Portuguese Version

Year:  2004  Vol. 70   Ed. 6 - (2º)

Artigo Original

Pages: 735 to 738

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Cidofovir effects on recurrent laryngeal papillomatosis in children: preliminary report

Author(s): Melissa A. G. Avelino , Raquel L. Gutzman , Reginaldo R. Fujita , Shirley Pignatari , Luc L. M. Weckx , Paulo Pontes

Keywords: Key words: laryngeal papillomatosis, cidofovir, HPV virus.

Abstract:
Summary Objective: To demonstrate the effect of local application of Cidofovir in children with recurrent laryngeal papillomatosis (RLP), following our 2002 institutional protocol of RLP treatment. Study Design: Preliminary/clinical prospective. Material and Method: Our casuistic included 5 RLP pediatric patients assisted at the otolaryngologic pediatric clinic of the Federal University of São Paulo. They were all submitted to local application of Cidofovir and had up to a year follow-up. Before starting the treatment with Cidofovir, these patients had been submitted to at least three surgical procedures with histopathological exam confirming the diagnosis of papillomatosis (inclusion criterions); with no clinical evidence of nephropathy or hepatic disturbs (exclusion criterions). The protocol consisted of surgical removal of the lesions, followed by local application of 3 ml of Cidofovir (7,5mg/ml). The treatment cycle included a minimum of 3 applications, and at any sings of recurrences, another cycle of application would begin. Results: We observed that before the Cidofovir the recurrences in all of the 5 children had shorter intervals (one each three months). After the Cidofovir application, the evolution of the illness changed dramatically and the 5 patients stayed more than one year without need of surgery. No children presented laboratorial exams alteration, local or systemic collateral effects with local injection of Cidofovir. Based on our preliminary results we observed that local application of Cidofovir in children, promotes a good short-term control of the recurrences of RLP.

INTRODUCTION

Recurrent laryngeal papillomatosis (RLP) is a disease whose main characteristic is the presence of verruciform epithelial lesions that may be pedicle or sessile, single or multiple, but which are, usually, recurrent lesions1. This clinical entity leads to high morbidity because these lesions are confluent and develop into dysphonia (voice disorders) and dyspnea (changes in the respiratory pattern), both progressive conditions. The lesions may trigger respiratory failure due to airway obstruction and can even cause death. Recurrences have frustrated ENT doctors for several decades. In the specialty, this disease is considered as one of the most difficult conditions to control. The lesions affect mainly the larynx but may also affect the mouth, nose, pharynx, esophagus and the whole tracheobronchial tree. In the larynx, the most affect sites are the vocal folds, the epiglottis and the vestibular folds. Other common sites are: the nasal vestibular lumen, nasopharyngeal surface of the soft palate, carina and the bronchi2.

This epithelial proliferation, considered a benign neoplasia, is caused by human papillomavirus (HPV) infection, a multiple type DNA virus. HPV-6 and HPV-11 types are the most common in laryngeal papillomatosis, but we may also see HPV-16 and HPV-18 types,3-6 which may have malignancy potential. Fortunately, we seldom find HPV-16 and HPV-18 types in children with RLP6, but one must always request HPV typing and, whenever these two types are present, one must consider higher malignancy potential.

Although this is a benign disease, its clinical evolution implies frequent hoarseness and upper airway obstruction relapses. Thus, patients are often submitted to multiple surgeries. Children usually have more aggressive relapses and poorer prognosis. Doyle, in 19947, while studying patients with severe recurrent laryngeal papillomatosis showed, in his series, that although no adults had to be submitted to tracheotomy, 60% of children were submitted to tracheotomy.

Relapse control requires excessive larynx manipulations, which may lead to permanent sequelae such as stenosis, formation of anterior and posterior membranes, vocal fold lesions, formation of granulation tissue, among other disorders. 4,7,8.

Different therapeutic approaches have been developed for treating recurrent laryngeal papillomatosis: larynx microsurgery with mechanical removal or CO2 laser removal; the use of anti-metabolites, hormones, podophyllin, alpha interferon, indol-3-carbinol, photodynamic therapy and antiviral agents. The antiviral agents that have already been used in RLP are Acyclovir, Ribavirin and Cidofovir. As Acyclovir and Ribavirin have shown poor results, the most used antiviral agent has been Cidofovir.

Cidofovir [(S)-1-(3-Hydroxy-2-Phosphonyimethoxypropyl) Cytosine, HPMPC, Vistide®] is an antiviral that has been proven quite effective in the inhibition of virus replication such as herpes, adenovirus, cytomegalovirus and papillomavirus 14-16. This drug has been approved by the FDA (Food and Drug Administration) to be used in retinitis caused by cytomegalovirus in patients with AIDS. The first reports on the use of Cidofovir were published in 1993, by Kurtzman et al.14, showing the outcomes in animals. Snoeck et al.17, 1995 were the first researchers to use Cidofovir in humans with anal lesions caused by HPV. They used a gel formulation in three patients with good outcomes. Its use in RLP was first reported by Snoeck in 199816. Since then, several authors have been showing positive outcomes with the use of this medication in RLP treatments. 18-25. If administered by IV it may cause hepatotoxicity and nephrotoxicity but, when used as local applications, there has been no report of any type of local or systemic side effects.

