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Systemic Bevacizumab for Treatment of Respiratory Papillomatosis:
International Consensus Statement
Douglas R. Sidell, MD ; Karthik Balakrishnan, MD, MPH ; Simon R. Best, MD ; Karen Zur, MD ;
Julia Buckingham, MS; Alessandro De Alarcon, MD ; Fuad M. Baroody, MD; Jonathan M. Bock, MD ;
Emily F. Boss, MD; Charles M. Bower, MD; Paolo Campisi, MD ; Sharon F. Chen, MD;
Jeffrey M. Clarke, MD; Kevin D. Clarke, MD; Alejandro Cocciaglia, MD; Robin T. Cotton, MD;
Giselle Cuestas, MD; Kara L. Davis, MD; Victor H. DeFago, MD; Frederik G. Dikkers, MD;
Ines Dossans, MD; Walter Florez, MD; Elizabeth Fox, MD; Aaron D. Friedman, MD ; Nazaneen Grant, MD;
Osama Hamdi, BS ; Norman D. Hogikyan, MD; Kaalan Johnson, MD; Liane B. Johnson, MD;
Romaine F. Johnson, MD ; Peggy Kelly, MD; Adam M. Klein, MD; Claire M. Lawlor, MD;
Nicolas Leboulanger, MD ; Alejandro G. Levy, MD; Derek Lam, MD; Greg R. Licameli, MD;
Steve Long, MD; David G. Lott, MD; Dayse Manrique, MD; James Scott McMurray, MD;
Kara D. Meister, MD ; Anna H. Messner, MD; Michael Mohr, MD; Pamela Mudd, MD;
Anthony J. Mortelliti, MD; Daniel Novakovic, MD ; Julian Ongkasuwan, MD ; Shazia Peer, MD;
Krysztof Piersiala, MD; Jeremy D. Prager, MD ; Seth M. Pransky, MD; Diego Preciado, MD;
Tiffany Raynor, MD; Rico N. P. M. Rinkel, MD ; Hugo Rodriguez, MD; Verónica P. Rodríguez, MD;
John Russell, MD; María Laura Scatolini, MD; Patrick Scheffler, MD; David F. Smith, MD ;
Lee P. Smith, MD; Marshall E. Smith, MD; Richard J. H. Smith, MD; Abraham Sorom, MD;
Amalia Steinberg, MD; John A. Stith, MD; Dana Thompson, MD; Jerome W. Thompson, MD;
Patricio Varela, MD; David R. White, MD; Andre M. Wineland, MD ; Christina J. Yang, MD;
Carlton J. Zdanski, MD; Craig S. Derkay, MD
From the Department of Otolaryngology-Head and Neck Surgery (D.R.S., K.B., K.D.M., P.S.), Stanford University School of Medicine, Stanford,
California, U.S.A.; Aerodigestive and Airway Reconstruction Center (D.R.S., K.B., K.D.M.), Lucile Packard Children’s Hospital Stanford, Stanford, California,
U.S.A.; Department of Otolaryngology-Head and Neck Surgery, Division of Laryngology, and, Department of Oncology (S.R.B.), Johns Hopkins University
School of Medicine, Baltimore, Maryland, U.S.A.; Division of Pediatric Otolaryngology (K.Z.), Children’s Hospital of Philadelphia, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.; Maternal and Child Health Research Institute (J.B.), Lucile Packard Children’s
Hospital, Stanford University School of Medicine, Stanford University, Stanford, California, U.S.A.; Department of Otolaryngology, Division of Pediatric
Otolaryngology (A.D.A., R.T.C.), Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.;
Section of Otolaryngology-Head and Neck Surgery and Department of Pediatrics (F.M.B.), University of Chicago Medicine and The Comer Children’s
Hospital, Chicago, Illinois, U.S.A.; Department of Otolaryngology and Communication Sciences, Division of Laryngology and Professional Voice (J.M.B.),
Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.; Department of Otolaryngology-Head and Neck Surgery and the Department of Health Policy
and Management, Division of Pediatric Otolaryngology (E.F.B., A.M.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.;
Department of Otolaryngology Head and Neck Surgery, Division of Pediatric Otolaryngology (C.M.B.), University of Arkansas for Medical Sciences (UAMS),
Arkansas Children’s Hospital, Little Rock, Alaska, U.S.A.; Department of Otolaryngology –Head and Neck Surgery (P.C.), Hospital for Sick Children,
University of Toronto, Toronto, Canada; Department of Pediatrics, Division of Infectious Diseases (S.F.C.), Lucile Packard Children’s Hospital Stanford,
Stanford, California, U.S.A.; Department of Medicine, Division of Oncology (J.M.C.), Duke Cancer Institute, Duke University School of Medicine, Durham,
North Carolina, U.S.A.; Pediatric Otolaryngology, Division of Otolaryngology Head and Neck Surgery (K.D.C.), University of British Columbia (UBC, UVIc),
Victoria General Hospital, Victoria, British Columbia, Canada; ENT-Respiratory Endoscopy Department (A.C.), Garrahan Children’s Hospital, Buenos
Aires, Argentina; Respiratory Endoscopy Section, ENT Department (G.C., V.P.R.), Hospital General de Niños “Dr. Pedro de Elizalde”, Buenos Aires,
Argentina; Department of Pediatrics, Division of Pediatric Oncology (K.L.D.), Bass Center for Childhood Cancer and Blood Disorders, Stanford University,
