1
1
laryngeal papilloma. Current management includes ob-
servation, laser excision, and cold knife excision; how-
ever, treatment is frequently followed by recurrence of
disease. Multiple surgical interventions can result in
vocal fold scarring and voice difficulties. Although some
cases of respiratory papilloma regress with time, par-
ticularly during adolescence, most patients have life-
long disease. Long-standing disease can result in ma-
lignant transformation or spread of benign disease into
al. In the study of Snoeck et al., cidofovir was injected
within the lesions of 17 subjects with laryngeal papilloma
without debulking at a concentration of 2.5 mg/mL as com-
pared with 6.25 mg/mL in the current study. The average
dose in the previous study was 17.5 mg per injection as
compared with 22.5 mg in the current study. In the previous
study, patients were treated every 2 weeks as compared with
every 4 weeks in the current study. In the previous study, an
average of seven injections resulted in disease remission as
compared with six injections in the current study. The re-
duction in number of injections needed to achieve remission
was most likely attributable to the increased concentration
of medication and introduction of the pinching injection tech-
nique outlined earlier. Preprotocol duration and anatomical
staging were the only variables that correlated with the
number of injections required to achieve disease control.
Subjects with longer duration of disease and more extensive
disease required more injections for remission.
5
,6
the tracheobronchial tree.
The antiviral medication cidofovir has received FDA
approval for treatment of CMV retinitis in human immu-
nodeficiency virus (HIV)–positive patients. Cidofovir is a
cytosine analogue and becomes incorporated into the ge-
nome of DNA viruses. Programmed cellular death occurs
in epithelial cells infected by replicating papilloma viruses
that incorporate cidofovir into the viral genome. However,
this does not eradicate the dormant DNA virus within
infected tissues. Intravenous administration of cidofovir
at a maintenance dose of 5 mg/kg per week for the treat-
ment of CMV retinitis has been associated with protein-
Increasing the cidofovir concentration, increasing the
injection frequency, or debulking the lesions before cido-
fovir injection could further reduce the number of treat-
ments required to achieve disease remission. Higher con-
centrations of medication would require additional study
of local and systemic toxicity. In the current study, we did
not debulk lesions before cidofovir injections in hopes of
developing a better understanding of the efficacy and local
toxicity of the drug alone in the treatment of laryngeal
papilloma. A disadvantage of debulking therapy before
cidofovir injection includes an increased risk of additional
vocal fold scarring. However, if a reduction in numbers of
treatments is identified in subjects receiving debulking
therapy, the additional risk of scarring may be warranted,
especially in subjects who have previously received ag-
7
uria, elevated creatinine, and irreversible renal failure.
The intralesional cidofovir dose in the present study
ranges from 0.45 to 0.90 mg/kg per injection. In a previous
intralesional injection study of cidofovir, renal toxicity
was monitored by blood chemistry analysis and no
1
changes were identified. In this study, no systemic toxic-
ity was identified. Although a local inflammatory response
was frequently observed in our study during the 7th to
1
4th day period after each injection, we identified no new
areas of scarring, web formation, or impaired vibration of
the vocal fold mucosa.
A final concern regarding intralesional use of cidofo-
vir is tumorigenicity. According to the minutes of the
meetings from the Center for Drug Evaluations and Re-
search from the Joint Antiviral Drugs Advisory Commit-
tee and Ophthalmologic Drugs Subcommittee (FDA) in
which the drug cidofovir received approval for the use in
CMV retinitis, animal studies demonstrated the develop-
ment of adenocarcinomas with subcutaneous injections in
female rats. However, these findings were not seen in
studies on primates. During Phase I and II studies in
humans, no increased incidence of tumorigenicity was
identified in HIV-positive patients treated with intrave-
nous cidofovir for CMV retinitis. In previous reports on
the use of intralesional cidofovir, no new carcinomas have
9
,10
gressive surgical management. Pransky et al.
have
reported debulking in combination with cidofovir in a se-
ries of 10 children. In their reports, the authors identified
significant control of laryngeal papilloma in children with
aggressive disease compared with previous treatments
with excisional therapy alone. The children entering into
the study of Pransky et al. were subjects who required
10
monthly excisions to prevent airway obstruction. Al-
though not all subjects achieved remission, the frequency
of recurrences diminished significantly. Cidofovir in com-
bination with debulking therapy appeared to alter the
biological behavior of the HPV infection in subjects receiv-
ing cidofovir.
1,2,8–10
been identified in either adults or children.
In the
1
study of Snoeck et al., two patients were identified with
verrucous carcinoma of the larynx before treatment with
cidofovir. In both subjects, their lesions resolved with ci-
dofovir, and post-treatment biopsy specimens revealed no
evidence of papilloma or carcinoma. Although the tumor-
igenicity of intralesional cidofovir is a potential concern,
no subjects to date have developed laryngeal carcinomas
after the use of intralesional cidofovir. Because of these
concerns, we recommend the use of intralesional cidofovir
under strict protocol and informed consent so that safety
and efficacy data can be collected.
CONCLUSION
Intralesional injection of cidofovir is an excellent
treatment option with limited local and systemic toxici-
ties. However, pure injection therapy requires persever-
ance from both patient and surgeon to achieve remission.
Although this drug is effective in managing replicating
HPV infections in almost all adults, the long-term remis-
sion rates for patients with respiratory papilloma are un-
known. In a future report, we will characterize the long-
term treatment response to intralesional cidofovir in
subjects with respiratory papilloma.
Intralesional cidofovir as an injection-only treat-
ment has been reported for esophageal papilloma by
8
Van Custem et al. and for laryngeal papilloma by Snoeck et
Laryngoscope 112: April 2002
Bielamowicz et al.: Laryngeal Papilloma
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