Cidofovir and Bevacizumab as adjuvant therapies in the treatment of recurrent laryngeal papillomatosis: systematic review and proportional meta-analysis

Cidofovir and Bevacizumab as adjuvant therapies in the treatment of recurrent laryngeal papillomatosis: systematic review and proportional meta-analysis | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 26 June 2025 V1 Latest version Share on Cidofovir and Bevacizumab as adjuvant therapies in the treatment of recurrent laryngeal papillomatosis: systematic review and proportional meta-analysis Authors : Rafael Toledo Baston , Regina Helena Garcia Martins [email protected] , Antonio Gil Azevedo 0009-0000-5838-0163 , Antônio José Maria Cataneo , and Erica Nishida Hasimoto Authors Info & Affiliations https://doi.org/10.22541/au.175092497.78832611/v1 393 views 176 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective: To evaluate, through a systematic review and proportional meta-analysis, the efficacy of cidofovir and bevacizumab in the treatment of laryngeal papillomatosis. Method: This study followed a systematic review design. Databases including Medline, Embase, Lilacs, Scopus, Web of Science, Cochrane Central, and SciELO were searched for randomized clinical trials. In the absence of such studies, observational studies assessing the use of cidofovir and/or bevacizumab in patients with laryngeal papillomatosis were considered. The outcomes analyzed included partial or complete response, number of surgeries before and after treatment, and Derkay scale scores before and after treatment. Statistical analysis was performed using the StatsDirect 3.1.20 software, conducting a proportional meta-analysis. Results: Twenty-eight observational studies involving 393 patients treated with cidofovir, nine studies with 95 patients using bevacizumab, and two randomized clinical trials with 35 patients divided among placebo, cidofovir, and bevacizumab groups were included. The complete response rate was 59% (95% CI: 49-69%) for cidofovir and 26% (95% CI: 10-47%) for bevacizumab. Regarding partial response, rates were 34% (95% CI: 25-45%) for cidofovir and 59% (95% CI: 36-80%) for bevacizumab. A reduction in the number of surgeries after medication use was observed across all analyzed studies. Changes in the Derkay scale scores were evaluated in 11 studies with cidofovir and 3 with bevacizumab, with most showing a reduction in scores after treatment. Conclusion: Cidofovir demonstrated higher rates of complete response in the available evidence. However, more controlled clinical studies are necessary to obtain more robust analyses and definitive conclusions. Abstract Objective: To evaluate, through a systematic review and proportional meta-analysis, the efficacy of cidofovir and bevacizumab in the treatment of laryngeal papillomatosis. Method: This study followed a systematic review design. Databases including Medline, Embase, Lilacs, Scopus, Web of Science, Cochrane Central, and SciELO were searched for randomized clinical trials. In the absence of such studies, observational studies assessing the use of cidofovir and/or bevacizumab in patients with laryngeal papillomatosis were considered. The outcomes analyzed included partial or complete response, number of surgeries before and after treatment, and Derkay scale scores before and after treatment. Statistical analysis was performed using the StatsDirect 3.1.20 software, conducting a proportional meta-analysis. Results: Twenty-eight observational studies involving 393 patients treated with cidofovir, nine studies with 95 patients using bevacizumab, and two randomized clinical trials with 35 patients divided among placebo, cidofovir, and bevacizumab groups were included. The complete response rate was 59% (95% CI: 49-69%) for cidofovir and 26% (95% CI: 10-47%) for bevacizumab. Regarding partial response, rates were 34% (95% CI: 25-45%) for cidofovir and 59% (95% CI: 36-80%) for bevacizumab. A reduction in the number of surgeries after medication use was observed across all analyzed studies. Changes in the Derkay scale scores were evaluated in 11 studies with cidofovir and 3 with bevacizumab, with most showing a reduction in scores after treatment. Conclusion: Cidofovir demonstrated higher rates of complete response in the available evidence. However, more controlled clinical studies are necessary to obtain more robust analyses and definitive conclusions. Key words : Cidofovir; bevacizumab; laryngeal papillomatosis; systematic review. Key points Recurrent laryngeal papillomatosis is a difficult disease to control • There is no well-defined gold standard treatment • Intralesional cidofovir