Stanford, California, U.S.A.; Pediatric Surgery (V.H.D.), Sanatorio del Salvador Privado SA, Cordoba, Argentina; Department of Otorhinolaryngology (F.G.D.),
Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands; Otolaryngology-Head and Neck Surgery (I.D.), Hospital Pereira Rossell, Montevideo,
Uruguay; Department of Otolaryngology (W.F.), Instituto Nacional de Salud del Niño de San Borja, Lima, Peru; Comprehensive Cancer Center, St Jude
Children’s Research Hospital (E.F.), Memphis, Tennessee, U.S.A.; Department of Otolaryngology, Head and Neck Surgery (A.D.F.), University of Cincinnati
School of Medicine, Cincinnati, Ohio, U.S.A.; Department of Otolaryngology, Division of Laryngology (N.G.), Medstar Georgetown University Hospital,
Georgetown, Washington, District of Columbia, U.S.A.; Howard University College of Medicine (O.H.), Washington, District of Columbia, U.S.A.;
Department of Otolaryngology-Head and Neck Surgery (N.D.H.), University of Michigan Medical School, Ann Arbor, Michigan, U.S.A.; University of
Washington School of Medicine (K.J.), Department of Otolaryngology Head and Neck Surgery, Division of Pediatric Otolaryngology, Seattle, Washington,
District of Columbia, U.S.A.; Department of Surgery (L.B.J.), Dalhousie University, Division of Paediatric Otolaryngology-Head and Neck Surgery, IWK
Health Centre, Halifax, Nova Scotia, Canada; Department of Otolaryngology-Head and Neck Surgery (R.F.J.), University of Texas (UT) Southwestern
Medical Center, Dallas, Texas, U.S.A.; Department of Otolaryngology, Head and Neck Surgery, Division of Pediatric Otolaryngology (P.K., J.D.P.), Children’s
Hospital Colorado affiliated with University of Colorado, Anschutz, Aurora, Colorado, U.S.A.; Department of Otolaryngology-Head and Neck Surgery,
Division of Laryngology (A.M.K.), Emory Voice Center, Emory University School of Medicine, Atlanta, Georgia, U.S.A.; Department of Otolaryngology,
Laryngoscope 00: 2021 Sidell et al.: Systemic Bevacizumab for Papillomatosis
1
The Laryngoscope
© 2021 The American Laryngological,
Rhinological and Otological Society, Inc.
Objectives/Hypothesis: The purpose of this study is to develop consensus on key points that would support the use of
systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance
surrounding the use of this treatment modality.
Study Design: Delphi method-based survey series.
Methods: A multidisciplinary, multi-institutional panel of physicians with experience using systemic bevacizumab for the
treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated
with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center
characteristics; 4) prior treatment characteristics; and 5) prior work-up.
Results: The international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolar-
yngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items
were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center
Characteristics (22), and Prior Workup Characteristics (18).
Conclusion: This consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic
bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this ther-
apy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab’s use in combination
with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to
help shape best-practice applications of systemic bevacizumab for patients with early-onset or less-severe disease phenotypes.
Key Words: Systemic bevacizumab, Avastin, consensus.
Level of Evidence: 5.
Laryngoscope, 00:1–9, 2021
INTRODUCTION
HPV-associated recurrent respiratory papillomatosis
(RRP) is the most common benign airway neoplasm, with
estimated incidence of 4.3/100,000 children and 3–4/100,000
adults annually, though this figure is declining.
1-5
While RRP
incidence and prevalence have declined in countries with
widespread access to the HPV vaccine, many countries con-
tinue to suffer intense RRP burden. Although mortality in
the United States is often the consequence of pulmonary dis-
ease, in many countries, laryngeal obstruction may remain a
dominant source of mortality. To date, there is no cure.
Surgical excision/debridement remains the gold stan-
dard treatment, though various topical, intralesional, and
systemic adjuvant therapies have been tried.
1,6
Unfortu-
nately, these therapies are not universally effective, and
each has an associated risk profile.
