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Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement

Authors:
  • Stanford Children's Health; Lucile Packard Children’s Hospital--Stanford

Abstract

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 otolaryngology, 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 therapy. 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. Level of Evidence 5. Laryngoscope, 2021
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 Schefer, 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 Childrens 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.), Childrens 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 Childrens
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 Childrens 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 Childrens
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 Childrens 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 Childrens 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 Childrens 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
Childrens 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.), Childrens
Hospital Colorado afliated 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 ve 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 identied, 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 bevacizumabs 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, 00:19, 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 34/100,000
adults annually, though this gure 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 prole.
1,6-9
Division of Pediatric Otolaryngology (C.M.L., P.M., D.P.), Childrens 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 Childrens 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 Childrens 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 Childrens 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 Childrens Hospital, Houston, Texas, U.S.A.; Division of Otorhinolaryngology (S.P.), University of Cape Town and Red Cross War
Memorial Childrens Hospital, Cape Town, South Africa; Division of Ear, Nose and Throat Diseases (K.P.), Karolinska Institutet, Karolinksa University
Hospital, Stockholm, Sweden; Rady Childrens Hospital (S.M.P.), San Diego, California, U.S.A.; Department of Otolaryngology, Head and Neck Surgery (T.R.),
Texas Childrens 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.), Childrens Health Ireland, Dublin, Ireland; Divisions of Pediatric Otolaryngology,
Pulmonary Medicine, and the Sleep Center (D.F.S.), Cincinnati Childrens 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 Childrens 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.), Conuence 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 Childrens Hospital
Medical Center, St. Louis, Missouri, U.S.A.; Division of Pediatric Otolaryngology Head and Neck Surgery Ann and Robert H Lurie Childrens 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 Childrens 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 Childrens Hospital, Charleston, South Carolina, U.S.A.; Department
of Otolaryngology-Head and Neck Surgery (C.J.Y.), Albert Einstein College of Medicine, Monteore Medical Center, Childrens Hospital at Monteore,
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 Childrens 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, Childrens Hospital of the Kings Daughters, Norfolk, Virginia, U.S.A.
Additional supporting information may be found in the online version of this article.
Editors Note: This Manuscript was accepted for publication on December 17, 2020
The authors have no funding, nancial relationships, or conicts 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
2
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 benet all patients and is impracti-
cal for diffuse tracheal disease or pulmonary lesions.
Systemic administration of bevacizumab for RRP
was rst 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 signicant
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 identied vari-
ability in treatment dosing, treatment frequency, and
degree of response. The authors concluded that systemic
bevacizumab showed signicant 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 modied 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, rst identifying
individuals with experience treating, or planning to treat, adults
or children with RRP using systemic bevacizumab. An initial
email contacted approximately 250 individuals identied as
potential experts in the eld 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 inviteeswork). Indi-
viduals were asked to conrm 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 conrmed 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.
Modied 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 515 characteris-
tics within each of ve 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 modied
Delphi method worked to preserve intent of the study groups
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
patients 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 19 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 dened 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 nal
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 identied, 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 inuence 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 claried 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 ve groups including: 1) availability of
specic specialists at the treating center 2) availability of
specic services, 3) availability of specic 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 identied 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-ve characteristics were
initially identied, 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 identied and prioritized charac-
teristics of patients who may benet 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 identied 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 benets 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 benecial
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 Modied 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
Signicant reduction in patients 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 signicant risk of difcult 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 difcult 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 specic 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 certied 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 benet 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 difcult 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-
cic staging system was not agreed upon. Nevertheless,
documentation of endoscopic and clinical examination
ndings can be considered reasonable, the use of a spe-
cic 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 nal 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 dene absolute prerequisite criteria for
the use of IV bevacizumab, we do hope that clinicians will
nd this document useful in structuring patient selection
and workup, treatment administration practices (inde-
pendent of specic dosing regimens), and center design,
as they consider the key questions of which patients are
likely to benet, 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 Childrens Hospital Stanford, Stanford
University School of Medicine.