has been shown to be effective in controlling recurrences • Intravenous bevacizumab has been indicated in severe cases • the lack of clinical trials prevents us from demonstrating the superiority of one drug over another Cidofovir and Bevacizumab as adjuvant therapies in the treatment of recurrent laryngeal papillomatosis: systematic review and proportional meta analysis Introduction Recurrent laryngeal papillomatosis (RLP) is caused by the Human Papillomavirus (HPV), a DNA virus from the Papillomaviridae family with subtypes 6 and 11 found in approximately 90% of cases 1-3 . The larynx is the most frequently affected site. Lesions typically appear initially in the glottis, followed by the supraglottis and subglottis (Figure 1). Extralaryngeal occurs in 5 to 20% of cases, and its associated to high morbidity and mortality 4-6 . The primary treatment for laryngeal papillomatosis is surgery. Adjuvant therapies include antiviral agents, immunobiologicals drugs, dynamic phototherapy, retinoids, Cox-2 inhibitors and gene therapies 7 . Among the wide range of treatments, two have gained prominence due to the their most promising results, cidofovir and bevacizumab 7-9 . Cidofovir is an antiviral agent analogous to cytosine nucleotides, is FDA (Food and Drug Administration) approved for intravenous treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. Cidofovir has well-known systemic side effects, such as nephrotoxicity, hepatic and hematopoietic dysfunction, and ocular toxicity 9-13 . The use of cidofovir in RLP is usually administered by intralesional injection to minimize systemic effects. Most studies recommend its use in patients who undergo six or more surgeries per year, children with extralaryngeal manifestations or large papillomatous lesions 12,13 . The recommended dose of cidofovir ranges from 2.5 and 7.5 mg/mL, repeated every two to six weeks 13 . The medication should be discontinued when the lesions are in complete remission. Bevacizumab is FDA- approved as a chemotherapy agent in the treatment of oncological diseases, inhibiting vascular growth associated with metastatic processes 14,15 . Vascular endothelial growth is a crucial mechanism in the pathophysiology of RLP, mediated by VEGF-A. By binding to VEGF-A, bevacizumab prevents its interaction with receptors on endothelial cells, reducing the growth of new blood vessels and, consequently, inhibiting disease recurrence 14,15 . In 2009, Nagel et al. 14 reported the first case in a 32-year-old patient who received systemic application of bevacizumab, after surgical debridement of lesions, resulting in significant symptoms improvement. Mohr et al. 15 published a series of cases with five patients with advanced disease associated with tracheal papillomatosis, demonstrating rapid and consistent improvement after the use of systemic bevacizumab. Promising results led to the publication of a national study in the USA which indicated that bevacizumab is a promising drug for the treatment of advanced RLP cases refractory 16,17 . Most studies use the intravenous route of administration. Described complications and side effects include pyogenic granulomas, proteinuria, epistaxis, hemoptysis, arterial hypertension, high creatinine levels, headache and thrombocytopenia. 15-17 . A systematic review evaluated the use of systemic and intralesional bevacizumab in 64 patients, showing an increased interval between surgeries in 95% of patients who received systemic bevacizumab and in 62% of those who received the medication intralesionally 18 . jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf There is a lack of standardization in the choice of drugs, routes of administration and dosages for the treatment of laryngeal papillomatosis, therefore, this systematic review aims to help specialists make the best decisions regarding adjuvant treatment with cyclofovir and bevacizumab. Objective Evaluate, through a systematic review and proportional meta-analysis, the effectiveness of cidofovir and bevacizumab in the treatment of recurrent laryngeal papillomatosis. Ethical considerations: the project was exempt from evaluation by the ethics committee because it is a systematic review of the literature. Study design: s ystematic review conducted at the Faculty of Medicine of XXXX, in accordance with the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions 19 , following the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 20 . Study types : a search was conducted for randomized clinical trials comparing the use of cidofovir and/or bevacizumab against each other, placebo, or other drugs. In the absence of such studies, observational