ORIGINAL ARTICLE

Use of Adjuvant Intralesional Bevacizumab

for Aggressive Respiratory Papillomatosis
in Children
Derek J. Rogers, MD; Shilpa Ojha, MBChB; Rie Maurer, MA; Christopher J. Hartnick, MD, MS Epi

Importance: Juvenile recurrent respiratory papilloma-
tosis (RRP) can be an aggressive disease process neces-
sitating frequent trips to the operating room with mul-
tiple anesthetics for tumor debulking and airway
preservation. Adjuvant therapy, such as that which is re-
ported in this article, may help reduce the number of op-
erative procedures affected children need each year and
therefore may also affect their overall quality of life (QOL).
Objective: To describe our experience with intral-
esional bevacizumab (Avastin) treatment for children with
severe RRP by comparing median number of surgical pro-
cedures per year, median duration of time between pro-
cedures, Derkay staging, and voice QOL before and af-
ter bevacizumab treatment.
Design: Prospective, consecutive case series.
Setting: Tertiary care aerodigestive center.
Participants: Ten children, aged 18 months to 18 years,
with severe RRP necessitating more than 4 operative in-
terventions in 1 year whose parents (or legal guardians)
consented to intralesional bevacizumab treatment.
Interventions: Intralesional bevacizumab adminis-
tered at concentration of 2.5 mg/mL for 3 consecutive
injections (with 532-nm pulsed KTP [potassium titanyl
phosphate] laser when necessary) at intervals of 2 to 3
weeks.
Main Outcome Measures: Time between surgical pro-
cedures, number of procedures per year, Derkay stag-
ing, total Pediatric Voice-Related Quality of Life
(PVRQOL) score, Emotional PVRQOL score, and Physi-
cal PVRQOL score defined by comparing the year lead-
ing up to first of 3 bevacizumab injections with the year
following the third bevacizumab injection.
Results: The median duration of time between surgical
procedures increased by 5.9 weeks after bevacizumab
(P=.002). The median number of procedures per year
decreased by 4 (P =.002). Derkay staging decreased by 6
(P =.03). The median total PVRQOL score increased by
25.5 (P=.02), the median Emotional PVRQOL score in-
creased by 11.3 (P = .047), and the median Physical
PVRQOL score increased by 14.3 (P =.047).
Conclusions and Relevance: Intralesional bevaci-
zumab treatment may increase duration of time be-
tween surgical procedures and decrease number of pro-
cedures per year, while improving voice QOL.
JAMA Otolaryngol Head Neck Surg. 2013;139(5):496-501

Author Affiliations:
Departments of Pediatric
Otolaryngology (Drs Rogers
and Hartnick) and
Otolaryngology–Head and Neck
Surgery (Dr Ojha),
Massachusetts Eye and Ear
Infirmary, Boston; and Brigham
and Women’s Hospital and
Massachusetts General
Hospital, Boston (Ms Maurer).
R
ECURRENT RESPIRATORY PAP- cause of hoarseness in the pediatric popu-
illomatosis (RRP) repre- lation.7 Some children may present with
sents the most common stridor from airway obstruction by the pap-
neoplasm of the pediatric illomas.
