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Table of Contents
EVIDENCE BASED LARYNGOLOGY
Year : 2011  |  Volume : 1  |  Issue : 1  |  Page : 22-26

Intralesional cidofovir for recurrent respiratory papillomatosis: Systematic review of efficacy and safety


Clinical Assistant Professor, University of British Columbia, Division of Pediatric Otolaryngology - Head and Neck Surgery, BC Children's Hospital, 4480 Oak Street, Vancouver, V6H 3V4, Canada

Date of Web Publication7-Feb-2011

Correspondence Address:
N K Chadha
University of British Columbia, Division of Pediatric Otolaryngology-Head and Neck Surgery, BC Children's Hospital, 4480 Oak Street, Vancouver, BC, V6H 3V4
Canada
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Source of Support: None, Conflict of Interest: None


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   Abstract 

Surgical debulking is the main treatment for recurrent respiratory papillomatosis (RRP); however, intralesional cidofovir has been widely used off-label as adjuvant therapy. Concern exists about the safety profile of this drug in humans. The objective of this systematic review was to explore current evidence for the efficacy and safety of intralesional cidofovir in RRP. A comprehensive search strategy was used in MEDLINE and the Cochrane Central Register of Controlled Trials. Human in vivo studies were eligible for inclusion. A total of 41 studies met the inclusion criteria, including 30 studies providing efficacy outcome data (one randomized controlled trial (RCT), two retrospective case-control studies, and 27 case series). The RCT showed no significant difference in outcome between placebo and intralesional cidofovir groups. One case-control study favored cidofovir, and the other favored the control group. Combining all series, the overall complete remission rate with intralesional cidofovir was 53%, with a rate of 63% in adult-only studies compared to 37% in pediatric-only studies. There was no evidence for an increased rate of dysplasia or malignancy associated with intralesional cidofovir. Vocal cord scarring was reported, and may be associated with higher doses, as may risk of nephrotoxicity through systemic absorption. High-quality evidence for efficacy of cidofovir is very limited. Intralesional cidofovir should only be used after informed consent, based on a discussion of available safety and efficacy evidence. This adjuvant therapy should only rarely be considered in children, as it may be less effective, and long-term risks are potentially increased.

Keywords: Adult, Children, Cidofovir, Human, Larynx, Papilloma, Respiratory papillomatosis Review


How to cite this article:
Chadha N K. Intralesional cidofovir for recurrent respiratory papillomatosis: Systematic review of efficacy and safety. J Laryngol Voice 2011;1:22-6

How to cite this URL:
Chadha N K. Intralesional cidofovir for recurrent respiratory papillomatosis: Systematic review of efficacy and safety. J Laryngol Voice [serial online] 2011 [cited 2021 Mar 2];1:22-6. Available from: https://www.laryngologyandvoice.org/text.asp?2011/1/1/22/76133


   Introduction Top


Recurrent respiratory papillomatosis (RRP) is a devastating disease causing significant impact on quality of life. [1] Surgical debulking forms the mainstay of treatment, however, in more severe cases, off-label usage of intralesional cidofovir as adjuvant therapy appears widespread. For example, a 2002 survey of American Society of Pediatric Otolaryngology members found that 34 out of 62 practices were using adjuvant intralesional cidofovir, [2] and a recent registry of 73 adult and pediatric RRP patients in France showed 91% had been exposed to cidofovir. [3] Evidence for cidofovir efficacy has remained unclear with limited high-quality studies available, [4] and animal studies generating concern about the safety profile of this drug in humans. Notably, in some studies adjuvant cidofovir has been used in mild RRP cases. Recent years have seen an upsurge in studies exploring the side effects and outcomes of cidofovir, in both observational and controlled research. There is a need for an up-to-date systematic appraisal of this treatment option.

The objective of this study was to systematically review the current evidence for the efficacy and safety of intralesional cidofovir in humans affected by RRP, with the aim of providing evidence-based guidance on its role in this disease.


   Method Top


A search strategy was developed to identify studies on the efficacy and safety of intralesional cidofovir in RRP. Databases searched included MEDLINE (from 1966 to September 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL) in Issue 3, 2010 of the Cochrane Library. Broad search terms for RRP, including 'recurrent respiratory papillomatosis', 'laryngeal papilloma', and 'RRP', were combined using Boolean operators and the search term 'cidofovir'. Reference lists from relevant articles including other reviews were searched. Searches were restricted to the English language. Studies considered for inclusion were comparative studies, observational studies, case series, case reports, and other study designs providing data on efficacy or safety. Only human in vivo studies were eligible. Where data for children and adults could be differentiated, these were considered separately to explore any differences. A meta-analysis was not possible due to the design of the identified studies.


