Skip to main content

Advertisement

SpringerLink
Log in

Intralesional cidofovir vs. bevacizumab for recurrent respiratory papillomatosis: a systematic review and indirect meta-analysis

  • Review Article
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Background

Specific HPV types cause recurrent respiratory papillomatosis (R.R.P.). When administered intralesionally, cidofovir, an antiviral agent, has shown favorable outcomes in reducing papilloma. Bevacizumab, an angiogenesis inhibitor, has demonstrated improved R.R.P. However, both treatments lack FDA approval for R.R.P. Our study aims to evaluate the efficacy and safety of intralesional Cidofovir and Bevacizumab for R.R.P. and compare the two interventions.

Methods

We searched five electronic databases to find relevant studies. After the screening, data were extracted from the included studies. Pooled ratios with 95% confidence intervals (CIs) were used for categorical outcomes, and mean difference (MD) was used for continuous outcomes. Statistical heterogeneity was evaluated using the chi-squared test for I2 statistics. The Cochrane Risk of Bias assessment tool was used to assess the methodological quality of randomized controlled trials (RCTs), while the National Institutes of Health's tool was used for observational studies. Analysis was done by Review Manager software.

Results

In our comprehensive meta-analysis of 35 articles involving 836 patients, cidofovir demonstrated an overall remission ratio of (0.90 [95% CI: 0.83, 0.98], p = 0.01), while bevacizumab (0.92 [95% CI: 0.79, 1.07]), p = 0.3). The complete remission ratio for cidofovir was (0.66 [95% CI: 0.57, 0.75], p > 0.0001), while bevacizumab was (0.29 [95% CI: 0.12, 0.71], p = 0.07). In partial remission, Bevacizumab showed a higher ratio than Cidofovir 0.74 [0.55, 0.99] vs. 0.40 [0.30, 0.54]. Bevacizumab had a pooled ratio of 0.07 [95% CI: 0.02, 0.30] in terms of no remission, indicating better outcomes compared to Cidofovir with a ratio of 0.28 [95% CI: 0.16, 0.51]. Additionally, Cidofovir showed a favorable decrease in the Derkay Severity Score (DSS) with a mean difference (MD) of 1.98 [95% CI: 1.44, 2.52].

Conclusion

Cidofovir had a higher impact on complete remission compared to Bevacizumab. Both showed partial remission, with Bevacizumab having a higher ratio. Moreover, Cidofovir showed a significant decrease in DSS. Bevacizumab had lower rates of no remission and recurrence and fewer adverse events compared to Cidofovir. However, the difference between the two treatments was not significant, except for partial remission.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Availability of data and material

The datasets were generated from open source databases. All data are available within the manuscript and its supplemental files.

References:

  1. Dickens P, Srivastava G, Loke SL, Larkin S (1991) Human papillomavirus 6, 11, and 16 in laryngeal papillomas. J Pathol 165:243–246. https://doi.org/10.1002/path.1711650308

    Article  CAS  PubMed  Google Scholar 

  2. Ağgünlü L, Erbaş G (2009) Recurrent respiratory papillomatosis with lung involvement. Diagn Interv Radiol 15:93–95

    PubMed  Google Scholar 

  3. Larson DA, Derkay CS (2010) Epidemiology of recurrent respiratory papillomatosis. APMIS 118:450–454. https://doi.org/10.1111/j.1600-0463.2010.02619.x

    Article  PubMed  Google Scholar 

  4. Ivancic R, Iqbal H, DeSilva B, Pan Q, Matrka L (2018) Current and future management of recurrent respiratory papillomatosis. Laryngoscope Investig Otolaryngol 3:22–34. https://doi.org/10.1002/lio2.132

    Article  PubMed  PubMed Central  Google Scholar 

  5. Rosenberg T, Philipsen BB, Mehlum CS, Dyrvig A-K, Wehberg S, Chirilǎ M et al (2019) Therapeutic use of the human papillomavirus vaccine on recurrent respiratory papillomatosis: a systematic review and meta-analysis. J Infect Dis 219:1016–1025. https://doi.org/10.1093/infdis/jiy616