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... Today's literature includes various case reports regarding bevacizumab treatment for RRP [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. However, the majority of authors reported their experiences almost exclusively in selected patients with advanced to severe papillomatosis, and high quality studies and clinical trials that objectify the efficacy of bevacizumab for RRP are lacking [24]. The goal of this systematic review was to give an overview of the available literature concerning the efficacy of bevacizumab for RRP, and to differ between intralesional and systemic treatment. ...
... According to the 'Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement' [24], two parameters are internationally recognized for objectifying RRP severity: need for tracheotomy and surgery frequency. Thus, the efficacy of bevacizumab can be derived by comparing the surgical interval before and after treatment [24]. ...
... According to the 'Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement' [24], two parameters are internationally recognized for objectifying RRP severity: need for tracheotomy and surgery frequency. Thus, the efficacy of bevacizumab can be derived by comparing the surgical interval before and after treatment [24]. Interestingly, one study did not report these surgical intervals [19]. ...
Article
Full-text available
Purpose To this day, there is no cure for recurrent respiratory papillomatosis (RRP). Multiple surgical procedures are performed to achieve symptom relief and prevention of airway obstruction. A promising drug for RRP is the vascular endothelial growth factor (VEGF) binding antibody bevacizumab. This chemotherapeutic agent has an angiogenesis-inhibiting effect which inhibits tumor growth. The objective of this review was to investigate the efficacy of bevacizumab as treatment option for RRP, and to explore the difference of its effects between intralesional and systemic treatment. Methods A systematic search was conducted in Cochrane, PubMed, and Embase. Articles were included if bevacizumab treatment was given intralesionally and/or systemically. The methodological quality of the studies was assessed using the CAse REport (CARE) guidelines. Results Of 585 unique articles screened by title and abstract, 15 studies were included, yielding a total of 64 patients. In 95% of the patients treated with systemic bevacizumab, the post-bevacizumab surgical interval was considerably prolonged. More than half of them did not need any surgical intervention during mean follow-up of 21.6 months. Treatment with intralesional bevacizumab showed a lower efficacy: in 62% of the patients, the post-bevacizumab surgical interval (mean, 1.8 months follow-up) was extended when compared to the interval before the treatment. Conclusion Systemically and intralesionally administered bevacizumab are effective treatment options for severe RRP. A systemic administration might be the treatment of first choice. Further prospective research with long term follow-up is advocated to elucidate this important topic.
... Bevacizumab bindt aan VEGF waardoor deze niet aan zijn receptor kan binden. 2,6 Als gevolg daarvan worden geen groeisignalen aan de tumor doorgegeven, wordt de angiogenese en zo ook de groei geremd en zullen recidiverende chirurgische ingrepen in theorie minder vaak nodig zijn. In dit rapport presenteren wij onze resultaten en ervaringen met bevacizumab bij een patiënt. ...
... Uit het recent verschenen 'Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement' werd duidelijk dat naast de noodzaak voor tracheotomie ook de operatiefrequentie een internationaal erkende maat is om de ernst van RRP te objectiveren. 6 Het effect van bevacizumab kan worden afgeleid door de operatiefrequentie van voor en na de behandeling met elkaar te vergelijken. In onze casuïstiek nam de operatiefrequentie gedurende het behandeltraject geleidelijk toe. ...
... De recent gepubliceerde 'International Consensus Statement' rekent een hoge operatiefrequentie, een progressief of ernstig ziektebeloop en uitbreiding van papillomatose in chirurgisch moeilijk bereikbare gebieden tot de duidelijke indicaties voor systemisch toegediende bevacizumab. 6 deze patiënten gemiddeld vier operaties per jaar (spreiding 2-11 per jaar). Ze kregen gemiddeld 8,5 (spreiding 2-17) behandelcycli met bevacizumab gedurende een follow-up van gemiddeld 274 dagen (spreiding 131-492 dagen). ...