larynx.1 The disease is char-
acterized by repeated growth of multiple
warts involving the larynx as well as other CME available online at
parts of the upper respiratory tract. The jamanetworkcme.com
incidence of RRP in the United States is and questions on page 444
about 0.2 to 1.1 per 100 000 children per
year,1 and its prevalence is estimated to be Children with RRP usually require mul- Author Aff
1.7 to 2.6 per 100 000 children.2,3 Recur- tiple surgical procedures to eradicate their Departmen
rent respiratory papillomatosis is most disease. The National Registry of Chil- Otolaryngo
commonly caused by human papilloma vi- dren with RRP noted an average of 4.4 pro- and Hartnic
rus (HPV) types 6 and 11.4,5 Occasion- cedures per year, totaling over 10 000 sur- Otolaryngo
ally, RRP is caused by HPV types 16 and gical procedures annually for children with Surgery (Dr
Massachuse
18.6 Infrequently, papillomas may un- RRP in the United States.8 Scarring and vo- Infirmary, B
dergo malignant transformation. Most chil- cal fold webbing may occur in these chil- and Women
dren with RRP present with hoarseness, dren after repeated procedures. Recur- Massachuse
making RRP the second most common rent respiratory papillomatosis resolves in Hospital, B

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496

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 most children, but some continue to have disease into
adulthood.9 Depending on the prevalence, the annual
medical costs of juvenile-onset RRP in the United States
are estimated at $42 million to $67 million.10 Children
diagnosed as having RRP before age 3 years are 3.6 times
more likely to have more than 4 surgical procedures per
year and almost twice as likely to have 2 or more ana-
tomical sites affected.2 Although several studies have sug-
gested that HPV type 11 is associated with more aggres-
sive disease, HPV type may only be weakly associated with
disease course when simultaneously accounting for pa-
tient age.11 A child born to a young primiparous mother
with condylomas is at high risk for developing RRP.12
Recurrent respiratory papillomatosis remains primar-
ily a surgically treated disease at the present time. Sur-
gical options include cold steel excision, microde-
brider, 532-nm KTP (potassium titanyl phosphate) laser,
carbon dioxide laser, 585-nm pulsed-dye laser, flashed
pumped-dye laser, and photodynamic therapy. The pri-
mary goal of surgery is to completely remove the papil-
lomas while preserving normal structures. Although the
carbon dioxide laser has become quite popular in recent
years, the most common method of papilloma removal
has now become the microdebrider.13
While surgery is currently the mainstay of treatment
for RRP, approximately 20% of cases require adjuvant
therapy.1 Adjuvant therapy may include oral indole-3-
carbinol, mumps vaccine, heat shock protein (HSP) E7,
interferon, and intralesional cidofovir. Indications for ad-
juvant therapy are the need for more than 4 surgical pro-
cedures per year, rapid regrowth of papillomas with air-
way compromise, or distal multisite spread of disease.1
Although historically interferon was a common ad-
juvant therapy for RRP, cidofovir has been the most widely
described injectable adjuvant treatment in the current lit-
erature. Cidofovir is a cytosine nucleotide analog known
to have considerable antiviral activity against a variety
of herpes viruses.14 The US Food and Drug Administra-
tion (FDA) has approved cidofovir for the treatment of
cytomegalovirus retinitis in patients with acquired im-
munodeficiency disease. The first use of cidofovir for the
treatment of RRP was described by Snoeck et al15; in their
study, 8 of 11 mostly adult patients showed excellent re-
sponses. Pransky et al16 followed 11 children with RRP
treated with intralesional cidofovir over 6 years and found
that 5 patients decreased their mean severity scores from
17.8 to 4.0 and no longer required cidofovir. Pransky et
al16 also reported remarkable decreases in the total num-
ber of surgical procedures per year and increases in the
interval between procedures for children with RRP treated
with cidofovir.17 The current standard of care was de-
rived from a systematic review by Chadha and James,18
which estimated the median intralesional cidofovir treat-
ment protocol to be a concentration of 2.5 mg/mL to 5
mg/mL, every 2 to 4 weeks for a year. Injecting cidofo-
vir in this manner is believed to limit malignant change
and provide durable remission by preventing an in-
crease of HPV type E6.16,19
Derkay and the Multidisciplinary Taskforce on Re-
current Respiratory Papillomas20 have published guide-
lines for clinicians interested in using cidofovir to treat
RRP because of potential carcinogenic effects in animal
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Table 1. Demographics of Children Treated
With Intralesional Bevacizumab
Patient No./Sex/Age at
First Bevacizumab
Treatment/Age at First Prior Cidofovir
RRP Treatment HPV Type Injections, No.
