Efficacy of cidofovir injection for the treatment of recurrent respiratory papillomatosis

doi:10.1016/j.jvoice.2003.07.007

Journal of Voice

Volume 18, Issue 4, December 2004, Pages 551-556

https://doi.org/10.1016/j.jvoice.2003.07.007 Get rights and content

Abstract

Summary

To evaluate the efficacy of intralesional cidofovir injection for the treatment of recurrent respiratory papillomatosis (RRP). It is a prospective, open-label study design. This prospective study included 16 RRP patients, ages 9 to 68 years, who were treated with intralesional injections of cidofovir combined with surgical excision of RRP. The disease states of the patients pretreatment and posttreatment were assessed by assigning RRP severity scores, examining the need for any surgical excision of RRP, and evaluating the presence of RRP upon long-term follow-up. Sixteen patients were treated with cidofovir; however, three were lost to follow-up. Thirteen patients are the subjects of this report. This study group included three pediatric patients. Ten of thirteen patients (76.9%) responded to the treatment and are presently in remission. One patient did not respond, and two patients relapsed after initial success or had a partial response. The responders consisted of eight adults and two children. The mean number of injections the responders received was 3.5, and the average follow-up period of the responders was 25.4 months. No immediate complication of cidofovir treatment was evident. However, three patients were found to have significant vocal fold scarring after long-term follow-up. Cidofovir has been found to be efficacious in treating RRP. Further study regarding long-term follow-up and the assessment of possible side effects after cidofovir intralesional injection for RRP is required.

Introduction

Recurrent respiratory papillomatosis (RRP) is a disease characterized by benign papillomatous growths of the aerodigestive mucosa.1., 2. RRP is the most common benign tumor of the larynx in children, but it affects all age groups. Although RRP can develop anywhere along the upper aerodigestive tract, the most frequently involved site is the larynx.3., 4. RRP patients most frequently present with hoarseness. Other symptoms may include stridor, dyspnea, failure to thrive, chronic cough, or recurrent pneumonia. Although the papillomatous lesions found in RRP are cytologically benign, their recurrent and aggressive growth in the larynx may produce respiratory obstruction, leading to a medical emergency. Moreover, the natural progression of RRP is unpredictable and variable; the disease may go into spontaneous remission in some patients, whereas in most, the disease is characterized by recurrent growth of the papillomas despite surgical removal.⁵ In extremely severe cases, the patient may need a tracheotomy to maintain the airway.

Human papillomavirus (HPV) types 6 and 11 are the causative agent for RRP.⁶ Currently, there is no medical or surgical cure for the HPV infection and the mainstay of the management of the disease has been palliative repetitive surgical removal of the papillomas to improve the airway and voice quality. This disease is a source of substantial morbidity, high costs, and psychological stress for the patient and the family, which necessitates investigations for effective RRP treatment modalities.

Cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)-propyl] cytosine, HPMPC) is an acyclic nucleoside phosphonate analog that blocks the replication of members of the DNA virus family by inhibiting the viral DNA polymerase. Cidofovir is approved by the Food and Drug Administration to treat the cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome. In addition, recent reports suggest the use of intralesional injection of cidofovir for the treatment of laryngeal papillomatosis.7., 8. The initial successes of these reports prompted additional studies investigating the intralesional injection of cidofovir for the treatment of RRP.9., 10., 11.

In this study, we prospectively assessed the efficacy of intralesional injection of cidofovir as the treatment for RRP.

Section snippets

Materials and methods

Patients with established diagnosis of RRP and documented recurrence after excision of RRP were eligible for inclusion in the study. Patients also had to have severe RRP as defined by a need for repeated surgeries at a maximum average interval of 3 to 4 months and/or extensive laryngotracheal RRP. This interval between surgery was typically based on voice quality in the adults and airway patency in the children. All patients failed prior sole adjunctive RRP treatment of indole-3-carbinol (I3C).

Results

Sixteen patients were eligible for the study. Three patients were lost to follow-up, leaving 13 patients in the study group (10 adults and 3 children). The follow-up status of each patient is summarized in Table 1.