   Results Top


The initial search identified 92 studies for consideration. After reviewing the abstracts and reference lists, 41 studies met the inclusion criteria. This included 30 studies providing efficacy outcome data, comprising one RCT, two retrospective case-control studies, and 27 case series. A further 11 studies identified provided information on the safety profile cidofovir in humans with RRP.

The remission rates and ages of the participants were extracted from the outcome studies. These articles are summarized in [Table 1]. The overall remission rate with intralesional cidofovir from the included studies was 131 out of 247 patients, or 53%. The case series were subdivided by whether they included children, adults, or both. Of note, the overall remission rate in the seven adult-only studies was 40 out of 64 (63%) compared to a remission rate of only 19 out of 51 (37%) in the eight pediatric-only studies.
Table 1: Summary of included studies of cidofovir efficacy, with >1 subject

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In the one available RCT, both the cidofovir and placebo groups showed a significant improvement in the extent of their disease after 12 months, but there was no significant difference between the groups. [5] The two retrospective case-control studies had contradictory results. One study showed a significant improvement in the cidofovir group compared to the non-cidofovir group, [6] and the other study showed the cidofovir group was less likely to have remission of RRP. [7]


   Discussion Top


Evidence for intralesional cidofovir efficacy

This systematic review identified several uncontrolled series in which intralesional cidofovir has been administered for RRP. One RCT [5] and two retrospective case-control studies [7] provided the only available comparative data. Although it is of interest to look carefully at published uncontrolled series to explore remission rates, extreme caution must be taken in interpreting their results. This is because the natural history of RRP in children and in adults is for improvement with time with or without the usage of cidofovir. Therefore in the absence of a control group, it is impossible and somewhat misleading to directly attribute any improvement or resolution in disease to the cidofovir compared to the resolution that would be seen because of conventional repeated surgical debulking combined with natural history of the disease leading to improvement.

This concern was borne out by the RCT by McMurray et al. [5] Nineteen patients were enrolled in this double-blind study, 10 receiving intralesional cidofovir versus nine receiving intralesional placebo. The Derkay severity score was significantly reduced from baseline at the two-month and 12-month follow-up assessments in both the cidofovir and the placebo groups. After 12 months, the mean Derkay severity score was reduced from 13.2 to 2.7 in the cidofovir group, and from 12.0 to 5.1 in the placebo group. There was no statistically significant difference between the placebo and cidofovir groups either pre-treatment or at 12 months. This suggests that the natural history was for an improvement in disease severity over time. Another explanation is that the injection of a fluid volume into the papilloma (which occurred in both study groups) may have some impact on the disease outside any antiviral effect. Also of note was the lack of improvement in the quality of life measures. This suggests that the Derkay severity score may have limitations as a primary outcome measure, and it has recently been shown to correlate poorly with validated quality of life measures in this disease. [1]

The retrospective cohort study by Mandell et al. reviewed seven children treated for RRP over a period of two years, with four of them receiving adjuvant intralesional cidofovir. [6] The pre-study disease extent was similar in both groups; however, final Derkay scores at 27 months were significantly better in the cidofovir cohort (P = 0.04). The study validity was reduced though by the lack of randomization, group demographic differences, lack of blinding, surgical technique variation, lack of placebo, and very small sample size. The retrospective case-control study by Verguts et al., analyzed 51 patients treated over a period of 34 years, of whom 30 were given adjuvant intralesional cidofovir. They found a remission rate of 53% of the cidofovir cohort, compared to 90% of the non-cidofovir group, giving an odds ratio of 8.3 against benefit of cidofovir. This study was also severely hampered by the lack of randomization potentially confounding differences between the groups.

Across all included case series, treatment frequency, cidofovir dosage, total injection numbers, and total treatment period varied considerably. The median treatment protocol was intralesional injections of 2.5−5 mg/mL cidofovir, every 2−4 weeks, over a 12-month period. If the results of all included studies are combined to provide an estimate of the overall efficacy of intralesional cidofovir in the 247 patients, 131 patients (53%) demonstrated complete remission during the follow-up period. Due to the lack of control groups in vast majority of studies, it is unclear whether the remission previously attributed to intralesional cidofovir may be somewhat explained by the natural history of the disease. It is of particular interest that the remission rate achieved in the studies of children was substantially lower than the remission rate in the studies of adults with RRP (37% versus 63%). Although no study has been systematically designed to compare outcomes with intralesional cidofovir between children and adults, one explanation of this finding is that children may be more resistant to this adjuvant therapy. This further supports caution in using this treatment in a pediatric group.