    Article  PubMed  Google Scholar 

  6. Mauz PS, Schäfer FA, Iftner T, Gonser P (2018) HPV vaccination as preventive approach for recurrent respiratory papillomatosis—a 22-year retrospective clinical analysis. BMC Infect Dis 18:343. https://doi.org/10.1186/s12879-018-3260-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Carifi M, Napolitano D, Morandi M, Dall’Olio D (2015) Recurrent respiratory papillomatosis: current and future perspectives. Ther Clin Risk Manag. https://doi.org/10.2147/TCRM.S81825

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pransky SM, Albright JT, Magit AE (2003) Long-term follow-up of pediatric recurrent respiratory papillomatosis managed with intralesional cidofovir. Laryngoscope 113:1583–1587. https://doi.org/10.1097/00005537-200309000-00032

    Article  CAS  PubMed  Google Scholar 

  9. Shirley WP, Wiatrak B (2004) Is cidofovir a useful adjunctive therapy for recurrent respiratory papillomatosis in children? Int J Pediatr Otorhinolaryngol 68:413–418. https://doi.org/10.1016/j.ijporl.2003.11.007

    Article  Google Scholar 

  10. Akst LM, Lee W, Discolo C, Knott D, Younes A, Koltai PJ (2003) Stepped-dose protocol of cidofovir therapy in recurrent respiratory papillomatosis in children. Arch Otolaryngol Head Neck Surg 129:841–846. https://doi.org/10.1001/archotol.129.8.841

    Article  PubMed  Google Scholar 

  11. Lee AS, Rosen CA (2004) Efficacy of cidofovir injection for the treatment of recurrent respiratory papillomatosis. J Voice 18:551–556. https://doi.org/10.1016/j.jvoice.2003.07.007

    Article  PubMed  Google Scholar 

  12. Sidell DR, Nassar M, Cotton RT, Zeitels SM, De Alarcon A (2014) High-dose sublesional bevacizumab (avastin) for pediatric recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 123:214–221. https://doi.org/10.1177/0003489414522977

    Article  PubMed  Google Scholar 

  13. Zeitels SM, Barbu AM, Landau-Zemer T, Lopez-Guerra G, Burns JA, Friedman AD et al (2011) Local injection of bevacizumab (Avastin) and angiolytic KTP laser treatment of recurrent respiratory papillomatosis of the vocal folds: a prospective study. Ann Otol Rhinol Laryngol 120:627–634. https://doi.org/10.1177/000348941112001001

    Article  PubMed  Google Scholar 

  14. Rogers DJ, Ojha S, Maurer R, Hartnick CJ (2013) Use of adjuvant intralesional bevacizumab for aggressive respiratory papillomatosis in children. JAMA Otolaryngol Head Neck Surg 139:496–501. https://doi.org/10.1001/jamaoto.2013.1810

    Article  PubMed  Google Scholar 

  15. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al (2019) Cochrane handbook for systematic reviews of interventions. https://doi.org/10.1002/9781119536604

  16. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, The PRISMA et al (2020) statement: an updated guideline for reporting systematic reviews. BMJ 2021:n71. https://doi.org/10.1136/bmj.n71

    Article  Google Scholar 

  17. Institution NH. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools n.d. Accessed 25 May 2023

  18. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ [Internet] n.d.

  19. The Cochrane Collaboration 2020. Review Manager (RevMan) [Computer program]. Version 5.4. n.d.

  20. Manzini M, Becker CF, Schweiger C, Manica D, Kuhl G (2014) Use of adjuvant bevacizumab for the treatment of recurrent respiratory papillomatosis: experience with five cases. Int Arch Otorhinolaryngol 18(S 01):a2439

    Article  Google Scholar 

  21. Ablanedo-Terrazas Y, Soda-Merhy A, Hernández-Palestina M, Ormsby CE, Reyes TG (2012) Intralesional cidofovir in severe juvenile respiratory papillomatosis. B-ENT 8:197–202

    CAS  PubMed  Google Scholar 

  22. Hall SR, Thiriveedi M, Yandrapalli U, Zhang N, Lott DG (2021) Sublesional bevacizumab injection for recurrent respiratory papillomatosis: evaluation of utility in a typical clinical practice. Ann Otol Rhinol Laryngol 130:1164–1170. https://doi.org/10.1177/0003489421998215