1/F/4 y/2 mo 11 4
2/F/13 y/8 y 6 3
3/M/22 mo/10 mo 6 0
4/F/18 mo/9 mo 11 0
5/F/8 y/2 y 6 0
6/M/20 y/16 y 11 2
7/M/8 y/3 y 6 0
8/M/6 y/2 y 6 6
9/F/2 y/9 mo 6 0
10/F/18 y/2 y 11 Unknown
Abbreviations: HPV, human papilloma virus; RRP, recurrent respiratory
papillomatosis.
studies21 and case reports showing malignant conver-
sion22 or progressive dysplasia in patients with RRP re-
ceiving intralesional cidofovir.23 With the growth of pa-
tient and family websites and web resources (http://www
.rrpf.org), many families come in with concerns and are
looking for alternative treatments. They often ask about
bevacizumab, and a paucity of long-term outcomes data
exists, especially in the pediatric population.
Bevacizumab (Avastin) is a human monoclonal anti-
body that binds to and neutralizes the biologic activities
of vascular endothelial growth factor (VEGF) isoforms,
blocking the interaction with their receptors.24 Rahbar
et al25 showed strong expression of VEGF-A in the epi-
thelium from papillomas in patients with RRP as well as
expression of VEGFR-1 and VEGFR-2 messenger RNAs
in underlying vascular endothelial cells. In a pilot study
and a prospective investigation thereafter, Zeitels et al26,27
showed good results using bevacizumab with 532-nm
pulsed KTP laser in adult patients. However, no stan-
dardized grading system was used to assess the visual ap-
pearance of the larynx, such as Derkay scores. Because
of the favorable results in our previous study28 and in the
studies by Zeitels et al,26,27 we sought to further investi-
gate the use of bevacizumab as adjuvant therapy in chil-
dren with RRP. The goal of this study was to describe
our experience with intralesional bevacizumab in chil-
dren with aggressive RRP by comparing the median num-
ber of surgical procedures per year, median duration of
time between procedures, Derkay staging, and voice qual-
ity of life (QOL) before and after bevacizumab treat-
ment. One must remember that this is a small case se-
ries, which should be used as motivation for a blinded,
randomized controlled trial in the future.
METHODS
PATIENTS
The Massachusetts Eye and Ear Infirmary institutional review
board approved this study. Ten children aged 18 months to 18
years at first bevacizumab treatment were included in this study
(Table 1). Children met inclusion criteria if they had under-
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 Table 2. Comparison of Medians Before and After Bevacizumab Injections
Measure
Duration between treatments, wk
Treatments per year
Derkay staging
Pediatric Voice-Related Quality of Life score
Total
Emotional
Physical
Abbreviations: PostTx, 1 year after third bevacizumab injection; PreTx, 1 year prior to first bevacizumab injection.
gone more than 4 procedures per year, either failed treatment
with cidofovir or did not want to try cidofovir, and wanted ad-
juvant therapy. Children were excluded if they had under-
gone fewer than 4 procedures per year, did not want adjuvant
therapy, or had a known sensitivity to bevacizumab. No pa-
tients who received bevacizumab were excluded from this re-
port. The 3 patients from our previous experience with beva-
cizumab28 were not included in this study. The age at first RRP
treatment ranged from 2 months to 16 years. Six of the pa-
tients were female, and 4 were male. Six of the patients had pap-
illomas positive for HPV type 6, and 4 were positive for HPV
type 11. Four of the patients had failed treatment with any-
where from 2 to 6 cidofovir injections.
The families were thoroughly counseled regarding various
adjuvant therapies. They were provided literature on bevaci-
zumab. A special informed consent form was developed with
the aid of the pharmacists at the Massachusetts Eye and Ear
Infirmary disclosing the off-label use of bevacizumab, includ-
ing risks and benefits. Families chose to either continue stan-
dard surgical therapy or start bevacizumab adjuvant therapy
after reading the consent form. Parents or legal guardians had
to sign both the expanded bevacizumab consent form and
standard consent form before bevacizumab was used in the
children.