studies were included. Inclusion criteria: adults with RLP treated with cidofovir or bevacizumab in studies with number of participants ≥ 5. Exclusion criteria: studies that did not assess the outcomes of interest or missing relevant data and review studies. Outcomes : Primary outcomes - Complete Response (CR): without surgical intervention during the follow-up; Partial Response (PR): increased interval between surgeries during the follow-up; Secondary outcomes - difference in the number of surgeries before and after treatment; change in the Derkay scale 21 before and after treatment. Search strategy for identifying studies: databases searched: MEDLINE, LILACS, Scopus, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, SciELO; ClinicalTrials.gov database, and additional sources of published and unpublished trials (grey literature), with no language restrictions. The search period was from the inception of each database up to October 30, 2024. Search strategy used in the Medical Subject Headings (MeSH) section of PUBMED/MEDLINE: bevacizumab or cidofovir and papilloma. Study Selection: i nitially, studies were grouped, and duplicate articles were removed using the EndNote program. Two authors (RTB;ENH), independently and blinded, examined the titles and abstracts and removed irrelevant articles. Full-text articles were retrieved for those considered potentially relevant. Discrepancies in inclusion were resolved through discussion between the authors, with the opinion of a third author (RHGM) if necessary. The reasons for excluding articles were documented (Figure 2). Data extraction and management: data from eligible studies were independently extracted by two researchers (RTB;ENH) using a specifically designed data extraction form which includes: demographic data, intervention, number of participants, outcomes, and follow-up duration. Risk of bias assessment: the risk of bias in the studies was performed based on the seven domains provided by the Robins-I tool (confounding, participant selection, intervention classification, deviations from the intended intervention, missing data, outcome assessment, and selective outcome reporting). Quantification of the intervention effect: each outcome was analyzed by proportional meta-analysis using a random effects model, obtaining the prevalence proportion of each outcome with its 95% confidence interval. In the comparisons of prevalence between two proportions, the confidence intervals were analyzed. If the confidence intervals did not overlap, a statistically significant difference was considered. If the confidence intervals overlapped, no statistical difference was assumed. Synthesis of results: the studies were grouped to present the proportional meta-analysis combining all of them. The random-effects model was used due to the inherent heterogeneity of observational studies 22 . The analysis was conducted using the StatsDirect program, version 3.1.20. The results were summarized with the aid of a forest plot. To quantify the inconsistencies of the studies in the meta-analysis, the heterogeneity test I² was used: I² = [(Q - df) / Q] x 100%, where Q is the chi-squared statistic and df is the degrees of freedom. Substantial heterogeneity was considered present when I² > 50%. In this case, variability in the effect estimates may result from heterogeneity rather than sampling error. Registration number in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42023397677. Results The searches were performed on 12/12/2023 and updated on 30/10/2024, totaling 1,923 studies from the following databases: Cochrane (31), EMTREE (454), LILACS (5), PUBMED (457), SCIELO via Web of Science interface (5), SCOPUS (433), and Web of Science (538). After the removal of 1,068 duplicate studies, a total of 855 studies remained for evaluation and 754 were excluded after title or abstract review, leaving 101 studies selected for full-text reading. Of these, 62 were excluded after full-text review, and 39 studies were included in the review (Figure 2). The main reasons for exclusion were: case series with fewer than five participants (n-9); review articles (n-20); incompatible outcomes (n-8), non-relevant information (n-25). Cidofovir was used in 28 studies (10, 12, 23-48), table 1; nine studies used bevacizumab (15, 16, 49-55), table 2. Of the 28 studies that used cidofovir, all administered the drug intralesionally, with highly variable initial doses and follow-up durations. Regarding complications, 10 studies reported bradycardia, renal and hepatic changes, mild/moderate dysplasia, neutropenia, vocal cord scars, pediatric osteoporosis, cutaneous rash, headache, precordial