    Article  PubMed  Google Scholar 

  23. Hoesli RC, Thatcher AL, Hogikyan ND, Kupfer RA (2020) Evaluation of safety of intralesional cidofovir for adjuvant treatment of recurrent respiratory papillomatosis. JAMA Otolaryngol Head Neck Surg 146:231–236. https://doi.org/10.1001/jamaoto.2019.4029

    Article  PubMed  PubMed Central  Google Scholar 

  24. McMurray JS, Connor N, Ford CN (2008) Cidofovir efficacy in recurrent respiratory papillomatosis: a randomized, double-blind, placebo-controlled study. Ann Otol Rhinol Laryngol 117:477–483. https://doi.org/10.1177/000348940811700702

    Article  PubMed  Google Scholar 

  25. Meacham RK, Thompson JW (2017) Comparison of cidofovir and the measles, mumps, and rubella vaccine in the treatment of recurrent respiratory papillomatosis. Ear, Nose Throat J 96:69–74. https://doi.org/10.1177/014556131709600209

    Article  PubMed  Google Scholar 

  26. Mikolajczak S, Quante G, Weissenborn S, Wafaisade A, Wieland U, Lüers JC et al (2012) The impact of cidofovir treatment on viral loads in adult recurrent respiratory papillomatosis. Eur Arch Oto-Rhino-Laryngol 269:2543–2548. https://doi.org/10.1007/s00405-012-2103-7

    Article  CAS  Google Scholar 

  27. Murono S, Nakanishi Y, Tsuji A, Endo K, Kondo S, Wakisaka N et al (2016) Intralesional cidofovir injection for recurrent respiratory papillomatosis in Japan. Auris Nasus Larynx 43:541–545. https://doi.org/10.1016/j.anl.2016.01.005

    Article  PubMed  Google Scholar 

  28. Naiman AN, Ayari S, Nicollas R, Landry G, Colombeau B, Froehlich P (2006) Intermediate-term and long-term results after treatment by cidofovir and excision in juvenile laryngeal papillomatosis. Ann Otol Rhinol Laryngol 115:667–672. https://doi.org/10.1177/000348940611500903

    Article  PubMed  Google Scholar 

  29. Naiman AN, Ceruse P, Coulombeau B, Froehlich P (2003) Intralesional cidofovir and surgical excision for laryngeal papillomatosis. Laryngoscope 113:2174–2181. https://doi.org/10.1097/00005537-200312000-00024

    Article  PubMed  Google Scholar 

  30. Avelino MA, Gutzman RL, Fujita RR, Pignatari S, Weckx LL, Pontes P. Cidofovir effects on recurrent laryngeal papillomatosis in children: preliminary report. Revista Brasileira de Otorrinolaringologia. 2004;70:734-8.

    Article  Google Scholar 

  31. Ablanedo-Terrazas Y, Estrada-Camacho O, Alvarado-de la Barrera C, Ramírez-García A, Tona-Acedo G, Bross-Soriano D et al (2022) Efficacy of cidofovir versus bevacizumab in recurrent respiratory papillomatosis: A randomized, double-blind, placebo-controlled pilot study. Acta Otorrinolaringol (English Ed) 73:82–88. https://doi.org/10.1016/j.otoeng.2020.12.001

    Article  Google Scholar 

  32. Pontes P, Avelino M, Pignatari S, Weckx LLM (2006) Effect of local application of cidofovir on the control of recurrences in recurrent laryngeal papillomatosis. Otolaryngol - Head Neck Surg 135:22–27. https://doi.org/10.1016/j.otohns.2005.10.060

    Article  PubMed  Google Scholar 

  33. Pontes P, Weckx LLM, Pignatari SSN, Fujita RR, Avelino MAG, Sato J (2009) Local application of ci dofovir as adjuvant therapy in recurrent laryngeal papillomatosis in children. Rev Assoc Med Bras 55:581–586. https://doi.org/10.1590/s0104-42302009000500023

    Article  PubMed  Google Scholar 

  34. Pransky SM, Brewster DF, Magit AE, Kearus DB (2000) Clinical update on 10 children treated with intralesional cidofovir injections for severe recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg 126:1239–1243. https://doi.org/10.1001/archotol.126.10.1239

    Article  CAS  PubMed  Google Scholar 

  35. Pudszuhn A, Welzel C, Bloching M, Neumann K (2007) Intralesional Cidofovir application in recurrent laryngeal papillomatosis. Eur Arch Oto-Rhino-Laryngol 264:63–70. https://doi.org/10.1007/s00405-006-0151-6