SURGICAL TECHNIQUE
Suspension microlaryngoscopy with microdebrider removal of
bulky disease followed by 532-nm pulsed KTP laser treatment
of sessile papillomas involving the anterior commissure, true
vocal folds, or ventricles represented standard surgical treat-
ment (as defined by the senior author, C.J.H.). Once this stan-
dard surgical treatment was complete, we performed bevaci-
zumab injections. Pransky et al16 used a 2-week interval between
cidofovir injections because they found greater than expected
papilloma regrowth when the interval was more than 2 weeks
and because of data from several prior studies.15,18,29 Our tech-
nique for adjuvant bevacizumab injections involved using a la-
ryngeal needle to inject a total of 0.5 mL of bevacizumab at a
concentration of 2.5 mg/mL into the areas most affected by the
papillomas. Each patient underwent a series of 3 bevacizumab
injections approximately 2 to 3 weeks apart. Our time points
started 1 year prior to the first bevacizumab injection and ended
1 year following the third injection.
STATISTICAL ANALYSIS
The duration of time between surgical procedures, number of
procedures per year, Derkay staging, total PVRQOL (pediatric
voice-related QOL) score, Emotional PVRQOL score, and Physi-
cal PVRQOL score the year after the third bevacizumab injec-
tion were compared with those from the year before the first
bevacizumab injection. Medians were compared owing to the
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PreTx PostTx Difference (95% CI) P Value
6.0 12.0 5.9 (3.7 to 10.2) .002
8.0 4.0 ⫺4.0 (⫺6.5 to ⫺2.5) .002
19.0 13.0 ⫺6.0 (⫺12.0 to ⫺2.3) .03
52.5 70.0 25.5 (⫺0.6 to 39.1) .02
20.0 32.5 11.3 (⫺0.1 to 16.0) .047
32.5 40.0 14.3 (⫺0.5 to 23.1) .047
small sample size and because the data did not achieve a nor-
mal distribution. The total PVRQOL score has a range of 0 to
100. The Emotional PVRQOL score was the sum of questions
4, 5, 8, and 10 from the PVRQOL questionnaire with a range
of 0 to 40, and the Physical PVRQOL score was the sum of ques-
tions 1, 2, 3, 6, 7, and 9 with a range of 0 to 60. The Wilcoxon
signed rank test was used to determine statistical significance.
The effect of HPV type and age of first RRP treatment were evalu-
ated, but regression did not allow for differences to be seen,
possibly owing to small sample size.
RESULTS
All 10 patients completed the aforementioned protocol.
The median duration of time between surgical proce-
dures, number of procedures per year, Derkay staging,
total PVRQOL score, Emotional PVRQOL score, and
Physical PVRQOL score the year after the third bevaci-
zumab injection were compared with those from the year
before the first bevacizumab injection (Table 2). The
median duration of time between surgical procedures in-
creased by 5.9 weeks after bevacizumab (95% CI, 3.7-
10.2; P = .002). The median number of procedures per
year decreased by 4 (95% CI, ⫺6.5 to ⫺2.5; P = .002).
Derkay staging decreased by 6 (95% CI, ⫺12.0 to ⫺2.3;
P = .03). If the 3 surgical procedures in which bevaci-
zumab was injected are included, the median number of
procedures the year after the first bevacizumab injec-
tion was 7.
The voice outcomes also improved after bevaci-
zumab treatment. The median total PVRQOL score in-
creased by 25.5 (95% CI, ⫺0.6 to 39.1; P = .02). When
broken down into separate parameters, the Emotional
PVRQOL score increased by 11.3 (95% CI, ⫺0.1 to 16;
P = .047), and the Physical PVRQOL score increased by
14.3 (95% CI, ⫺0.5 to 23.1; P = .047).
DISCUSSION
Pediatric RRP remains an extremely challenging disease
to treat. Ideally, medical treatment will eventually be de-
veloped in the future to treat RRP without the need for
multiple surgical procedures. Since maintaining an ad-
equate airway is an absolute necessity, repeated proce-
dures are performed at the expense of scarring and po-
tentially permanent voice disturbance. Adjuvant therapy,
such as cidofovir, is considered by surgeons to ensure
the longest time possible between surgical interven-
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 tions and ultimately to limit the total number of proce-
dures for each patient.