Ten of the 13 patients (76.9%) responded to cidofovir treatment and are currently in remission. All 10 patients showed no evidence of RRP on their follow-up visits and revealed an absence of RRP (except for Patient 2). Patient 2 has minimal RRP (severity score = 2) and no evidence of

Discussion

This study investigated the efficacy of intralesional injection of cidofovir combined with surgical excision for the treatment of RRP with a long-term follow-up. Patients with severe RRP were given injections of cidofovir at the time of the excision, and the outcome was determined during their follow-up examinations. Ten of 13 patients have had an excellent response to cidofovir and currently show no sign of the disease. These excellent results include significant follow-up for each patient

Conclusion

The study showed long-term success with cidofovir for the treatment of RRP. The intralesional injections of the drug produced a dramatic reduction of the lesions in a number of patients (76.9%). The adverse effects of the drug, especially the possible connection to vocal folscar formation after cidofovir treatment, are of concern and merit future investigation.

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Cited by (44)

Intralesional Cidofovir: A Systematic Review of Administration Protocols and Long-term Recurrence Rates in Adult and Juvenile Recurrent Respiratory Papillomatosis
2023, Journal of Voice
This is a systematic review aimed to explore Cidofovir administration protocols, recurrence rates, and long-term effectiveness for severe cases of recurrent respiratory papillomatosis (RRP). The primary goal was to identify current practices, determine the preferred protocol, and assess the adjuvant therapy's ability to prevent long-term papilloma recurrence in juvenile and adult-onset disease.
The following databases were searched: Pubmed, Google Scholar (pages 1–10), EMBASE, Scopus, ISI (clarivate), Cochrane Library, and Journal Storage from 1996 to June 2022. Articles that reported the use of intralesional Cidofovir in RRP and reported remission/recurrence rates with follow-up were included in the review. The systematic review was registered through PROSPERO and contains the detailed protocol for the conduction of the review.
A total of 389 records were identified, 126 titles and abstracts screened, 45 studies fully read, and 30 studies met the inclusion criteria. Two hundred and fourteen adult-onset RRP (AORRP) and 126 juvenile-onset RRP (JORRP) cases were treated with Cidofovir across the included studies. There was no universal protocol for administering Cidofovir, with variations in concentration, treatment period, number and interval of injections, and follow-up duration. Most lesions showed human papilloma virus types 6 and 11. Recurrence rates varied, and other outcomes reported included remission rates, lesion reduction, surgical intervals, and side effects. Some studies demonstrated significant improvements in disease severity and extended intervals between recurrences after Cidofovir administration.
The analysis of 30 studies reveals the need for greater consistency in reporting treatment parameters and outcomes. The use of recurrence-free period as an outcome measure and the potential benefits of a concentration of 7.5 mg/mL are identified. Additionally, the importance of viral typing within papilloma lesions is emphasized. To further enhance understanding and establish optimal protocols, future research should focus on uniform reporting, including severity, dosage, interval, treatment duration, functional outcome, and related procedures.
PROSPERO CRD42022299549.
Efficacy of cidofovir versus bevacizumab in recurrent respiratory papillomatosis: A randomized, double-blind, placebo-controlled pilot study
2022, Acta Otorrinolaringologica Espanola
Citation Excerpt :
Cidofovir, an acyclic nucleoside phosphonate that inhibits HPV replication by inhibition of DNA polymerase, is the antiviral most commonly used in medical adjuvant treatment for RRP despite it is not currently approved by the US Food and Drug Administration (FDA) for this indication.10 In prospective studies, adjuvant intralesional cidofovir has resulted in partial to complete regression of papillomas and decreased need for surgery.11–17 Intralesional administration has the advantage of maintaining plasma levels below those leading to toxicity, with no local side effect.17
After surgical resection of papilloma, adjuvant therapy may be recommended for the control of recurrent respiratory papillomatosis (RRP). As the efficacy of adjuvant therapy remains unproven, the aim of this study was to compare the efficacy of cidofovir versus bevacizumab used as adjuvant therapies for the control of RRP.