    Article  Google Scholar 

  36. Sappington J, Eisenbeis JF (2009) The effect of cidofovir injection concurrent with surgical resection for adult onset recurrent respiratory papillomatosis. Laryngoscope 119:96. https://doi.org/10.1002/lary.20388

    Article  Google Scholar 

  37. Shemen LJ, Shnayder Y (2006) Office-based intralesional cidofovir injections for nasal septal papilloma: A pilot study. Otolaryngol - Head Neck Surg 135:149–151. https://doi.org/10.1016/j.otohns.2005.12.028

    Article  PubMed  Google Scholar 

  38. Snoeck R, Wellens W, Desloovere C, Van Ranst M, Naesens L, De Clercq E et al (1998) Treatment of severe laryngeal papillomatosis with intralesional injections of cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine]. J Med Virol 54:219–225. https://doi.org/10.1002/(SICI)1096-9071(199803)54:3%3c219::AID-JMV13%3e3.0.CO;2-C

    Article  CAS  PubMed  Google Scholar 

  39. Tanna N, Sidell D, Joshi AS, Bielamowicz SA (2008) Adult intralesional cidofovir therapy for laryngeal papilloma: a 10-year perspective. Arch Otolaryngol - Head Neck Surg 134:497–500. https://doi.org/10.1001/archotol.134.5.497

    Article  PubMed  Google Scholar 

  40. Tjon Pian Gi REA, Ilmarinen T, Van Den Heuvel ER, Aaltonen LM, Andersen J, Brunings JW, et al. Safety of intralesional cidofovir in patients with recurrent respiratory papillomatosis: An international retrospective study on 635 RRP patients. Eur Arch Oto-Rhino-Laryngology 2013;270:1679–87. https://doi.org/10.1007/s00405-013-2358-7.

  41. Valera F, Maldonato L, Lima J, Küpper DS, Lacerda RN, Mamede R et al (2010) Efficacy of cidofovir in recurrent juvenile respiratory papillomatosis. Braz J Otorhinolaryngol 76:713–717. https://doi.org/10.1590/s1808-86942010000600008

    Article  PubMed  Google Scholar 

  42. Verguts MML, Genbrugge E, De Jong FICRS (2009) Treatment results in adult-onset recurrent respiratory papillomatosis. B-ENT 5:137–141

    CAS  PubMed  Google Scholar 

  43. Wierzbicka M, Jackowska J, Bartochowska A, Józefiak A, Szyfter W, Kȩdzia W (2011) Effectiveness of cidofovir intralesional treatment in recurrent respiratory papillomatosis. Eur Arch Oto-Rhino-Laryngology 268:1305–1311. https://doi.org/10.1007/s00405-011-1599-6

    Article  Google Scholar 

  44. Best SR, Friedman AD, Landau-Zemer T, Barbu AM, Burns JA, Freeman MW et al (2012) Safety and dosing of bevacizumab (Avastin) for the treatment of recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 121:587–593. https://doi.org/10.1177/000348941212100905

    Article  PubMed  Google Scholar 

  45. Bielamowicz S, Villagomez V, Stager SV, Wilson WR (2002) Intralesional cidofovir therapy for laryngeal papilloma in an adult cohort. Laryngoscope 112:696–699. https://doi.org/10.1097/00005537-200204000-00019

    Article  CAS  PubMed  Google Scholar 

  46. Chung BJ, Akst LM, Koltai PJ (2006) 3.5-Year follow-up of intralesional cidofovir protocol for pediatric recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol 70:1911–1917. https://doi.org/10.1016/j.ijporl.2006.06.018

    Article  PubMed  Google Scholar 

  47. Co J, Woo P (2004) Serial office-based intralesional injection of cidofovir in adult-onset recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 113:859–862. https://doi.org/10.1177/000348940411301102

    Article  PubMed  Google Scholar 

  48. Dikkers FG (2006) Treatment of recurrent respiratory papillomatosis with microsurgery in combination with intralesional cidofovir—a prospective study. Eur Arch Oto-Rhino-Laryngology 263:440–443. https://doi.org/10.1007/s00405-005-1013-3