Article
Recurrent respiratory papillomatosis (RRP) is a very rare disease of the airway mucosa caused by an infection with human papillomavirus (HPV). It is characterized by regular growth of papillomas in the larynx, trachea, or lung parenchyma, resulting in symptoms, such as dysphonia, dyspnea, chronic coughing, stridor, or wheezing. To this day, there is no cure for RRP and treatment mainly consists of surgical interventions in order to achieve symptom relief. In the literature, bevacizumab is increasingly being described as a successful therapy in the treatment of RRP. Here, we present the case of a 53-year- old man with laryngeal, tracheal, and pulmonary papillomatosis who had been receiving surgical treatment for RRP over several years, but was effectively treated with systemic bevacizumab.
... At present, the treatment targeting VEGF/VEGFR has become an important means of tumor treatment. The mechanism is mainly through competitive binding with endogenous VEGF, and inhibiting or reducing the binding of VEGF to vascular endothelial cell surface receptors, thereby inhibiting endothelial cell proliferation and angiogenesis, and finally playing a role in inhibiting tumor growth (26,27). ...
Article
Full-text available
Objective To investigate the efficacy of bevacizumab combined with chemotherapy in the treatment of colorectal cancer (CRC) and to analyze the effects on brain peptides, intestinal flora, and oxidative stress in CRC patients. Methods Eighty two patients with CRC who were admitted to our hospital from March 2018 to June 2021 were selected as the research subjects and divided into the control group ( n = 41) and the observation group ( n = 41). The control group was treated with XELOX chemotherapy, and the observation group was additionally treated with bevacizumab, which was repeated every 3 weeks for a total of two treatments. The therapeutic effects of the two groups were evaluated after treatment. The brain-gut peptide index, intestinal flora index and oxidative stress index were detected, and the adverse reactions of the two groups were recorded. Results In the control group, ER was 36.59% (15/41) and DCR was 73.17% (30/41). In the observation group, ER was 63.41% (26/41) and DCR was 90.24% (37/41). ER and DCR in the observation group were higher than those in the control group ( P < 0.05). After treatment, the levels of motilin and gastrin in the observation group were lower than those in the control group, and ghrelin was higher than that in the control group ( P < 0.05). After treatment, the levels of Bifidobacterium, Lactobacilli and Enterococcus in the observation group were higher than those in the control group, and the level of Escherichia coli was lower than that in the control group ( P < 0.05). After treatment, the SOD level of the observation group was lower than that of the control group, and the MDA level was higher than that of the control group. Conclusion Bevacizumab combined with chemotherapy has good efficacy in the treatment of colorectal cancer patients, which can effectively improve the gastrointestinal motility of patients, regulate the intestinal flora of the body, rebuild the microecological balance, effectively reduce the oxidative stress response of patients, and reduce the incidence of adverse reactions.
... Le tecniche chirurgiche di scelta prevedono sia procedure a freddo, con l'u-tilizzo di microdebrider o di taglienti, sia procedure laser CO2, diodi, KTP, sia radiofrequenza dipendentemente dall'esperienza del chirurgo [4]. La terapia medica trova poco spazio nel trattamento della JoRRP, ad eccezione del Bevacizumab, anticorpo monoclonale anti-VGFR, introdotto come adiuvante off label nei casi di papillomatosi respiratoria con decorso aggressivo [11]. 100.000 nel 2016, riportando un impatto evidente della vaccinazione quadrivalente per HPV sulle infezioni genitali materne in primo luogo e in secondo luogo sulla trasmissione verticale del virus con riduzione del numero di pazienti aff etti da JoRRP [5][6][7]. ...