pain, and malignancy, in a total of 25 patients (Table 3). Of the nine studies that used bevacizumab, only one administered the drug intralesionally, while all others used the systemic approach (table 4). The initial dose and follow-up duration varied across the studies. Regarding complications, six studies reported headache, nausea, epistaxis, thrombocytopenia, proteinuria, hemoptysis, hypertension, neutropenia, and elevated creatinine levels (Table 4). Effects of the Intervention Complete Response (CR) : of the 393 patients who used cidofovir, 242 achieved CR (59%, 95% CI: 49-69%, I²: 77%) (Figure 3). Of the 95 patients who used bevacizumab, 23 achieved CR (26%, 95% CI: 10-47%, I²: 79%) (Figure 4). Since the confidence intervals do not overlap, a statistically significant difference was observed between the interventions (Figure 5). Partial Response (PR) : of the 393 patients who used cidofovir, 130 patients achieved PR (34%, 95% CI: 25-45%, I²: 80%) (Figure 6). Of the 95 patients who used bevacizumab, 57 achieved PR (59%, 95% CI: 36-80%, I²: 81%) (Figure 7). Since the confidence intervals overlap, no statistically significant difference was observed between the interventions (Figure 8). jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Two randomized clinical trials were identified, one published in Mexico by Ablanedo-Terrazas et al. 23 and included 16 patients (five children and 11 adults), distributed into three groups: cidofovir (n=4), bevacizumab (n=6) and placebo (n=6) (Table 5). Another study was conducted in the USA by McMurray et al. 56 and included 19 patients, randomized into two groups: cidofovir (n=10) and placebo (n=9) (Table 5). In both studies, the drugs and placebo (0.9% saline solution) were administered intralesionally. The follow-up period was 12 months and no adverse effects were reported (Table 6). Neither study evaluated the primary outcomes, and the cidofovir group of the study by Ablanedo-Terrazas et al. 23 was not included in the analysis of secondary outcomes due to the small sample size. Number of surgeries before and after medication use : of the 28 studies that used cidofovir, only 3 provided data on the number of surgeries before and after the treatment (23,29,44), while 14 studies reported only the number of surgeries prior to medication use (Table 7). Akst 24 and Wierzbicka 48 mentioned a significant reduction after the use of cidofovir, but did not specify the extent of the reduction. Of the nine studies that used bevacizumab, five provided information on the number of surgeries before and after the use of the medication (15, 40,50,51,52) (Table 9). In all of these studies, a decrease in the number of procedures was observed after medication use. Derkay scale : of the 28 studies that used cidofovir, ten evaluated the Derkay scale before and after medication use (24,27,30,36,37,40, 41 44, 45, 46). In only one of these studies (41), no improvement was observed in six of the 11 patients who used the medication; in all the other nine studies, the authors reported a reduction in the scale score (Table 9). Of the nine studies that used bevacizumab, only two evaluated the Derkay scale (50,54). Both studies showed a significant reduction in the average score, which decreased from 10.22 to 1.16 (Colette et al. 50 ) and from 11.5 to 6 (Sidell et al. 54 ) Risk of Bias in the Included Studies The risk of bias was extended based on the seven domains provided below by the Robins-I tool: Confounding - all studies presented potential confounders, as patients with varying degrees of disease severity were included, with varying times between diagnosis and intervention. Additionally, the intervention used was related to the study period (cidofovir is an older medication compared to bevacizumab). Furthermore, characteristics inherent to the participants, such as age, sex, and comorbidities, were highly variable (significant risk of bias). Participant selection - :in all studies, only one intervention was performed, with no random assignment of treatment (significant risk of bias). Intervention classification - studies used different initial and maintenance doses, with variable administration times between doses (significant risk of bias). Deviations from the intended intervention - all individuals received the intervention initially assigned to them (low risk of bias). Missing data - some of the included studies had patient follow-up loss, leading to missing data (significant risk of bias). Outcome assessment - the included studies used different methods to assess the intervention as questionnaires to assess voice, patient self-reports regarding symptom