    Article  Google Scholar 

  49. Grasso M, Remacle M, Bachy V, Van Der Vorst S, Lawson G (2014) Use of cidofovir in HPV patients with recurrent respiratory papillomatosis. Eur Arch Oto-Rhino-Laryngology 271:2983–2990. https://doi.org/10.1007/s00405-014-3055-x

    Article  CAS  Google Scholar 

  50. Derkay CS, Bluher AE (2018) Recurrent respiratory papillomatosis: update 2018. Curr Opin Otolaryngol Head Neck Surg 26:421–425. https://doi.org/10.1097/MOO.0000000000000490

    Article  PubMed  Google Scholar 

  51. Graupp M, Gugatschka M, Kiesler K, Reckenzaun E, Hammer G, Friedrich G (2013) Experience of 11 years use of cidofovir in recurrent respiratory papillomatosis. Eur Arch Oto-Rhino-Laryngology 270:641–646. https://doi.org/10.1007/s00405-012-2221-2

    Article  CAS  Google Scholar 

  52. Lalezari JP (1997) Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 126:257. https://doi.org/10.7326/0003-4819-126-4-199702150-00001

    Article  CAS  PubMed  Google Scholar 

  53. Thomson PD (2003) Physicians’ desk reference. In: Physicians’ desk reference 2003, pp 3550–3550

  54. Wemer RD, Lee JH, Hoffman HT, Robinson RA, Smith RJH (2005) Case of progressive dysplasia concomitant with intralesional cidofovir administration for recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 114:836–839. https://doi.org/10.1177/000348940511401105

    Article  PubMed  Google Scholar 

  55. Lott DG, Krakovitz PR (2009) Squamous cell carcinoma associated with intralesional injection of cidofovir for recurrent respiratory papillomatosis. Laryngoscope 119:567–570. https://doi.org/10.1002/lary.20082

    Article  CAS  PubMed  Google Scholar 

  56. Bayan S, Faquin WC, Zeitels SM (2019) Glottic carcinoma in young patients. Ann Otol Rhinol Laryngol 128:25S-32S. https://doi.org/10.1177/0003489418818852

    Article  PubMed  Google Scholar 

  57. Chhetri DK, Blumin JH, Shapiro NL, Berke GS (2002) Office-based treatment of laryngeal papillomatosis with percutaneous injection of cidofovir. Otolaryngol Neck Surg 126:642–648. https://doi.org/10.1067/mhn.2002.125604

    Article  Google Scholar 

  58. Fusconi M, Grasso M, Greco A, Gallo A, Campo F, Remacle M et al (2014) Recurrent respiratory papillomatosis by HPV: review of the literature and update on the use of cidofovir. Acta Otorhinolaryngol Ital 34:375–381

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Zeitels SM, Lopez-Guerra G, Burns JA, Lutch M, Friedman AM, Hillman RE (2009) Microlaryngoscopic and office-based injection of bevacizumab (Avastin) to enhance 532-nm pulsed KTP laser treatment of glottal papillomatosis. Ann Otol Rhinol Laryngol 118:1–24. https://doi.org/10.1177/000348940911800901

    Article  Google Scholar 

Download references

Funding

The authors declare no funding sources.

Author information

Authors and Affiliations

  1. Department of Otolaryngology, Head and Neck Surgery, College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

    Faisal H. Zagzoog & Abdulsalam Alqutub

  2. Department of Otolaryngology, Head and Neck Surgery, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia

    Ahmed M. Mogharbel

  3. Department of Otolaryngology, Head and Neck Surgery, King Saud University Medical City, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Manal Bukhari & Mohammed I. Almohizea

Authors
  1. Faisal H. Zagzoog
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmed M. Mogharbel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdulsalam Alqutub
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manal Bukhari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammed I. Almohizea
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Faisal H. Zagzoog.

Ethics declarations

Conflict of interest

There are no conflicts of interest to declare.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zagzoog, F.H., Mogharbel, A.M., Alqutub, A. et al. Intralesional cidofovir vs. bevacizumab for recurrent respiratory papillomatosis: a systematic review and indirect meta-analysis. Eur Arch Otorhinolaryngol 281, 601–627 (2024). https://doi.org/10.1007/s00405-023-08279-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-023-08279-0

Keywords

Search

Navigation