Adjuvant therapy is an attractive treatment modality
in children with aggressive RRP, but limited data exist
concerning the optimal dosage, efficacy, and possible ad-
verse effects. Most studies involve small numbers of pa-
tients and/or lack consistent surgical and medical treat-
ment of these patients between institutions. Despite some
solid evidence showing efficacy of cidofovir in pediatric
RRP,16,17,30 not all children experience such remarkable
responses. Cidofovir use is also not without risk. Be-
cause of potential carcinogenic effects in animal stud-
ies21 and case reports of malignant conversion22 and pro-
gressive dysplasia in patients with RRP receiving
intralesional cidofovir,23 the Multidisciplinary Task Force
on Recurrent Respiratory Papillomas20 has published
guidelines for clinicians interested in using cidofovir to
treat RRP. Since cidofovir is not effective in all cases and
may be associated with a risk of malignant disease, par-
ents of children with aggressive RRP desire other adju-
vant treatments that are safe and beneficial.
Bevacizumab is a human monoclonal antibody that
binds to and neutralizes the biologic activities of VEGF
isoforms, blocking the interaction with their recep-
tors.24 In 1994, the FDA approved bevacizumab for the
treatment of metastatic colorectal cancer largely owing
to the pioneering work by Folkman.31 Bevacizumab has
been used in treatment of diabetic retinopathy, macular
degeneration, and other ophthalmologic conditions.32 Po-
tential risks from intravenous bevacizumab administra-
tion include, but are not limited to, bleeding, blood clot-
ting, high blood pressure, and hypothyroidism.24 No
adverse effects have resulted from intraocular injections
of bevacizumab at a dose 100 to 400 times lower than
the intravenous dose.33
After the study by Rahbar et al25 showing high lev-
els of VEGF-A in pediatric papilloma specimens and
the work by Zeitels et al 26,27 using bevacizumab in
adult patients with RRP, it seemed logical to assess the
efficacy of bevacizumab in children with aggressive
RRP. The initial bevacizumab dose used in adults
ranged from 5 to 12.5 mg at a concentration of 25
mg/mL.26,27 We used an initial concentration of 2.5
mg/mL, which had been used safely in pediatric oph-
thalmology.34 The concentrations were formulated by
our institutional pharmacy. The patients’ parents were
thoroughly counseled and given handouts regarding
bevacizumab and various adjuvant therapies before
initiating bevacizumab therapy, as outline in our prior
work. 28 Extrapolating from the data presented by
Chadha and James 18 in their systematic review of
intralesional cidofovir, we chose to perform 3 intra-
lesional bevacizumab injections at a concentration of
2.5 mg/mL every 2 to 3 weeks. One must also consider
the overall dose injected, especially in the pediatric
population. We injected approximately 0.5 mL at each
session.
In our study, children who were treated with intra-
lesional bevacizumab injections required 4 fewer surgi-
cal procedures per year and showed an increase in the
duration of time between procedures by 5.9 weeks. In
addition, the Derkay staging decreased by 6 points. While
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Does the child require > 4
treatments per year?
Yes No
Do the parents or child No Continue surgical debulking
desire adjuvant therapy? procedures as needed
Yes
Has the child failed cidofovir No Consider intralesional
or do the parents or child
cidofovir
refuse cidofovir?
Yes
Intralesional bevacizumab
injections at concentration of
2.5 mg/mL consecutively every
2 to 3 wk for 3 injections
Figure. Proposed algorithm for adjuvant use of intralesional bevacizumab in
recurrent respiratory papillomatosis.
these results may not be as dramatic as those with cido-
fovir presented by Pransky et al,17 they show that intra-
lesional bevacizumab may make a remarkable impact on
the patients and their families. Fewer surgical proce-
dures and more time between procedures will hopefully
lead to less scarring and fewer general anesthetics for these
patients. For 50% or more of the patients, 1 or 2 addi-
tional procedures resulted because of the decision to use
bevacizumab and thus may be associated with a signifi-
cant cost and burden. We have devised a potential algo-
rithm for the use of adjuvant intralesional bevacizumab
in our pattern of practice (Figure). Our definition of ci-
dofovir and bevacizumab failure is defined as requiring
the same number of procedures or more the year after
treatment with cidofovir or bevacizumab compared with
those required the year before cidofovir or bevacizumab
treatment. For those children who fail treatment with the
initial bevacizumab injections, we have begun treating
them with a series of 3 injections at a concentration of 5
mg/mL every 2 to 3 weeks. These data will be reported
in the future.