Article
Introduction Recurrent respiratory papillomatosis is a rare human papillomavirus (HPV) induced condition where warts grow within the airway and especially the larynx to effect voice and restrict breathing. Areas covered A PubMed search using the following search terms was performed: respiratory papillomatosis and cidofovir, alpha-interferon, bevacizumab, PD1, HPV vaccines. Surgery remains the mainstay of treatment. There has been a change in options available for adjuvant therapies with systemic bevacizumab and the potential benefits of prophylactic HPV vaccine. Despite efforts to identify a drug therapy to control RRP, no therapy yet remains which is predictable and effective in all. The current status of therapeutic vaccines and immunotherapy is discussed. Expert opinion The current adjuvant therapies do offer a reasonable expectation of control but the effect for the individual is unpredictable despite the therapies being based on good science. The current therapies would allow an escalating treatment strategy to be formulated, however a single therapy is unlikely to be curative. Multi-center trials are required such that adequate numbers to show an effect are achieved.
Objective Recurrent respiratory papillomatosis (RRP) is known for its recurrent relapse despite various surgical and non-surgical treatments. Vascular Endothelial growth factor (VEGF) receptor expression on tissue is reported to be raised in RRP, and anti-VEGF targeted treatment is being explored to decrease recurrences. This study aims to identify the patients most suitable for systemic anti-VEGF therapy. Methods The study design was a prospective cohort evaluation. The study group included all consecutive cases of RP treated surgically from November 2016–June 2019. Tissue receptor expression and serum levels of VEGF were assessed by immunohistochemistry and ELISA assay. Control samples for normal levels obtained by serum samples of healthy individuals and tissue samples obtained from healthy non-inflamed peripheral tissue of laryngectomy specimens. The tissue expression and serum levels of VEGF were compared with various disease-related factors of RP. Results 32 cases of RRPs were included in the study with a median age of 20.85 years (range: 3–60 years). The glottis was involved in all patients and tracheobronchial involvement was seen among 6 patients (18.75%). The systemic and tissue expression of VEGF-A was significantly higher among cases than controls (p= <0.001). The serum level of VEGF-A was significantly higher among cases with higher Derkay's score (>20) (p = 0.02) and tissue expression of VEGF-A was significantly higher in tracheobronchial RRP (p = 0.04). Conclusion Patients of RP with tracheobronchial involvement and high Derkay's score with strong tissue receptor expression & high serum level of VEGF can be identified as the patients wherein anti-VEGF monoclonal antibody treatment is more likely to be effective and merits further investigation to prove this.
Article
Full-text available
Objective Despite recent advancement recurrent respiratory papillomatosis (RRP) remains a rare but challenging benign airway neoplasm. In recent years there has been significant shifts in incidence of this disease due to changes in vaccination and prevention for human papilloma virus (HPV) and its related pathology. This review will highlight the epidemiology, prevention and treatment of RRP. Methods The PubMed database was searched using relevant MeSH terms including “recurrent respiratory papillomatosis.” The titles and abstracts were reviewed to assess relevance and unrelated articles were excluded. A full‐text review for select articles was performed, the data and discussions were interpreted and synthesized to create a concise update on the management of RRP. Results With the increasing utilization of the 9‐valent and quadrivalent HPV vaccine in Australia, we have seen a significant decrease in the incidence of RRP. Preliminary data in the US shows a similar trend of decreased incidence after implementation of vaccination. Single dose Gardasil in developing countries has shown sustained immunization for at least 7 years. Preliminary clinical trials and retrospective studies have shown the HPV vaccine may have benefit as a treatment method in addition to prevention for HPV related diseases. Bevacizumab (Avastin), a VEGF monoclonal antibody, has shown promise as a systemic treatment for RRP. The Corona Virus Disease 2019 (COVID‐19) pandemic has affected perioperative management of RRP. Conclusion RRP continues to decline in incidence since the implementation of HPV vaccination. Advancement in the medical management including Bevacizumab show promise as an additional option for the management of RRP.
