Discussion
Recurrent respiratory papillomatosis is a challenging airway disease, especially in children who generally present with more aggressive disease and have higher recurrence rates than adults.14 Multiple surgeries are often necessary to maintain airway patency and laryngeal anatomy. The mean number of yearly surgical procedures per child is 5.1 with an average of 20 procedures in a child’s lifetime.15 Many adjuvant medical therapies, including interferon-alfa, celecoxib, intralesional cidofovir, and intralesional bevacizumab, have failed to reliably decrease surgical frequency.8
Recently, systemic bevacizumab has been shown to decrease papilloma burden and reduce surgical frequency. Bevacizumab targets VEGF to inhibit angiogenesis, indirectly inhibiting papilloma growth. Studies have shown strong expression of VEGF in papilloma epithelium and VEGFR-1 and VEGFR-2 in underlying vascular endothelium in patients with RRP.16 However, bevacizumab does not affect the underlying viral infection, and risk of recurrence after stopping treatment is possible.9,11,17 While current evidence supports the use of bevacizumab for RRP, in vitro and in vivo models of RRP are difficult to establish, limiting the identification of other potential therapeutic targets.18
In this article, we present two children who received systemic bevacizumab-awwb given significant disease recurrence. The biosimilar bevacizumab-awwb is structurally, functionally, and clinically similar to bevacizumab.19 Both patients received identical 10 mg/kg initiation and maintenance dosing schedules with a follow-up of 23 months and 15 months, respectively. Immediate improvement in respiratory and vocal symptoms was observed after just one cycle. Normal vocal quality often correlates with significant reduction of laryngeal lesions which was observed during follow-up laryngoscopies.13Both patients remain asymptomatic without need for surgical intervention after more than a year of treatment. The only side-effects observed were trace self-resolving proteinuria and stomachache, consistent with prior studies demonstrating tolerability of bevacizumab among children.4
Systemic bevacizumab is still a novel therapy for RRP, and standardized treatment protocols are lacking. Recently, an international consensus statement on ideal patient and treatment center characteristics was proposed. Consensus was reached that multiple disciplines, including pediatric oncology, are necessary to optimize systemic bevacizumab administration for RRP, highlighting a novel treatment paradigm for this benign but aggressive airway tumor.20 However, long-term effects of systemic bevacizumab and appropriate dosing schedules, including treatment endpoint, remain unknown. Anecdotal evidence suggests spacing cycles as detailed above from every 3 months to every 4 months to every 6 months and holding at that interval. If symptoms recur at any point, treatment frequency can be increased. Accumulated clinical experience through multidisciplinary partnerships, including primarily pediatric oncology and otolaryngology, may facilitate future multi-institutional efforts to standardize bevacizumab administration. Unfortunately, given the rarity and potential severity of RRP, randomized placebo-controlled trials are not feasible or ethically justified. A national registry of patients treated with systemic bevacizumab detailing treatment schedules and disease progression would be essential to inform future therapy decisions.