1,6-9
Division of Pediatric Otolaryngology (C.M.L., P.M., D.P.), Children’s National Health System, George Washington University School of Medicine, Washington,
District of Columbia, U.S.A.; Head and Neck Surgery, Pediatric Otolaryngology (N.L.), Necker Enfants Malades Hospital, Paris University, Paris, France;
Department of Pediatrics, Division of Pediatric Hematology and Oncology (A.G.L.), Arnold Palmer Hospital Center for Children’s Cancer and Blood
Disorders, Orlando Health, Orlando, Florida, U.S.A.; Department of Otolaryngology-Head and Neck Surgery (D.L.), Oregon Health and Science University,
Portland, Oregon, U.S.A.; Department of Otolaryngology (G.R.L.), Boston Children’s Hospital, Boston, Massachusetts, U.S.A.; Department of Head and Neck
Surgery (S.L.), Kaiser Permanente, Hillsboro, Oregon, U.S.A.; Department of Otorhinolaryngology, Division of Laryngology (D.G.L.), Mayo Clinic Arizona,
Phoenix, Arizona, U.S.A.; Department of Otorhinolaryngology (D.M.), Universidad Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil; Pediatric
Otolaryngology (J.S.M.), University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, U.S.A.; Department of Otolaryngology/Head and
Neck Surgery (A.H.M.), Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, U.S.A.; Department of Hematology, Oncology and
Respiratory Medicine (M.M.), University Hospital Muenster, Muenster, Germany; Department of Otolaryngology-Head and Neck Surgery (A.J.M.), State
University of New York (SUNY) Upstate Medical University, Syracuse, New York, U.S.A.; Department of Otolaryngology, Head and Neck Surgery (D.N.),
Central Clinical School, Faculty of Medicine and Health, University of Sydney, The Canterbury Hospital, Sydney, New South Wales, Australia; Department
of Otolaryngology, Division of Adult and Pediatric Laryngology, Bobby R. Alford Department of Otolaryngology Head and Neck Surgery (J.O.), Baylor
College of Medicine, Texas Children’s Hospital, Houston, Texas, U.S.A.; Division of Otorhinolaryngology (S.P.), University of Cape Town and Red Cross War
Memorial Children’s Hospital, Cape Town, South Africa; Division of Ear, Nose and Throat Diseases (K.P.), Karolinska Institutet, Karolinksa University
Hospital, Stockholm, Sweden; Rady Children’s Hospital (S.M.P.), San Diego, California, U.S.A.; Department of Otolaryngology, Head and Neck Surgery (T.R.),
Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, U.S.A.; Department of Otolaryngology (R.N.P.M.R.), Amsterdam UMC, Vrije
Universiteit Amsterdam, Amsterdam, Netherlands; Respiratory Endoscopy Department (H.R., M.L.S.), Hospital de Pediatria Prof Dr. Juan P. Garrahan,
Buenos Aires, Argentina; Department of Paediatric Otolaryngology (J.R.), Children’s Health Ireland, Dublin, Ireland; Divisions of Pediatric Otolaryngology,
Pulmonary Medicine, and the Sleep Center (D.F.S.), Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati,
Ohio, U.S.A.; Division of Otolaryngology-Head and Neck Surgery, Pediatric Otolaryngology (L.P.S.), Donald and Barbara Zucker School of Medicine at
Hofstra/Northwell, Steven and Alexandra Cohen Children’s Medical Center of New York, New Hyde Park, New York, U.S.A.; Division of Otolaryngology-
Head and Neck Surgery (M.E.S.), University of Utah School of Medicine, Salt Lake City, Utah, U.S.A.; Department of Otolaryngology-Head and Neck
Surgery (R.J.H.S.), University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.; Otolaryngology, Head and Neck Surgery (A.S.), Confluence Health,
Wenatchee, Washington, District of Columbia, U.S.A.; Otolaryngology, Head and Neck Surgery (A.S.), Alaska Native Medical center, Anchorage, Alaska,
U.S.A.; Department of Otolaryngology-Head and Neck Surgery, Division of Pediatric Otolaryngology (J.A.S.), SSM Cardinal Glennon Children’s Hospital
Medical Center, St. Louis, Missouri, U.S.A.; Division of Pediatric Otolaryngology Head and Neck Surgery Ann and Robert H Lurie Children’s Hospital of
Chicago (D.T.), Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A.; Department of Otolaryngology-Head and Neck Surgery,
Division of Pediatric ENT, LeBonheur Children’s Hospital, College of Medicine (J.W.T.), University of Tennnessee, Memphis, Tennessee, U.S.A.; Pediatric
Surgery Department (P.V.), Universidad de Chile, Mackenna Children Hospital, Clinica Las Condes Medical center, Santiago, Chile; Division of Pediatric
Otolaryngology (D.R.W.), Medical University of South Carolina (MUSC) Shawn Jenkins Children’s Hospital, Charleston, South Carolina, U.S.A.; Department
of Otolaryngology-Head and Neck Surgery (C.J.Y.), Albert Einstein College of Medicine, Montefiore Medical Center, Children’s Hospital at Montefiore,
New York, New York, U.S.A.; Department of Otolaryngology/Head and Neck Surgery, Division of Pediatric Otolaryngology/Head and Neck Surgery (C.J.Z.),
North Carolina Children’s Hospital, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.; and the Department of
Otolaryngology-Head and Neck Surgery (C.S.D.), Eastern Virginia Medical School, Children’s Hospital of the King’s Daughters, Norfolk, Virginia, U.S.A.
Additional supporting information may be found in the online version of this article.
Editor’s Note: This Manuscript was accepted for publication on December 17, 2020
The authors have no funding, financial relationships, or conflicts of interest to disclose.
Send correspondence to Douglas R. Sidell, MD, Otolaryngology-Head and Neck Surgery, Division of Pediatric Otolaryngology, Stanford University
School of Medicine. 801 Welch Road, Stanford, CA 94305. E-mail: dsidell@stanford.edu
Laryngoscope 00: 2021 Sidell et al.: Systemic Bevacizumab for Papillomatosis
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RRP and Bevacizumab
Vascular growth appears to be a universal patho-
physiologic contributor to RRP proliferation and recur-
rence. Selective vascular ablation using KTP (potassium
titanyl phosphate) laser concurrent with surgical debride-
ment has shown promise in reducing recurrence.