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Recurrent respiratory papillomatosis (RRP) is the recurrent growth of small, benign tumors, or papillomas, in the respiratory tract, caused by human papillomavirus (HPV). Currently, there is no cure. Palliative treatments seek to prevent airway obstruction, keep underlying tissues healthy, and maintain voice quality. The most common intervention, the local surgical removal of papillomas, may be inadequate as a standalone treatment for pediatric populations that experience rapid papilloma regrowth, as repeated surgeries cause increased damage to the surrounding tissues and impose significant emotional and economic burden on families. Interferon α and Cidofovir have been shown to lengthen the time between surgical interventions and/or decrease the total number of procedures needed, although the evidence of their efficacy and safety is controversial. Novel therapies, including photodynamic therapy, indole-3-carbinol, anti-reflux medication, heat shock protein, and Mumps and HPV vaccination, may provide potential avenues for treatment, but require further research. Among all the novel therapies investigated, systemic bevacizumab seems to offer the most promising alternative to surgery. Randomized control trials to investigate its impact, especially in a pediatric population, should be conducted before implementing it as a standard form of care. This review will summarize the latest literature on medical care for aggressive RRP disease.
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Objectives Develop multidisciplinary and international consensus on patient, disease, procedural, and perioperative factors, as well as key outcome measures and complications, to be reported for pediatric airway reconstruction studies. Methods Standard Delphi methods were applied. Participants proposed items in three categories: 1) patient/disease characteristics, 2) procedural/intraoperative/perioperative factors, and 3) outcome measures and complications. Both general and anatomic site‐specific measures were elicited. Participants also suggested specific operations to be encompassed by this project. We then used iterative ranking and review to develop consensus lists via a priori Delphi consensus criteria. Results Thirty‐three pediatric airway experts from eight countries in North and South America, Europe, and Australia participated, representing otolaryngology (including International Pediatric Otolaryngology Group members), pulmonology, general surgery, and cardiothoracic surgery. Consensus led to inclusion of 19 operations comprising open expansion, resection, and slide procedures of the larynx, trachea, and bronchi as well as three endoscopic procedures. Consensus was achieved on multiple patient/comorbidity (10), disease/stenosis (7), perioperative‐/intraoperative‐/procedure‐related (16) factors. Consensus was reached on multiple outcome and complication measures, both general and site‐specific (8 general, 13 supraglottic, 15 glottic, 17 subglottic, 8 cervical tracheal, 12 thoracic tracheal). The group was able to clarify how each outcome should be measured, with specific instruments defined where applicable. Conclusion This consensus statement provides a framework to communicate results consistently and reproducibly, facilitating meta‐analyses, quality improvement, transfer of information, and surgeon self‐assessment. It also clarifies expert opinion on which patient, disease, procedural, and outcome measures may be important to consider in any pediatric airway reconstruction patient. Level of Evidence 5. Laryngoscope, 2018
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Recurrent respiratory papillomatosis (RRP) is a primary benign disease, which is characterized by papillomatous growth in the respiratory tract. Malignant transformation occurs in only 3-5% of cases, however, local growth of the benign papillomas is interpreted as clinically malignant in a markedly higher proportion of patients. Local surgical or endoscopic interventional debulking or excision is currently the commonly selected treatment method and antiviral therapy is a potential adjuvant approach. However, the long-term management of RRP patients, who commonly require multiple procedures over numerous years, is challenging and the overall therapeutic armamentarium remains unsatisfactory. The administration of systemic bevacizumab treatment in a series of five patients with long histories of RRP, who required repeated local interventions to control papilloma growth is evaluated. Treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was administered at a dose of 5 mg/kg (n=1), 10 mg/kg (n=3) or 15 mg/kg (n=1) intravenously to the five RRP patients, who were clinically classified as exhibiting progressive disease. Endoscopic evaluations were performed prior to the first infusion of bevacizumab and intermittently at variable time points during the course of therapy. Histopathological analyses were performed using pre- and post-treatment papilloma biopsies, including immunohistochemical analyses of VEGF and phosphorylated VEGF receptor (VEGFR)-2 expression. The patients received between three and 16 courses of bevacizumab (median, six courses). The first course was initiated when progression following the previous intervention was observed. An immediate response to bevacizumab treatment was demonstrated in all five RRP patients. While the cumulative number of interventions in the five patients was 18 throughout the 12 months prior to the initiation of bevacizumab treatment, only one patient required interventional treatment due to a malignant transformation during the 12 months following treatment with bevacizumab (18 vs. 1 interventions, P=0.042). Histopathological analyses revealed regressive perivascular edema and normalization of the vascular structure, however, immunohistochemical analyses of the VEGF and phosphorylated VEGFR-2 expression did not demonstrate any changes following therapy. Due to the limited number of alternative treatments, VEGF-targeted therapies may represent a promising novel strategy in the treatment of RRP, which may have the potential to modify the current treatment standards, particularly in patients with poorly accessible papilloma lesions, however, this requires further investigation in clinical trials.