Evidence for intralesional cidofovir safety

A previous systematic review explored the side effects of cidofovir in RRP treatment, including 31 studies published up to August 2007. [8] Of 188 adult and pediatric patients, minor side effects potentially related to cidofovir injection included two patients with mild cutaneous rash, [9] one patient with repeated headache, [9] three cases of vocal cord scarring, [10] and one supraglottic web. [10]

Man et al. recently described a case in which a 40-year-old man who had responded poorly to multiple papilloma excisions and intralesional cidofovir injections was subsequently treated with two higher doses cidofovir injections (6 mL of 15 mg/mL and 6 mL of 10 mg/mL). [11] He later developed severe worsening of voice caused by a large mucosal bridge and a deep pit associated with one vocal fold, presumed to be caused by the high cidofovir doses.

The significance of dysplasia in recurrent papillomatosis is unknown. Adult and juvenile-onset RRP appear to have substantially different rates of dysplasia; however, this does not appear to show any correlation with cidofovir usage. The review by Broekema et al. identified five cases of dysplasia being developed in RRP patients while on cidofovir (2.7% of patients). [8] These included a 58-year-old non-smoking female with severe dysplasia, [12] a 45-year-old non-smoking male with moderate dysplasia, [13] and a 28-year-old female non-smoker with moderate dysplasia. [14] The other two patients showed lesions microscopically compatible with verrucous carcinoma, and both were male smokers, 66 and 77 years old, although it is unclear whether this abnormality preceded the treatment. [9] Of note, the risk of malignant degeneration in RRP without cidofovir has been estimated at (2-3%), therefore consistent with the rate in these 188 patients regardless of their cidofovir exposure. [8] In the six more recent studies identified in the present review, with a total of 59 previously unreported RRP patients treated with cidofovir, no further cases of dysplasia were reported.

Adult and juvenile-onset RRP appear to have substantially different rates of dysplasia, but this does not appear to show any correlation with cidofovir usage. A recent retrospective review of 13 adults treated with intralesional cidofovir analyzed papilloma biopsies from multiple time-points. [15] Although 95% of RRP biopsies showed some degree of dysplasia, the severity of dysplasia did not correlate with time since cidofovir exposure, and did not suggest any dysplastic progression. In contrast, a recent retrospective review of multiple biopsies from 21 children treated for RRP, less than 1% showed dysplasia. None of the seven children who had cidofovir showed dysplasia. [16] Similar results were found in another retrospective review of pediatric patients with RRP, in which multiple specimens from 17 pediatric patients, seven of whom had received cidofovir, showed no dysplasia in their specimens. [17]

Intravenous cidofovir has previously shown nephrotoxicity with proteinuria, glucosuria, bicarbonaturia, polyuria, and increased serum creatinine. [18] Two studies have monitored cidofovir concentration after intralesional injection for RRP. [9],[19] The concentration of cidofovir used in the studies was 2.5 mg/mL and 7.5 mg/mL. Measured plasma concentrations of intralesional cidofovir varied, and were below those expected from intravenous administration. Despite this, in some cases, concentrations reached the upper recommended therapeutic levels to prevent nephrotoxicity, confirming the importance of awareness of this as a potential risk. In view of the concern related to higher dose cidofovir causing vocal fold injury, and the risk of nephrotoxicity, the optimal concentration should be 2.5−5 mg/mL, [20] and total dose should be less than that reported to lead to toxicity in intravenous infusion (3 mg/kg). [19]

Suggested guidelines on usage

The findings of this systematic review implore caution should be taken in administering cidofovir as adjuvant treatment in recurrent respiratory papillomatosis. The multidisciplinary task force on RRP has previously recognized that more information needs to be obtained about the long-term safety of cidofovir in humans. This group has recommended that cidofovir should only be routinely used as adjuvant therapy in patients with moderate to severe RRP, not responding to surgery alone. Another recommendation from the task force, which seems well-supported by more recent evidence through the present review, was that patients with more mild disease, particularly children, should be discouraged in most cases from seeking treatment with cidofovir. Perhaps the most important recommendation was that informed consent to be obtained and documented before administration of cidofovir, including a frank discussion of the nephrotoxic and carcinogenic potential of this drug. Information in the present review suggests that this discussion should be expanded further to include a clear account of the current lack of adequate evidence for the efficacy of cidofovir in RRP. The consent discussion should therefore carefully address the potential risk-to-benefit ratio and must be individualized.


   Conclusions Top


Until availability of a large, double-blind, placebo-controlled RCT using conventional concentrations of intralesional cidofovir, there is little current evidence to support the efficacy of cidofovir for RRP. Caution must be taken in considering administration of this potentially toxic adjuvant therapy, particularly in non-severe cases. Intralesional cidofovir should only be used after informed consent, based on a discussion of available safety and efficacy evidence. It is the opinion of the author that based on current available evidence, intralesional cidofovir should only rarely be considered in children, as it may be less effective, and long-term risks are potentially increased. [39]

 
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