7
Simi-
larly, intralesional inhibition of vascular endothelial
growth factor (VEGF) in RRP patients has demonstrated
reductions in disease recurrence and frequency of surgical
debridement required.
7-9
Bevacizumab, a recombinant VEGF-binding anti-
body that inhibits interaction with the VEGF receptor,
has been used for over 15 years as systemic chemother-
apy to inhibit vascular growth associated with metastatic
malignancy. It has also been administered locally in
patients with hereditary hemorrhagic telangiectasias and
in children with retinopathy of prematurity.
8
Off-label
intralesional injection of bevacizumab at the time of sur-
gical debridement reduces RRP burden and surgical fre-
quency in select children and adults.
1,6-9
Unfortunately,
this strategy does not benefit all patients and is impracti-
cal for diffuse tracheal disease or pulmonary lesions.
Systemic administration of bevacizumab for RRP
was first reported in 2009. Nagel and colleagues
described a 32-year-old male with pulmonary and tra-
cheal disease requiring laser-debridement four times a
year over a 10-year period. The patient had significant
regression of his papilloma following systemic adminis-
tration of bevacizumab.
2
In 2014, Mohr and colleagues
presented 5 patients with advanced tracheal
papillomatosis treated with systemic bevacizumab. All
patients demonstrated rapid and dramatic improvement
of disease burden.
10
In 2016, Zur and Fox used systemic
bevacizumab for extensive pulmonary and
laryngotracheal papillomatosis in a 12-year old
tracheostomy-dependent child with refractory disease,
describing complete laryngeal disease resolution after
3 months of treatment. The patient was ultimately
decannulated and remains free of gross disease with
interval infusions.
11
Subsequently, a nationwide survey identified vari-
ability in treatment dosing, treatment frequency, and
degree of response. The authors concluded that systemic
bevacizumab showed significant promise in patients with
advanced, treatment-resistant papillomatosis.
12
These data suggest systemic bevacizumab may be an
important option for patients with severe or otherwise
life-threatening disease resistant to other therapies. Nev-
ertheless, many facets of treatment remain
undetermined. This study aimed to develop consensus on
key points of patient selection, disease attributes, and
treatment center characteristics appropriate for the use
of systemic bevacizumab. We used a modified Delphi
approach to identify and survey an international body of
physicians with expertise in RRP treatment and experi-
ence using systemic bevacizumab to treat RRP.
MATERIALS AND METHODS
The Delphi method provides a structured approach to
achieve expert consensus in the absence of adequate data to
guide situational assessment and decision-making.
13
This
method has proved useful in addressing a range of healthcare
questions.
14,15
Previously described approaches have either used
direct discussion between expert panelists (in person or via tele-
phone) or have avoided discussion.
14,15
This design is based on
previously published work.
15
This study was reviewed and
exempted by the Stanford University Institutional Review
Board.
Statistical analysis was performed using Excel 2010
(Microsoft Corp, Redmond, Washington). Web-based surveys
used Qualtrics (Qualtrics, Provo, UT). Surveys were distributed
by email via individualized links. This non-human-subjects sur-
vey was exempt from IRB-review.
Identifying Study Participants
We used a snowball sampling strategy, first identifying
individuals with experience treating, or planning to treat, adults
or children with RRP using systemic bevacizumab. An initial
email contacted approximately 250 individuals identified as
potential experts in the field by the study facilitators and lead
authors through several different mechanisms (social media
channels, web groups, patient organizations, working group lists,
prior publications, and direct knowledge of invitees’work). Indi-
viduals were asked to confirm their experience and their interest
in participating and were allowed to also suggest other partici-
pants. Inclusion criteria included individuals who responded to
the survey; agreed to participate in the study; and confirmed a
history of, or planned future use of, systemic bevacizumab for
RRP during the study period. All surveys and invitation emails
were sent in English. Individuals who did not respond to the sur-
vey, declined to participate, could not participate due to language
barrier, or did not have experience using systemic bevacizumab
to treat RRP were excluded.
Modified Delphi Process
The multidisciplinary, international group of experts
responded to a web-based survey asking them to propose factors
to be considered or adhered to when using systemic
bevacizumab. Respondents were asked to list 5–15 characteris-
tics within each of five domains: 1) patient characteristics; 2) dis-
ease characteristics; 3) treating center characteristics; 4) prior
treatment characteristics; and 5) prior work-up. Respondents
could also propose additional domains.
Open-ended responses were consolidated and organized by
theme. This process included combining responses with identical
meanings, re-wording or re-phrasing responses for clarity, and
translating responses to the English language. Facilitators with
experience in the treatment of RRP and in using the modified
Delphi method worked to preserve intent of the study group’s
responses. Each survey was sent with a two-week requested
response time and one reminder sent during the response period.