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Hintergrund: Die rezidivierende respiratorische Papillomatose (RRP) ist ein seltenes Krankeitsbild, das durch humane Papillomaviren hervorgerufen wird und charakterisiert ist durch multiple exophytische Läsionen und deren unkontrolliertes Wachstum innerhalb des Respirationstraktes. Häufigste Komplikation der RRP ist die Stenosierung der Trachea. Medikamentöse Therapieoptionen sind bislang wenig effektiv. Die Inhibition des vaskulären endothelialen Wachstumsfaktors (VEGF) durch Bevacizumab könnte eine erfolgversprechende Therapieoption bei RRP sein. Kasustik: Es wird über einen 32-jährigen männlichen Patienten mit RRP berichtet, der seit 1996 vierteljährlich wegen symptomatischer Trachealstenose behandelt wird. Die einzig wirksame Behandlung war die Laserkoagulation. Andere Therapien zeigten keinen Effekt. Im Mai 2006 wurden intrapulmonale Läsionen der RRP diagnostiziert, ohne Nachweis von Malignität. Von Dezember 2007 bis Juni 2008 wurde der Patient mit Bevacizumab behandelt. Darunter war eine deutliche Remission der RRP sowie der Symptomatik zu beobachten. Unter dieser Behandlung war keine zusätzliche Laserabtragung notwendig. Schlussfolgerung: Die VEGF-Hemmung durch Bevacizumab scheint eine neue effektive Option im Krankheitsmanagement der RRP zu bieten.
Purpose of review: Recurrent respiratory papillomatosis (RRP) is the most common as well as the costliest benign airway neoplasm in the United States [Ivancic et al. (2018). Laryngoscope Investig Otolaryngol 3:22; Derkay (1995). Arch Otolaryngol Head Neck Surg 121:1386]. In addition, it is potentially deadly, with risk of airway obstruction as well as a 3-7% risk of malignant conversion [Schraff et al. (2004). Arch Otolaryngol Head Neck Surg 130:1039]. This review highlights exciting advancements over the past 1-2 years in scientific understanding of the pathophysiology, epidemiology, natural history, prevention, and treatment of this difficult disease. Recent findings: Recent studies have yielded the following findings: The primary quality of life reduction that patients perceive is voice-related; the membranous vocal folds are the most frequently involved anatomic subsite in adult-onset RRP; there may be a correlation between laryngopharyngeal reflux, herpes simplex virus type 2, and adult-onset RRP; there has been a decline in RRP incidence in Australia following the implementation of a national vaccination program; addition of educational audiovisual aids assists in vaccine acceptance rates; preventive vaccination can be used as treatment for pediatric as well as adult RRP patients with demonstrable effects on antibody titers and reoperation rates; calreticulin-linked DNA vaccines show promise in reducing the growth rate of human papilloma virus (HPV)11 E6/E7-expressing tumors in mice; injection of bevacizumab is associated with no adverse tissue affects; systemic bevacizumab is effective as a treatment for severe uncontrolled disease; pegylated interferon treatment is effective in select severe pediatric RRP disease; and finally, increased rates of programed death 1 T-lymphocyte infiltration and programed death-ligand 1 expression are seen on both papilloma and infiltrating immune cells. Summary: RRP is declining in incidence but remains a challenging disease to treat with great costs to patients, families, and the healthcare system. As the disease continues to be better understood, new frontiers are opening in treatment, particularly for severe or poorly controlled disease. Until the disease can be eradicated, it remains a vital area of research to help prevent new cases and treat afflicted patients.