improvement or worsening or laryngoscopic examination (observer-dependent). (significant risk of bias). Selective outcome reporting - no selective reporting of outcomes was observed (low risk of bias). Since there was critical risk of bias in three additional domains, the included studies were considered to have a critical risk of bias overall. jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Discussion Cidofovir demonstrated a higher CR rate compared to bevacizumab. However, these findings may change over time, as the number of studies evaluating bevacizumab is still small, limiting the representativeness of its results. On the other hand, the PR response rate did not show significant differences between the two drugs, suggesting that both may be effective in reducing lesion volume, even if they do not lead to complete disease resolution. Tanna et al. 10 reported a CR rate 49% of patients treated with intralesional cidofovir. Snoek et al 12 analyzed 17 patients, with an average treatment duration of three months, and observed that 14 of them did not require new interventions during the follow-up period, which lasted an average of 13.1 months. Similarly, Prannsky et al. 45 , analyzed 11 children with RRP, who previously required laryngeal microsurgery for lesion removal every two to six weeks, and found that 10 of them completed the proposed treatment, and five achieved complete remission during a 51.6-month follow-up period. Bevacizumab has a lower CR rate compared to cidofovir, it has shown promise in recent studies. Zeitels et al. 55 reported CR rate of 33% in patients treated with intralesional bevacizumab, which is lower than that observed with cidofovir but still significant. Additionally, studies such as Mohr et al. 15 highlighted that bevacizumab may be particularly useful in cases of refractory RRP, where other therapies have failed or in patients who do not respond to cidofovir or have contraindications to its use. Applicability of evidence The choice of treatment should consider several factors: route of administration, required infrastructure, cost, safety profile, and individual characteristics. All 28 selected studies evaluating cidofovir used it intralesionally. This method allows high local drug concentrations but requires hospital support and general anesthesia. In contrast, among the studies evaluating bevacizumab, eight used it systemically and one intralesionally. In the study by Zeitels et al. 55 involving 20 adult RRP patients, intralesional bevacizumab was applied to one vocal fold while the other received a saline solution after bilateral lesion removal. The results showed a good response to intralesional bevacizumab, with three patients not requiring further intervention and 16 presenting smaller lesions compared to the saline-treated vocal fold. Systemic administration of bevacizumab is less invasive, provides broader drug distribution and reduces the need for hospital infrastructure. This makes systemic administration a more commonly used approach. In Brazil, the cost of the bevacizumab is still relatively high and systemic doses often require multiple vials, particularly for adults. Cidofovir is cheaper and the contents of the vial allow for multiple intralesional applications. Quality of evidence The quality of the evidence in this review is limited by several factors. The included studies had small sample sizes, there was significant variability in the study protocols, including administered doses, application intervals, number of cycles, maintenance doses, treatment duration, and patient follow-up periods. Cidofovir has been used in RRP management since the mid-1990s, providing a more extensive database in terms of efficacy and safety. Studies such as Tanna et a 10 reported follow-ups of up to 10 years. In contrast, bevacizumab, introduced more recently, has fewer long-term data available, with follow-up periods ranging from six months to two years and a limited number of evaluated patients (ranging from 5 to 23 in the selected studies). Based on the Newcastle-Ottawa Scale evaluation of the included studies, the methodological quality was variable, with total scores ranging between 4 and 5 points for most studies. Participant selection received moderate scores, while comparability between groups was limited or nonexistent in most publications. Additionally, the outcome/exposure domain had lower scores, reflecting the heterogeneity in criteria for assessing results. Bias assessment in the review process This review was impacted by biases inherent to the included studies. Most studies had small sample sizes (5 to 34). Study design: cidofovir studies - 