From analyses of consolidated and anonymized responses,
a new survey was generated and sent to respondents. This sur-
vey comprised statements that participants were directed to rate
for relevance in treatment decision-making. Statements were
either those that required the choice of a single statement
(e.g., “Please evaluate the following two statements. Please
choose the statement that you agree with the most regarding the
patient’s age at the time of onset of RRP”), or those that required
rating a statement for importance. Respondents were thus
instructed to rate items on a 1–9 Likert scale (9 = most impor-
tant) or presented forced-choice questions (choose one state-
ment). Facilitators directed respondents to distinguish between
rating items important to consider before starting bevacizumab,
Laryngoscope 00: 2021 Sidell et al.: Systemic Bevacizumab for Papillomatosis
3
versus rating items that would increase the chance of using
bevacizumab. To this end, instructional text was added to each
segment of questions: “If you are more likely to administer
bevacizumab to a patient that has had multiple life-threatening
airway issues, you would rate this as more important on the 1-9
scale –even if it were not something that would need to be pre-
sent before you started treatment”. We calculated mean, median,
mode, maximum, and minimum rating for each item.
Based on predetermined cutoffs established in previous
Delphi consensus statements,
14,15
we established a priori criteria
for consensus (mean rating ≥7, with ≤1 response ≥2 points away
from mean) and near consensus (mean rating ≥6.5, with ≤2
responses ≥2 points away from mean).
For results of forced choice questions (choose one state-
ment), we calculated percentage of respondents for each state-
ment and defined consensus as a supermajority of ≥75% and
near consensus as ≥66% (and not reaching supermajority
status).
14,15
Summary data (mean, median, mode, maximum and mini-
mum; or percentage of respondents for forced choice questions) of
the previous Delphi survey were provided in an Excel sheet to
each study group member prior to subsequent survey rounds.
Respondents were directed to consider the previous survey
results when rerating a statement. The mean and median from
the most recent round of results were included within the survey
at the end of each statement. A total of four survey rounds were
completed.
RESULTS
International Body of Experts
Over the duration of the study, all 70 individuals
participated at the pre-determined minimum required
level of completion (at least 50% of surveys). The final
working group represented 12 countries and 56
institutions. The study group comprised pediatric and
adult otolaryngologists (n = 61), adult and pediatric
hematologist-oncologists (n = 6), pediatric surgeons
(n = 2), pediatric infectious disease (n = 1), and one
provider with family medicine and epidemiology training.
Summary of Responses
A total of 189 characteristics were identified, includ-
ing 185 items requiring rating, and four forced-choice
items. A total of 56 rated items met consensus criteria,
14 items near-consensus, and 114 items were excluded
(Table I). Forced-response items are shown in Table II.
Eliminated items are shown in Appendix, Table 1.2 and
Table 2.2.
Domain 1 outlined patient characteristics and con-
sisted of 4 groups representing 20 characteristics and two
forced-choice questions. Forced choice items were related
to both age at the time of diagnosis and age at the time of
surgery; the majority of respondents felt that age should
not influence the use of systemic bevacizumab.
Domain 2 outlined key disease characteristics associ-
ated with 1) location and/or appearance of disease, 2) dis-
ease severity and/or progression of disease, 3) papilloma
staging system/score, and 4) histopathology and virology.
Domain 3 clarified treatment center characteristics
recommended for safe systemic bevacizumab use. Of
40 items initially submitted, 21 met consensus criteria,
3 near-consensus, and 16 were eliminated. The domain
was divided into five groups including: 1) availability of
specific specialists at the treating center 2) availability of
specific services, 3) availability of specific facilities, 4)
availability of a tumor board and/or multidisciplinary
treatment group and 5) research infrastructure/data
collection.
Domain 4, Prior Treatment, was divided into three
groups, focusing on prior non-surgical interventions
(Group 1) and prior surgical interventions (Groups 2 and
3). Eleven initially identified characteristics in Group
1 were all eliminated. Groups 2 and 3 contained forced-
choice questions addressing frequency and number of
prior surgical interventions. While frequency of prior sur-
gical interventions was felt important by the majority of
participants, total number of prior interventions was not.
Finally, domain 5 dealt with prior workup. It was
divided into 13 groups. Seventy-five characteristics were
initially identified, with 18 meeting consensus criteria,
5 near-consensus, and 52 eliminated. The majority of con-
sensus items related to pre-treatment laboratory evalua-
tion, with additional consensus items associated with
preoperative airway evaluation, referral and consulting
services, and general health history requirements.
DISCUSSION
This investigation identified and prioritized charac-
teristics of patients who may benefit from systemic
bevacizumab therapy while minimizing treatment risks,
as well as elements of care systems that might promote
safe administration, including prior patient workup,
treatment center factors, and care providers administer-
ing therapy. Importantly, those items that met consensus
should not be identified as essential components prior to
the initiation of therapy, but instead suggestions of ideal-
state considerations for IV bevacizumab use.
Mounting evidence supports the use of systemic
bevacizumab for RRP treatment. However, high-level
studies and clinical trials are lacking, and it remains
an off-label indication while risks and benefits continue
to be elucidated. The majority of centers participating
in this study treat only a small cohort of individuals,
and practice patterns vary between institutions. Case
reports have focused on patients with severe, recidivis-
tic disease and a longstanding history of surgical inter-
vention.
10-12
These reports have served as a foundation
for the use of systemic bevacizumab for RRP, but prac-
tice patterns are often extrapolated from an admixture
of oncologic indications and previous anecdotal experi-
ence. As such, variability in dosing, frequency, and the
timing of surgical debridement persist. This variability
may be an obstacle to institutions and clinicians consid-
ering offering this treatment option. Patients may then
be sent to centers with prior experience using systemic
bevacizumab for RRP or denied a potentially beneficial
treatment, reducing access to potentially lifesaving
therapy.