Article
Objectives/hypothesis: Aggressive laryngeal, tracheal, and pulmonary papilloma is an extremely challenging clinical problem without proven treatment options. A recent German report documented promising results with systemic bevacizumab. The objective of this study is to report the initial experience of this novel treatment in the United States for recurrent respiratory papillomatosis (RRP). Study design: Cases series. Methods: Electronic survey of the RRP Task Force of the American Society of Pediatric Otolaryngology, American Broncho-Esophagological Association, and physicians known to the authors to have used systemic bevacizumab for RRP. Results: Eleven completed surveys were obtained. In three cases, systemic bevacizumab was considered clinically but not administered. Eight patients were treated with systemic bevacizumab, all for aggressive papillomatosis uncontrolled by surgical and adjuvant therapy, including seven of eight with pulmonary disease. Treatment dosing ranged from 5 to 10 mg/kg every 2 to 4 weeks, with all patients responding (7/8 partial response, 1/8 complete response). In four patients who had postbevacizumab chest imaging, three demonstrated improvement of disease and one stabilization. Treatment interval could be lengthened in seven patients and clinical response maintained. One patient with long-standing pulmonary disease (>10 years) was diagnosed with malignant transformation while on treatment, and bevacizumab was discontinued in lieu of other chemotherapeutic agents. All other patients continue on systemic bevacizumab with minimal complications (hemoptysis n = 1, proteinuria n = 1). Conclusions: Systemic bevacizumab appears to have significant promise in the most treatment-resistant and aggressive forms of papillomatosis with a low complication profile. These results suggest bevacizumab should be studied in a formal clinical trial for RRP. Level of evidence: 4. Laryngoscope, 2017.
Article
Recurrent laryngeal papillomatosis (RRP) can be a devastating condition for a child to endure, and pulmonary involvement may have terminal consequences. Adjuvant therapies have been trialed and reported over the years; however, these chemotherapy options have not been successful. Bevacizumab (Avastin, Genetech Inc., South San Francisco, CA) is a vascular endothelial factor (VEGF) inhibitor that has shown promise in the management of papillomatosis. Most research has focused on intralesional injections of this antiangiogenic drug. The systemic use of bevacizumab is not as well described. This is a case report of a 12-year-old female diagnosed with severe laryngotracheal papillomatosis near birth who underwent a tracheostomy tube placement at 1 year of age. She required weekly debridements to prevent tracheal obstruction. When lung involvement was diagnosed at 1 year of age, cidofovir was started intravenously. Over the course of the past 10 years, the patient was managed with celecoxib (Celebrex, Pfizer, New York, NY), anti-reflux medications, zithromycin, propranolol, Gardasil (Merck and Co., Kenilworth, NJ), and a 7-year course of interferon-alpha. Intravenous bevacizumab was started when the patient's pulmonary status deteriorated. There was remarkable improvement in her laryngotracheal disease within 6 weeks of therapy. Following 3 months of bevacizumab, the patient's disease was completely resolved at the laryngeal level and nearly gone in the trachea, and she was decannulated. A computed scan was performed following 5 months of intravenous bevacizumab, and the pulmonary RRP nodules completely resolved. The patient had no major or minor complication from the chemotherapy to date. Systemic Bevacizumab is a promising modality of adjuvant therapy for significant papillomatosis. Laryngoscope, 2016
Article
