing a low-dose computed tomography (CT) thorax scan in all adult-onset recurrent respiratory papillomatosis patients at the time of initial diagnosis. In juvenile-onset recurrent respiratory papillomatosis patients the Pai et al.^{Reference Pai, Wasserman, Ji, Gilman, Hung and Faquin38} algorithm recommends performing low-dose CT at 7 years of age in those with risk factors and at 18 years of age in those without. If no pulmonary nodules or cysts are detected, then the recommendation is for a surveillance low-dose CT thorax scan every five years. If a nodule or cyst is detected then, depending on its size, either close monitoring with interval surveillance low-dose CT or further diagnostic workup is required.

However, the Pai et al.^{Reference Pai, Wasserman, Ji, Gilman, Hung and Faquin38} clinical algorithm does not specifically address management of patients where tracheal or proximal bronchial disease is identified at laryngo-tracheo-bronchoscopy. These patients may not necessarily have appreciable disease on cross-sectional imaging, but the presence of papilloma in these regions is a sign of more aggressive recurrent respiratory papillomatosis disease^{Reference Alanazi, Karas and Husain37} and confers a higher risk of progression to pulmonary involvement.^{Reference Yang, Li, Ma, Xiao, Wang and Ding39} To our knowledge, there is no published recommendation for radiological surveillance in this patient cohort. Within our department, after discussion with specialist colleagues in radiology and respiratory, we have reached a consensus to perform an interval surveillance low-dose CT every two years in these patients.

As HPV infection is also a risk factor for the development of cervical and oropharyngeal malignancy, many patients worry that recurrent respiratory papillomatosis might lead to one of these types of cancer in the future or put their sexual partners at risk. However, the few studies that have addressed concurrent infection in the head and neck and genital tracts suggest that oral oncogenic HPV infection occurs independently of cervical oncogenic HPV infection.^{Reference Wierzbicka, Klussmann, San Giorgi, Wuerdemann and Dikkers40}

Current adjuvant treatments

While surgical intervention is the mainstay of management for recurrent respiratory papillomatosis, approximately 20 per cent of patients will require adjuvant treatments to achieve disease control.^{Reference Schraff, Derkay, Burke and Lawson41} Accepted criteria for considering initiation of adjuvant treatment include disease requiring four or more surgeries per year, rapid regrowth of lesions with airway compromise, or spread of disease to the distal airway.^{Reference Alanazi, Karas and Husain37}

The next paragraphs describe the different available adjuvant therapies in detail.

Gardasil vaccine

Gardasil is an HPV vaccine prepared from purified virus-like particles of the major capsid L1 protein that is found on the external surface of the virus.^{Reference Harper and DeMars42} The initial quadrivalent Gardasil vaccine was approved for use in 2006 against HPV strains 6, 11, 16, and 18. A 9-valent vaccine Gardasil-9 was subsequently approved for use against the additional strains of 31, 33, 45, 52, and 58 in 2014.^{Reference Benedict and Derkay43}

Gardasil vaccination leads to a persistent neutralising antibody response and has been shown to have a profound effect on the prevention of recurrent respiratory papillomatosis in countries where vaccination rates are high, such as in Australia where they demonstrated a significant decrease in the incidence of recurrent respiratory papillomatosis from 0.16 to 0.02 per 100 000 children.^{Reference Novakovic, Cheng, Zurynski, Booy, Walker and Berkowitz44} Furthermore, there is increasing evidence that national Gardasil vaccination programs are cost-effective and have a positive effect on public health by reducing the burden of HPV-related diseases, including HPV-associated cancer.^{Reference Patel, Brotherton, Pillsbury, Jayasinghe, Donovan and Macartney45–Reference Owusu-Edusei, Palmer, Ovcinnikova, Favato and Daniels47}

Gardasil vaccination is also thought to have a role as an adjuvant treatment. A 2019 systematic review and meta-analysis of 63 patients from 5 studies found that the mean interval between surgical procedures increased from 7.02 months to 34.45 months.^{Reference Rosenberg, Philipsen, Mehlum, Dyrvig, Wehberg and Chirilǎ48} An updated meta-analysis in 2023 of 101 patients from three studies reported an estimated overall reduction of 0.123 recurrences or surgeries per month following Gardasil vaccination.^{Reference Goon, Sauzet, Schuermann, Oppel, Shao and Scholtz49} These findings suggest that HPV vaccination is effective as both a preventative measure and a therapeutic adjunct that can reduce the frequency of surgical interventions required by recurrent respiratory papillomatosis patients.