We thus hope to provide a standardized and consis-
tent infrastructure and patient selection framework for
Laryngoscope 00: 2021 Sidell et al.: Systemic Bevacizumab for Papillomatosis
4
centers that currently provide, or may in future provide,
systemic bevacizumab therapy for RRP. This investi-
gation is an early step in the investigation of appro-
priate systemic bevacizumab use for patients with
RRP; it does not address dosing protocols, timing of
surgical interventions, or management of patients in
remission or relapse. Several salient points merit
mention.
TABLE I.
List of Items to Identify and Obtain Pre-Determined Consensus on Characteristics Associated With Systemic Bevacizumab Use for the
Treatment of RRP Across Five Domains Using a Modified Delphi method. Fifty-six Rated Items Met Consensus Criteria, and 14 Items Met
Near-Consensus Criteria.
Group Statement
Consensus
Status
Domain 1. Patient Characteristics
1. Social and Demographic
Characteristics
Significant reduction in patient’s quality of life Consensus
Patient is able to adhere to treatment regimen including blood work/serology/checkup schedule Consensus
Patient is able to undergo repeated laryngoscopy and bronchoscopy Consensus
Patient or legal guardian/parent are agreeable to off-label medication use Consensus
Patient is not pregnant or lactating Consensus
Patient is not planning on becoming pregnant during or for 6 mo after end of treatment Consensus
2. Lack of standard of care option Patient has significant risk of difficult airway/airway obstruction with anesthesia Consensus
Domain 2. Disease Characteristics
1. Location and/or appearance of
disease
Progressive pulmonary disease by serial chest computed tomography (CT) imaging (≥20% increase by
RECIST 1.1 criteria on 2 subsequent scans at least 3 mo apart)
Consensus
Primarily tracheobronchial or pulmonary parenchyma Consensus
Disease extends beyond upper 1/3 of trachea Consensus
Involves upper, middle, and lower trachea Consensus
Esophageal and tracheal involvement Consensus
ANY extralaryngeal extension (pharynx, esophagus, trachea, bronchus, lung) Consensus
Disease in locations difficult to treat by standard techniques Consensus
2. Disease severity and/or
progression of the disease
Recurrent or multiple documented events of respiratory distress Consensus
Rapid progression of disease beyond the larynx Consensus
Patient has required emergent airway management more than one time prior to performing operative
treatment to remove papilloma
Consensus
Tracheostomy due to disease burden Near
consensus
Long-term ventilation due to disease burden Near
consensus
Rapidly progressing or rapidly enlarging bulky disease Near
Consensus
3. Papilloma staging system/score A recurrent respiratory papillomatosis staging system should be used to describe papilloma burden
prior to the use of systemic bevacizumab (Avastin)
Near
Consensus
4. Histopathology and Virology of
the disease
Malignant transformation present Near
consensus
Cytologic dysplasia or atypia present Near
consensus
Domain 3. Treatment Center Characteristics
Presence and/or availability of the
following specialists are at the
treating center
Otolaryngologist is available. If the patient is a child/pediatric patient then the treating center should
have pediatric otolaryngologist available
Consensus
If there is pulmonary disease, pulmonologist is available Consensus
Oncologist is available. If the patient is a child/pediatric patient then the treating center should have
pediatric oncologist available
Consensus
Pathologist is available for tissue diagnosis, evaluation for dysplasia Consensus
The otolaryngologist present has experience managing patients with recurrent respiratory
papillomatosis
Consensus
The practitioners/oncologists at treating center have experience giving systemic bevacizumab (Avastin)
(for any indication) and/or treating the side-effects of systemic bevacizumab (Avastin)
Consensus
The treating center treats multiple patients with ongoing or active RRP Near
consensus
(Continues)
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TABLE I.
