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.