This randomized, double-blind, placebo-controlled pilot study was performed in a national respiratory disease referral centre. Patients with RRP were recruited prospectively and were divided into juvenile or adult RRP. Participants were randomly assigned to receive adjuvant therapy with cidofovir, bevacizumab or placebo. The study drug or placebo was administered after direct microlaryngoscopy with papilloma resection using cold instruments. The Derkay severity score and the Voice Handicap Index (VHI) were assessed at 3–6-week intervals, for a total of 3 visits. Follow-up included VHI and Derkay score assessments at 2-month intervals over the course of one year. Annual rates before and after surgical treatment were compared.
Five children and 11 adults were enrolled in the study. After one year, the group treated with cidofovir had a significant decrease in Derkay score (p = .027). No difference between treatment arms was observed in the annual surgery rate. There was a significant decrease in the VHI score in all treatment groups (p < .001), and no significant difference was observed between groups (p = .32).
While we observed a significant decrease in RRP severity with intralesional cidofovir, we were unable to provide proof of efficacy of intralesional bevacizumab.
Clinicaltrials.gov Identifier: NCT02555800.
Tras la extirpación quirúrgica de los papilomas, puede recomendarse terapia adyuvante para el control de la papilomatosis respiratoria recurrente (PRR). Como la eficacia de la terapia adyuvante no está demostrada, el objetivo de este estudio fue comparar la eficacia de cidofovir frente a bevacizumab, utilizados como terapias adyuvantes para el control de PRR.
Estudio piloto aleatorizado, doble ciego y controlado por placebo, realizado en un centro nacional de referencia de enfermedades respiratorias. Se reclutó prospectivamente a los pacientes con PRR, y se dividieron en 2 grupos: PRR de jóvenes y PRR de adultos. A los participantes se les asignó aleatoriamente la administración de terapia adyuvante de cidofovir, bevacizumab o placebo. La administración de los fármacos de estudio o placebo se realizó tras practicar microlaringoscopia directa con extirpación de papilomas, utilizando instrumental frío. Se llevaron a cabo evaluaciones utilizando la puntuación de gravedad de Derkay y la escala VHI (Voice Handicap Index) a intervalos de 3 a 6 semanas, con un total de 3 visitas. El seguimiento incluyó evaluación de las escalas VHI y Derkay a intervalos de 2 meses, durante el curso de un año. Se compararon las tasas anuales pre- y postratamiento quirúrgico.
El estudio incluyó 5 niños y 11 adultos. Transcurrido un año, el grupo tratado con cidofovir reflejó una reducción significativa en la escala Derkay (p = 0,027). No se observó diferencia alguna entre las ramas terapéuticas en la tasa quirúrgica anual. Se vio una reducción significativa en la puntuación VHI en todos los grupos terapéuticos (p < 0,001), y no se observó diferencia significativa entre los grupos (p = 0,32).
A pesar de verse una reducción significativa de la gravedad de PRR con la administración de cidofovir intralesional, no pudimos probar la eficacia de bevacizumab intralesional.
Recurrent Respiratory Papillomatosis
2021, Cummings Pediatric Otolaryngology
This chapter discusses the etiology, immunology, epidemiology, and transmission of recurrent respiratory papillomatosis, highlighting pertinent aspects of the history, physical examination, airway management, and other considerations. Principles for surgical and nonsurgical management and the indications for adjuvant therapies are discussed, along with their outcomes. Ongoing research initiatives and promising strategies to improve our understanding of this frustrating disease are also reviewed, including the potential effect of a nine-valent human papillomavirus vaccine on its incidence.
Interventional bronchoscopy for HPV 16 and 66 with the use of spraying interferon-α (2b) plus bevacizumab and anti-reflux agent
2021, Respiratory Medicine Case Reports
Voice Outcomes Following Multiple Surgeries for Recurrent Respiratory Papillomatosis
2020, Journal of Voice
Citation Excerpt :
Surgical excision is the primary means to accomplish these goals, using a CO2 or potassium titanyl phosphate (KTP) laser, a microdebrider, or cold steel instruments.2,12,13 Adjuvant treatments such as bevacizumab, cidofovir, interferon, indol-3-carbinol, and immunotherapy with reactive human papilloma virus vaccination have also been used in conjunction and separate from surgery with varying degrees of success.4,7,13–17 In order to maintain airway patency and improve their voice quality, adult patients may require over 40 surgeries over their lifetime.3,12,18