The American Academy of Otolaryngology-Head & Neck Surgery released a position statement in 2021 supporting the use of Gardasil-9 vaccination in all recurrent respiratory papillomatosis patients 9–45 years of age.⁵⁰ Its use in patients under 9 or over 45 years of age is considered “off-label” and therefore its use in these patients should be based on a shared-decision-making process. While not contraindicated, there is a lack of evidence regarding the potential benefits of administration of the Gardasil-9 vaccination to patients with recurrent respiratory papillomatosis who have previously received the quadrivalent Gardasil vaccine.⁵¹ However, a large randomized, double-blinded, placebo-controlled trial published in 2015 investigated the effect of administering the Gardasil-9 vaccine to healthy adolescent and adult females who had previously received the quadrivalent Gardasil vaccine.^{Reference Garland, Cheung, McNeill, Petersen, Romaguera and Vazquez-Narvaez52} The study found that administration of the Gardasil-9 vaccine was safe and well tolerated, and led to seroconversion in more than 98 per cent of participants with significant increases in antibody titres to all 9 HPV sub-types. The practice at our centre is to offer Gardasil-9 vaccination to both unvaccinated recurrent respiratory papillomatosis patients and those who have previously received the quadrivalent Gardasil vaccine.

Intralesional Cidofovir

Cidofovir, a cytosine nucleotide analogue, exhibits its antiviral action by incorporating into the DNA chain of viruses and inhibiting the viral DNA polymerization process. Its long intracellular half-life leads to an antiviral effect that can last from several days to weeks. While the FDA approved Cidofovir for the treatment of cytomegalovirus (CMV) retinopathy in acquired immunodeficiency syndrome (AIDS), it has been used off-label intralesionally for recurrent respiratory papillomatosis since 1998.^{Reference Tjon Pian Gi, Dietz, Djukic, Eckel, Friedrich and Golusinski53}

Optimal timing and dosing for Cidofovir treatment in recurrent respiratory papillomatosis lacks consensus. A 2013 study of 82 surgeons concluded that standalone indications for use included a requirement for six or more operations/year, increasing frequency of surgery, or extra-laryngeal spread in paediatric patients.^{Reference Derkay, Volsky, Rosen, Pransky, McMurray and Chadha54} Initiation should be considered in patients who exhibited a combination of factors such as requiring four or more operations per year, persistent disease at the anterior or posterior commissures, and failure to respond to their current surgical regime. While most surgeons reported administering up to five injections to determine efficacy for the patient, some allowed up to 10 injections, and others did not observe a limit. Typical doses used are 20–40 mg (< 4 ml) in adults and 20 mg (< 2 ml) in paediatrics, with scheduled administration every 3–6 weeks. Safe total dosing limits for Cidofovir were deemed to be 3 mg/kg.⁵¹

Regarding efficacy, a Cochrane review in 2012 of 92 publications found insufficient evidence to support the efficacy of intralesional Cidofovir over placebo.^{Reference Chadha and James55} The review included one randomized controlled trial published in 2008 of 15 adults and 4 children.^{Reference McMurray, Connor and Ford56} Although significant improvement in the Derkay Severity Score^{Reference Derkay, Malis, Zalzal, Wiatrak, Kashima and Coltrera3} (measure of disease extent) within the Cidofovir and placebo groups was found at 2- and 12-month follow-ups, no significant difference was found between Cidofovir and placebo groups, nor any difference between groups, in the number of procedures performed. However, a more recent literature review conducted in 2020 reported that intralesional Cidofovir achieved a complete response rate in 74 per cent of 185 patients with adult-onset recurrent respiratory papillomatosis and 56.5 per cent of 85 patients with juvenile-onset recurrent respiratory papillomatosis.^{Reference Gazia, Galletti, Freni, Bruno, Sireci and Galletti57} The mean concentration used in the studies was 7.5 mg/ml, and the mean number of injections was 6, with 26 days between injections.

With regard to adverse effects, concerns have been raised regarding intralesional Cidofovir administration and the development of vocal fold scarring. While a porcine model showed no effect after a course of four injections of up to 5 mg (10 mg/mL) doses of intralaryngeal Cidofovir to the porcine vocal fold,^{Reference Connor, Brown, Palazzolo, Kunkel and Eller58} a canine model showed dose-dependent irreversible atrophy and scarring of the canine vocal fold after a course of 12 injections of 20 mg (40 mg/mL) or 37.5 mg (75 mg/mL) doses.^{Reference Chhetri, Jahan-Parwar, Hart, Bhuta, Berke and Shapiro59} Cidofovir is also contraindicated during pregnancy due to potential teratogenicity, and there have been concerns raised about the risk of nephrotoxicity as well as possible carcinogenesis. With regards to nephrotoxic effects, these are known to be dose-dependent and have only been observed with high-dose systemic administration.^{Reference Lalezari, Stagg, Kuppermann, Holland, Kramer and Ives60}