The voice outcomes also improved after bevaci-
zumab when comparing the total PVRQOL scores as well
as the Emotional PVRQOL and Physical PVRQOL scores
separately. Parents felt that their children’s QOL was no-
ticeably improved. These results compared favorably with
those presented by Zeitels et al26,27 even though our dose
of bevacizumab was considerably lower. Whether these
improved voice outcomes were directly due to bevaci-
zumab or merely a result of fewer procedures remains
to be elucidated. However, cidofovir has been reported
to stiffen the vocal cords through scarring and fibro-
sis,35 which we have not found to occur with the use of
bevacizumab.
Our study had a few limitations. Our sample popula-
tion was small, and we were unable to assess the effect
of age, HPV type, and sex in patients treated with beva-
cizumab. Also, all surgical procedures were performed
according to the senior author’s technique. Multicenter
trials would likely help investigate different surgical tech-
niques. The dose of bevacizumab was merely an estima-
tion based on the use of this medication in pediatric oph-
thalmology, and the time interval between injections was
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 deduced from prior cidofovir data. The amount
injected into the papillomas was not exactly the same
3.
for every patient and varied based on the severity of
disease. Larger longitudinal trials may better assess the
effect of age of first RRP treatment, HPV type, sex,
dose and time interval of bevacizumab, potential scar- 4.
ring, and histopathologic changes over time. Using the
difference in the median number of surgical proce-
dures per year before and after intralesional bevaci- 5.
zumab in this pilot study and assuming a diminish-
ment of 2 procedures per year because of the natural
6.
course of RRP, a randomized control trial between
intralesional bevacizumab and placebo would need 38 7.
patients (19 in the bevacizumab group and 19 in the
placebo group) to show a significant difference in the
number of procedures per year (power = 90%; ␣ = .05; 8.
Mann-Whitney test).
In conclusion, our pilot study suggests that bevaci- 9.
zumab may indeed limit the number of surgical proce-
dures required per year and increase the duration 10.
between procedures in patients with aggressive RRP,
while simultaneously improving voice outcomes. Physi- 11.
cians should consider bevacizumab as an adjuvant
therapy in this unique subset of patients. While we are
hopeful of bevacizumab’s efficacy, we are aware that 12.
our data would be compatible with other explanations:
disease variability with regression to the mean; the gen- 13.
erally favorable natural history of RRP; bias (even sub-
consciously). It is possible that bevacizumab is not effi-
cacious. One should note that this study is a small case 14.
series. A larger, blinded, randomized controlled, multi-
center study would answer the question. 15.
Submitted for Publication: August 26, 2012; final revi-
sion received November 7, 2012; accepted December 6,
2012. 16.
Correspondence: Christopher J. Hartnick, MD, MS Epi,
Department of Pediatric Otolaryngology, Massachu-
setts Eye and Ear Infirmary, 243 Charles St, Boston, MA 17.
02114 (Christopher_Hartnick@meei.harvard.edu).
Author Contributions: All authors had full access to all 18.
the data in the study and take responsibility for the in-
tegrity of the data and the accuracy of the data analysis.
19.
Study concept and design: Rogers, Ojha, and Hartnick. Ac-
quisition of data: Rogers, Ojha, and Hartnick. Analysis and
interpretation of data: Rogers, Mauer, and Hartnick. Draft- 20.
ing of the manuscript: Rogers and Ojha. Critical revision
of the manuscript for important intellectual content: Rog-
21.
ers and Hartnick. Statistical analysis: Rogers and Ojha. 22.
Administrative, technical, and material support: Rogers,
Ojha, and Hartnick. Study supervision: Rogers and Hart-
nick. 23.
Conflict of Interest Disclosures: None reported.
Additional Information: This study was presented at the 24.
American Society of Pediatric Otolaryngology (ASPO)
Spring Meeting; April 26, 2013; Arlington, Virginia. 25.
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