Objectives/hypothesis: Recurrent respiratory papillomatosis (RRP) is a disease with a high disease burden. Few studies have assessed quality of life (QoL) of RRP patients. This study compares QoL of these patients with controls. Associations between QoL and sociodemographic and illness-related factors are examined, as is uptake of psychosocial care and speech therapy. Study design: Prospective cross-sectional questionnaire research. Methods: Ninety-one RRP patients (response = 67%) from two university hospitals in the Netherlands and Finland completed the following patient reported outcome measures: (HADS), 15-dimensional health-related quality-of-life scale (15D), Voice Handicap Index (VHI) and the RAND 36-item health-related quality-of-life survey instrument (RAND-36) assessing health-related QoL and voice handicap, and they provided sociodemographic, illness-related, and allied healthcare use. Descriptive analyses, χ2 tests, t tests, analysis of variance tests, and Pearson correlations were computed to describe the study population and to examine differences between groups. Results: RRP patients had significantly higher mean scores on depression, health-related QoL (15D) and on voice problems (VHI), and significantly lower mean scores on anxiety than controls. Dutch patients had more pain and a decreased general health perception (RAND-36) than controls. Dutch patients and older patients were more depressed, women were more anxious, older patients had lower health-related QoL, and smoking was significantly associated with voice handicap. Patients who had received psychosocial care had significantly higher HADS-depression mean scores than patients who did not receive psychosocial care. Conclusions: Having RRP has significant effect on voice-related QoL and depression, but has no negative effect on anxiety and health-related QoL. Risk factors for decreased functioning are different than previously hypothesized by many authors. Prevention should be aimed at these risk factors. Level of evidence: 4. Laryngoscope, 127:1826-1831, 2017.
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To develop general and site-specific treatment effect and outcome measures to standardize the reporting of head and neck lymphatic malformation (HNLM) treatments. Consensus statement/expert opinion. Multiple tertiary academic institutions. The modified Delphi method is an iterative process of collecting expert opinions, refining opinions through discussion and feedback, statistically aggregating opinions, and using these aggregates to generate consensus opinion in the absence of other data. The modified Delphi method was used by a multi-institutional group of otolaryngology and interventional radiology experts in the field of vascular anomalies to formulate a list of recommended reporting outcomes for the study and treatment of head and neck lymphatic malformations. Through 3 rounds of iteration, 10 expert panelists refined 98 proposed outcome measures and 9 outcome categories to a final consensus set of 50 recommended outcome measures in 3 global categories (general, demographics, and treatment complications) and 5 site-specific categories (orbit, oral cavity, pharynx, larynx, and neck). We propose the first consensus set of standardized reporting measures for clinical and treatment outcomes in studies of HNLMs. Consistent outcome measures across future studies will facilitate comparison of treatment options and allow systematic review. We hope that these guidelines facilitate the design and reporting of subsequent HNLM studies. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.
Article
We review and report the use of high-dose bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP) in pediatric patients. We included all patients with pediatric-onset RRP who underwent bevacizumab (25 mg/mL) injections by a single practitioner. A series of 5 consecutive subepithelial injections were administered at 4- to 6-week intervals with concomitant 532 nm KTP laser ablation. The lesions were staged according to the Derkay staging system. The outcomes included pretreatment and posttreatment Derkay scores, the time interval between procedures, and voice outcomes. The demographic data extracted included sex, age at diagnosis, and current age. Nine patients were included in this study, with 1 patient lost to follow-up; their median age was 8 years (range, 3 to 21 years). The mean bevacizumab dose was 14.25 mg (range, 5 to 45 mg). There was a median Derkay score of 11.5 (range, 4 to 23) at the time of diagnosis and a median 58% improvement following therapy. All patients demonstrated an increased time interval between injections, for a median improvement of 2.05× (range, 1.6× to 3.25×). Evidence exists in support of vascular endothelial growth factor as an important factor in the development of RRP. Although some variability in response is demonstrated by this study, high-dose bevacizumab appears to yield promising results for pediatric patients with RRP.