The concern regarding carcinogenesis stems from toxicology studies performed in rodents which were terminated early due to the development of mammary adenocarcinoma.^{Reference Broekema and Dikkers61} However, the total doses delivered were greater than the equivalent human systemic exposure received at the recommended dose for CMV retinopathy, and it should be noted that the development of mammary adenocarcinoma is a frequent occurrence in rodent pharmacological studies. These findings were not replicated in similar primate studies, albeit at intravenous doses equivalent to 0.7 times the human systemic exposure.^{Reference Derkay62} Concerns regarding a possible dysplastic effect of the drug were raised in a case, reported by Wemer et al. in 2005, of progressive dysplasia seemingly associated with intralesional administration of Cidofovir in a patient with adult-onset recurrent respiratory papillomatosis.^{Reference Wemer, Lee, Hoffman, Robinson and Smith63} However, a subsequent international retrospective study of 635 adult-onset recurrent respiratory papillomatosis patients demonstrated no differences in renal dysfunction or the incidence of upper airway and tracheal malignancies between Cidofovir and non-Cidofovir groups.^{Reference Tjon Pian Gi, Ilmarinen, van den Heuvel, Aaltonen, Andersen and Brunings64}

Intralesional Bevacizumab

Bevacizumab is a human monoclonal antibody that can bind to and inhibit vascular endothelial growth factor expressed on papilloma epithelium. This subsequently inhibits angiogenesis, which is thought to be a crucial factor in determining the rate of papilloma recurrence. Both systemic and intra-lesional administration have been described for the treatment of recurrent respiratory papillomatosis, with the first systemic use reported in 2009.^{Reference Nagel, Busch, Blankenburg and Schütte65}

The efficacy of Bevacizumab as a treatment option was assessed in a recent systematic review published in 2022.^{Reference Pogoda, Ziylan, Smeeing, Dikkers and Rinkel66} Sixty-four patients were included from 15 case series or case report studies, with 54 of the 64 patients having juvenile-onset recurrent respiratory papillomatosis. When administered intralesionally, Bevacizumab was not found to be as effective as systemic administration, with only 62 per cent (13 out of 21) of patients showing a prolongation in the post-treatment surgical interval (4–12 weeks) compared to the pre-treatment interval (2–6 weeks). The occurrence of side effects was discussed in eight of the reported cases, with no side effects found.

The intra-lesional efficacy of Bevacizumab was further assessed in a randomised, placebo-controlled trial of 16 participants (5 children, 11 adults) comparing Bevacizumab to Cidofovir after cold steel papilloma resection.^{Reference Ablanedo-Terrazas, Estrada-Camacho, Alvarado-de la Barrera, Ramírez-García, Tona-Acedo and Bross-Soriano67} Cidofovir exhibited a significant Derkay Severity Score decrease after one year (p = 0.027), while Bevacizumab and placebo showed no significant changes. All treatment groups experienced a significant decrease in voice handicap index score (p < 0.001), attributed to surgical papilloma resection.

Systemic Bevacizumab

A 2021 Delphi study involving 70 international experts provided consensus statement on systemic Bevacizumab use in recurrent respiratory papillomatosis.^{Reference Sidell, Balakrishnan, Best, Zur, Buckingham and De Alarcon68} The consensus suggested that age at surgery or at time of diagnosis should not be a deciding factor in the treatment of patients with recurrent respiratory papillomatosis, with both paediatric and adult patients open to consideration. Disease characteristics that were supported by consensus or near-consensus included progressive and/or severe disease burden, disease in locations difficult to treat, need for tracheostomy due to disease burden, and increasing Derkay Severity Score over the preceding year.

Systemic Bevacizumab appears to be more effective than intralesional administration for the treatment of recurrent respiratory papillomatosis.^{Reference Wemer, Lee, Hoffman, Robinson and Smith63} Systemic treatment with Bevacizumab led to considerably longer surgical intervals in 95 per cent (41 out of 43 cases) of patients post-treatment (3–17 months) compared to pre-treatment (1–8.6 weeks). In 55 per cent (24 out of 43) of patients, no further surgical interventions were required during follow up. Side effects were observed in 44 per cent (19 out of 43) of patients and included proteinuria, epistaxis, haemoptysis, hypertension, headache, thrombocytopaenia, hyperthyroidism and nausea. However, these were all classified as mild and self-limiting.

There is no universally adopted dosing protocol for the use of systemic Bevacizumab as an adjuvant treatment in recurrent respiratory papillomatosis. One suggested regime following standard chemotherapy guidelines is a 10 mg/kg target dose with infusions given initially every 3–4 weeks for 6 cycles, before a maintenance regime of infusions every three months for two years with surveillance laryngo-trachea-bronchoscopies.^{Reference Fernandez-Bussy, Labarca, Vial, Soto, Mehta and Jantz69}