Continued
Group Statement
Consensus
Status
Presence and/or availability of the
following outpatient and/or
inpatient services at the treating
center
Radiology services Consensus
Oncology services Consensus
Internal medicine or pediatric care services Consensus
Center has experienced chemotherapy nurses Consensus
An outpatient infusion center or infusion day-clinic is available Consensus
The center has designated intensive care unit (ICU) or a pediatric ICU (PICU) if the patient is a child Consensus
If pediatric patient, the center has pediatric anesthesiologists and or pediatric surgical specialists Consensus
The center is a tertiary care medical center Consensus
The center has an otolaryngology team capable of age-appropriate complex airway management Consensus
The center is able to admit/hospitalize the patient during the administration of medication if needed Consensus
The center has an anesthesia team with specific skills and experience in managing patie nts with
respiratory papilloma
Consensus
The center is able to maintain close communication with local oncologists if they are not present at the
primary treating center
Near
consensus
Facilities present at the treating
center
A certified pharmacy is accessible before and after treatment Consensus
Capable of monitoring the patient during systemic infusions Consensus
Ability to perform transfusions in the event of bleeding Consensus
Tumor board/multidisciplinary
treatment group
The center has a multidisciplinary follow-up with all available services as needed: (pediatrics, infectious
disease, oncology, hematology, otorhinolaryngology, pneumonology/pulmonary medicine)
Consensus
Research infrastructure/data
collection
The treating center has the capacity to participate in a clinical study or trial of off-label use of
medication
Near
Consensus
Domain 4. Prior Treatment Characteristics
All proposed statements (Likert criteria) in Domain 4 were eliminated
Domain 5. Prior Workup
Complete Blood Count (CBC) Patients should have a complete blood count (CBC) drawn prior to receiving systemic bevacizumab
(Avastin)
Consensus
Patients should have a normal complete blood count (CBC) documented prior to receiving systemic
bevacizumab (Avastin)
Consensus
Metabolic Panel [Sodium,
Potassium, Chloride, Carbon
Dioxide (bicarbonate), Glucose,
Total Bilirubin, Total Protein,
Blood Urea Nitrogen (BUN),
Creatinine, Albumin, Total
Protein, Calcium, Magnesium,
Potassium]
Patients should have a comprehensive metabolic panel (CMP) drawn prior to receiving systemic
bevacizumab (Avastin)
Consensus
Hepatic Function Patients should have hepatic function tests (alanine transaminase (ALT) aspartate transaminase (AST),
alkaline phosphatase (ALP), albumin, total protein, bilirubin, gamma-glutamyltransferase (GGT),
lactate dehydrogenase (LD), drawn prior to receiving systemic bevacizumab (Avastin)
Consensus
Urinalysis and Urine studies Patients should have a urinalysis completed prior to receiving systemic bevacizumab (Avastin) Consensus
Patients should have a urine total protein:creatinine ratio completed prior to receiving systemic
bevacizumab (Avastin)
Consensus
Other Lab Tests Patients should have a urine pregnancy test prior to receiving systemic bevacizumab (Avastin) Consensus
Patients should have a negative urine pregnancy testing prior to receiving systemic bevacizumab
(Avastin)
Consensus
Oncology should determine, order, and evaluate all serology prior to the patient receiving systemic
bevacizumab (Avastin).
Consensus
Cardiology/Pulmonology/Radiology
Studies: Imaging Studies
Patients should have chest computed tomography (CT) performed prior to receiving systemic
bevacizumab (Avastin)
Near
consensus
General Heath History
Requirements
Patients should not have a history of major open surgery within 28 d prior to initiating systemic
bevacizumab (Avastin)
Consensus
Patients should not have a known hypersensitivity to bevacizumab (Avastin) prior to initiating systemic
bevacizumab (Avastin)
Consensus
Patients should not have a known upcoming elective surgery scheduled prior to initiating systemic
bevacizumab (Avastin)
Consensus
(Continues)
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Patient Characteristics
The consensus suggests that age at surgery or at
time of diagnosis should not be a deciding factor in the
treatment of patients with RRP. No available information
suggests this treatment should be withheld or adminis-
tered based on age alone; both pediatric and adult
patients have seen both partial benefit and complete
remission from disease.
10-12
Patients should adhere to the
following: 1) undergo laryngoscopy and bronchoscopy to
manage disease as needed during the treatment period,
2) agree to off-label use of the medication with informed
consent, and 3) avoid pregnancy and lactation during and
surrounding the treatment period.
RRP Treatment History
No single characteristic of past surgical or non-
surgical RRP treatment met consensus criteria. The total
number of past surgical interventions was also not impor-
tant. In contrast, frequency of surgical interventions
should be considered prior to initiating systemic
bevacizumab treatment. The consensus suggested that
rapidity of papilloma re-accumulation may represent dis-
ease severity better than longevity of disease.
Disease Characteristics
Several consensus and near-consensus items over-
lapped. For example, consensus items supporting sys-
temic bevacizumab use included progressive and/or
severe disease burden, and disease in locations difficult to
treat with standard surgical intervention. Similar items
achieving near-consensus included need for tracheostomy
or long-term ventilatory support due to disease burden,
rapidly progressing or rapidly enlarging bulky disease,
and increasing Derkay score over the preceding year.
This suggests that patients with tracheostomy or long-
term mechanical ventilation due to disease burden or
disease progression over the preceding year may still be
candidates for treatment, but that these items in isolation
do not necessarily make practitioners more likely to use
systemic medication. Although the general use of a stag-
ing system to describe RRP burden prior to initiation of
systemic bevacizumab met near-consensus criteria, a spe-
cific staging system was not agreed upon. Nevertheless,
documentation of endoscopic and clinical examination
findings can be considered reasonable, the use of a spe-
cific staging system (e.g., Derkay score) notwithstanding.
Prior Evaluation/Workup
This section aimed to describe optimal patient prep-
aration and evaluation prior to initiating systemic
bevacizumab therapy. Overall, the working group felt
that an oncology service should determine, order, and
evaluate all laboratory studies prior to initiating systemic
bevacizumab. Of eight laboratory studies meeting consen-
sus for being checked before initiating treatment, only the
complete blood count (CBC) was recommended to be nor-
mal prior to treatment, possibly owing to the bleeding
risk associated with systemic bevacizumab. To date, anec-
dotal accounts of bleeding following systemic
bevacizumab use for RRP are limited to bloody sputum or
bloody secretions following debridement of papilloma on
the day of infusion. As a precaution, bevacizumab infu-
sions are often given on the day of surgical debridement
after the procedure, or a few days later.
TABLE I.