Recurrent Respiratory Papillomatosis (RRP) is a rare disease caused by the human papilloma virus that presents as warty, exophytic growths in the upper airway. RRP in the larynx can lead to severe airway obstruction and voice changes. It is clinically known that patients with RRP frequently experience dysphonia. The purpose of this study was to assess the impact of multiple surgical treatments on RRP patients’ voice outcomes, and to determine whether a higher number of repeated surgeries lead to decreased voice quality.
A retrospective cohort study was conducted of adult RRP patients (n = 23) who underwent multiple surgeries. Group 1 included patients (n = 11) who had <5 surgeries (range 2–4 surgeries) and Group 2 included patients (n = 12) who had ≥5 surgeries (range 5–50+ surgeries). Voice recordings were selected from the following clinic visits: initial office visit (initial presurgery), first postsurgery, and the last clinic encounter(s) with no immediate planned surgery. Blinded auditory-perceptual ratings along with cepstral and spectral acoustic measures assessed voice severity.
There was significant improvement from the initial presurgery visit compared to each postoperative visit over time for all voice outcome measures for both Group 1 and Group 2. The results of the study indicated that the number of surgeries did not significantly affect mean postoperative voice outcomes, and there were no significant differences between patient groups for voice quality over time.
The results of this study suggest that RRP patients’ voice quality may not suffer cumulative negative effects when using modern tissue-sparing surgical techniques.
Surgical treatment and adjuvant therapies of recurrent respiratory papillomatosis
2013, Brazilian Journal of Otorhinolaryngology
Citation Excerpt :
Other therapies and drugs such as indole-3-carbinol, photodynamic therapy, and cis-retinoic acid were studied, but none grew to become the therapy of choice for subjects with RRP3,10. In recent years, antiviral drug cidofovir [(S)-1-[(3-hydroxy-2-phosphonyl methoxy) propyl] cytosine (HPMPC)] was introduced as a potent replication inhibitor for HPV, adenovirus, cytomegalovirus, and herpesvirus2,10,31–41. Cidofovir has been used as an adjuvant drug since 1998.
Recurrent respiratory papillomatosis or recurrent laryngeal papillomatosis is a disease of the larynx caused by human papilloma virus, characterized by verrucous epithelial lesions and usually recurring. In the literature there are several types of treatment, such as surgery to cold, laser and/or use of microdebrider, as of adjuvant therapies; all possible to decrease the permanent sequelae of the disease.
To review the literature regarding this disease with emphasis on surgical techniques and adjuvant therapies used today.
We used the literature review, through surveys based electronic data in the public domain, to search for articles between 1992-2012, using keywords: papilloma, human pappiloma virus infection, larynx, therapeutic, papilloma virus vaccine.
We surveyed 357 articles, of which 49 were used as the basis for this review. Scientific studies indicate a reduction of relapse in most adjuvant therapeutic presented. However, the survey showed different methodologies and samples, which did not allow to compare the types of treatment and adjuvant therapies.
The choice of surgical technique varies among studies, but there is a trend to use the microdebrider. The newer adjuvant therapies, such as cidofovir, quadrivalent vaccine against human papilloma virus and bevacizumab, require further studies.

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^☆: Presented at the Annual Meeting of the Eastern Section of the American Laryngological, Rhinological and Otological Society, Inc., Philadelphia, Pennsylvania, January 25-27, 2002.

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Efficacy of cidofovir injection for the treatment of recurrent respiratory papillomatosis☆

Abstract

Summary

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusion

Otolaryngol Clin North Am

Otolaryngol Head Neck Surg

Opthalmology

Exp Eye Res

Recurrent respiratory papillomatosis

Obstet Gynecol Clin North Am

Sites of predilection in recurrent respiratory papillomatosis

Ann Otol Rhinol Laryngol

Recurrent respiratory papillomatosis

Insight Otolaryngol