7 case series (1 retrospective), 10 prospectives, 9 cohort (1 retrospective, 1comparative), 2 retrospectives. Bevacizumab studies - 5 case series, 2 retrospectives, 1 prospective, 1cohort . The ROBINS-I tool assessment indicated a critical risk of bias, particularly in the domains of confounding factors, participant selection, intervention classification, missing data, and outcome assessment. This variability, combined with heterogeneity in treatment protocols, affected the comparability of outcomes and introduced bias into the overall results. Due to the nature of the available data, where most studies reported response rates for a single drug without direct comparisons, a proportional meta-analysis was performed. Agreement or divergence with other studies The findings of this review align with previously published evidence. Guragain et al. 57 highlight the potential of bevacizumab in reducing lesion severity and the risk of recurrence but Derkay et al 58 emphasize that the long-term safety of bevacizumab in RRP patients still requires further research. Implications for practice and future research The results of this review reinforce the importance of considering factors such as efficacy, safety, cost, and necessary infrastructure when selecting adjuvant therapy for RRP. While cidofovir is widely used and has more robust long-term efficacy data, bevacizumab, despite being more recent, emerges as a promising alternative, particularly in cases where surgical access is difficult due to lesion extension or when a less invasive approach is preferable. HPV vaccination appears to be an important adjuvant strategy. Rosemberg et al. 59 demonstrated that vaccination can significantly extend the interval between surgeries. More recently, Aga et al. 60 reported CR in patients treated with intralesional bevacizumab combined with the Gardasil-9 vaccine, with a Derkay score reduction from 41 points to zero after treatment. Despite these promising results, controlled studies are still needed to fully confirm the efficacy of vaccination in RRP management. jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Conclusion Cidofovir was associated with higher complete response rates in the available studies, but a greater number of controlled clinical trials are needed for more consistent analyses and conclusions. Legends Figure 1- Laryngeal papillomatosis Figure 2- PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only. Figure 3. Forest plot of complete response with cidofovir . Figure 4. Forest plot of complete response with bevacizumab. Figure 5. Confidence intervals of complete response. Figure 6. Forest plot of partial response with cidofovir. Figure 7. 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Supplementary Material File (figure 2. article eligibility flowchart.jpg_2.docx) Download 32.34 KB File (table 1. cidofovir.docx) Download 22.47 KB File (table 2. bevacizumab.docx) Download 17.19 KB File (table 3. cidofovir - routcome.docx) Download 23.39 KB File (table 4. bevacizumab- outcome.docx) Download 17.48 KB File (table 5.evaluation of the two randomized clinical trials with respect to the country of publication, study design and period, sex and age of the participants.docx) Download 15.21 KB File (table 6.evaluation of randomized clinical trials regarding route of administration, initial dose, follow-up time, presence of complications and response to medication.docx) Download 14.84 KB File (table 7. number of surgery before and after cidofovir.docx) Download 13.70 KB File (table 8. number of surgery before and after bvcz.docx) Download 12.63 KB File (table 9.derkay scale before and after cidofovir treatment.docx) Download 12.85 KB Information & Authors Information Version history V1 Version 1 26 June 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Rafael Toledo Baston Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina View all articles by this author Regina Helena Garcia Martins [email protected] Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina View all articles by this author Antonio Gil Azevedo 0009-0000-5838-0163 Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina View all articles by this author Antônio José Maria Cataneo Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina View all articles by this author Erica Nishida Hasimoto Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina View all articles by this author Metrics & Citations Metrics Article Usage 393 views 176 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Rafael Toledo Baston, Regina Helena Garcia Martins, Antonio Gil Azevedo, et al. 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