Continued
Group Statement
Consensus
Status
Recurrent respiratory
papillomatosis (RRP)-related
symptom
Patients have had multiple episodes of life-threatening airway obstruction prior to starting bevacizumab
(Avastin)
Near
consensus
Cardiovascular and Hematologic
History
Patients have no history of thrombophilia prior to starting bevacizumab (Avastin) Consensus
Patients have no history of ischemic or hemorrhagic cardiovascular event prior to starting bevacizumab
(Avastin)
Near
consensus
Patients have no history of ischemic or hemorrhagic neurologic event prior to starting bevacizumab
(Avastin)
Near
consensus
Airway endoscopic evaluation Patients have undergone diagnostic microlaryngoscopy and bronchoscopy in the operating room prior
to starting systemic bevacizumab (Avastin)
Consensus
Patients have undergone microlaryngoscopy, bronchoscopy and biopsy with viral typing in the
operating room prior to starting systemic bevacizumab (Avastin)
Consensus
Patients have a biopsy excluding malignancy prior to starting systemic bevacizumab (Avastin) Consensus
Patients have undergone microlaryngoscopy and bronchoscopy in the operating room within 1 mo of
starting systemic bevacizumab (Avastin)
Near
consensus
Referral/Consulting Service
Characteristics
Patients (or parents, if the patient is a child) have consented to off-label use of systemic bevacizumab
(Avastin) prior to starting the medication
Consensus
Patients have been evaluated by an oncologist prior to starting systemic bevacizumab (Avastin) Consensus
Consensus: mean rating ≥7, with ≤1 response ≥2 points away from mean. Near consensus: mean rating ≥6.5, with ≤2 responses ≥2 points away from
mean.
16
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The requirement for chest computed tomography
(CT) prior to systemic bevacizumab met near-consensus
criteria; however, no single imaging study met consensus.
It would thus be reasonable to make the decision to per-
form pretreatment radiologic studies on a patient-by-patient
basis. Many patients with extra-laryngeal disease have
undergone chest CT, and this would be reasonable in any
patientatriskofpulmonaryinvolvement.
10-12
Finally, the working group supported diagnostic lar-
yngoscopy and bronchoscopy in the operating room prior
to initiating systemic bevacizumab therapy. For studies
on papilloma tissue, consensus was reached for both
human papilloma virus typing and evaluation for malig-
nancy. We suggest that understanding of the presence,
location, and histologic characteristics of disease is impor-
tant before initiating systemic therapy.
Treating Facility and Personnel
Because a key premise of this investigation was to
optimize safe patient care, it is important to understand
facility and personnel characteristics important to this
process. Participants felt that systemic bevacizumab
administration is best done at centers able to assess and
promptly manage complications or adverse effects. Con-
sensus was reached on the necessity of specialists capable
of assessing the disease anatomically and histologically
and providing age-appropriate care for pediatric patients.
Importantly, consensus was reached that multi-
disciplinary coordinated team care is necessary.
Final Considerations
As with any consensus statement, this study has
important limitations. First, it is based on expert opinion,
though obtained and developed through standardized and
structured methods. The results are therefore vulnerable to
biases in individual respondents, though these may be
countered by the Delphi method of leveraging “groupthink”
bias to achieve convergence and consensus. Second, a priori
criteria for consensus and near consensus, while necessary,
may eliminate apparently sensible items. This result may
be useful in that it questions conventional wisdom, but it
also means that this consensus statement should be taken
as a foundation rather than a final set of criteria for safe
and effective bevacizumab use. Eliminated items should not
necessarily be seen as unimportant. Heterogeneity of spe-
cialties and geographic practice settings may also have
prevented some consensus, though the advantage is a better
representation of viewpoints. Finally, not all possible coun-
tries and specialties were included, which may also intro-
duce biases. From a public health standpoint, this
consensus may make access to systemic bevacizumab more
challenging if widely adopted, because it recommends treat-
ment at high-level facilities less accessible in resource-
limited areas.
CONCLUSION
This consensus statement provides guidance for cli-
nicians planning to offer systemic bevacizumab, and for
clinicians and centers already offering bevacizumab who
want to assess and optimize their practice. Although it is
not intended to define absolute prerequisite criteria for
the use of IV bevacizumab, we do hope that clinicians will
find this document useful in structuring patient selection
and workup, treatment administration practices (inde-
pendent of specific dosing regimens), and center design,
as they consider the key questions of which patients are
likely to benefit, which patients are likely safe to receive
treatment, and how to optimally deliver this treatment.
This report also provides a structure to allow additional
centers to offer this treatment and may facilitate
bevacizumab use in combination with other RRP treat-
ment protocols. Standardized delivery systems will also
allow future multi-institutional research efforts, including
dosing regimens, which were not studied here. These
results may also guide best-practice applications of sys-
temic bevacizumab in selected patients with early-onset
or less-severe disease phenotypes. Finally, this may stim-
ulate the formation of an international patient registry to
prospectively track patient characteristics and outcomes
following systemic bevacizumab therapy, and to allow
systematic evaluation of this therapy over time.
ACKNOWLEDGEMENTS
The authors would like to acknowledge research support
provided by the Maternal and Child Research Institute,
Lucile Packard Children’s Hospital Stanford, Stanford
University School of Medicine.
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