The use of Cidofovir as treatment for recurrent laryngeal papillomatosis is quite recent. Nevertheless, the studies that have been published are unanimous about its absolute efficacy although there are some differences regarding the standardization of its use in controlling the relapses and its proper administration. For this reason, we must carry out more standardized and controlled studies with the drug so that we may assess cure expectations or relapses control.

The objective of this study is to show, by means of this preliminary report, the effects of Cidofovir in children with RLP, complying with a protocol adopted in our services since 2002.

MATERIAL AND METHOD

In this trial we have included 5 children who have been followed up for at least one year as outpatients, follow-up in our pediatric laryngology clinic and who have complied with a protocol for Cidofovir use. They all have agreed to sign a Free Informed Consent Form, as determined by the standards of the Ethics and Research Committee, Medical School, Federal University of Sao Paulo.

In order to be included in this protocol, the patients had to comply with some inclusion and exclusion criteria:

A. Inclusion Criteria:

1. Diagnosis confirmed by clinical pathology analysis.

2. At least two relapses after surgical procedure.

3. Material collection for HPV typing.

B. Exclusion Criteria:

1. Chronic use of hepatotoxicity drugs.

2. Liver disorders.

3. Kidney disorders.

After inclusion and exclusion criteria were met, the protocol consisted of surgical treatment with suspension laryngoscopy with cold steel removal of papillomatosis lesions and local injection of Cidofovir (concentration and dose of 7.5mg/ml) up to 3 ml. These children were submitted to a cycle at least for 3 applications within intervals of 2-3 weeks, when no lesions occurred. In case there were signs of lesion relapse, the lesion was removed and a new cycle of applications began.

When tracheal site was affected, the same dose was used after the removal of the lesions, via bronchoscopy with the use of a 0° and 4 mm non-flexible endoscope and with cup forceps.

All the lesions removed in the procedure were sent to clinical pathology analysis. Part of the lesion was removed before starting the use of Cidofovir and sent to a Molecular Biology laboratory to check HPV typing. The proposed typing test was done by PCR (Polymerase Chain Reaction).

After each application, we requested new laboratorial exams such as blood count, alkaline phosphatase, gamma-GT, TGO, TGP, urea and creatinine.

These children were followed up every 2 weeks with video nasofibroscopy and video laryngoscopy (whenever possible). At any sign of relapse, they were submitted to debulking and a new cycle of 3 applications began, as recommended. After a 2-month relapse-free period, they were submitted to monthly follow-up consisting of video nasofibroscopy and video laryngoscopy for early detection of any sign of relapse.

We have adopted the protocol described above to observe the patients response to the adopted therapy in a standardized way.

OUTCOMES

In this preliminary trial, we have included 5 children who had been followed up for more than one year: 3 were males and 2 females, ages ranging from 3 to 9 years of age, mean age: 5.2 years. Among these children, only one had tracheotomy and had the disease spread to the lower airways.

Child number 1, male, 6 years, born and coming from Aracaju, who had already undergone 5 previous surgeries in intervals of approximately 2 months between each procedure. He was included in the protocol and submitted to total of 9 applications of Cidofovir. After 6 applications, he had no relapses for a 11-month period, after which he showed a small lesion focus in the left vocal fold (asymptomatic); he was, then, submitted to a new 3-application cycle and has now been followed up for 1 year and 2 months with no signs of relapse. His typing for HPV detected HPV-11.

Child number 2, male, 5 years, born and coming from Rio de Janeiro, had already been submitted to 10 previous surgeries and had been, by that time, tracheotomized for one year. The disease had spread through the whole trachea to the carina. The interval between procedures was approximately of 2-3 months. After his inclusion in our protocol, he was submitted to 9 applications of Cidofovir in the larynx and in the trachea. After the 5th Cidofovir application, he was decannulated. Currently, he has been followed up for 1 year and 3 months. It was not possible to have his HPV typing but the material is stored in the Molecular Biology laboratory, in perfect conditions to preserve the virus structure.

Child number 3, male, 3 years, born and living in Sao Paulo, had already undergone 4 previous surgeries with 1-2 months intervals between procedures. After his inclusion in the protocol, he was submitted to 10 Cidofovir applications. Currently, in a follow-up of 1 year and 3 months, he shows no signs of relapse. The HPV type responsible for RLP in this patient was type HPV-6.

Child number 4, female, 3 years, born and coming from Maranhão, had already been submitted to 3 surgeries in intervals of 3 months, approximately. After her inclusion in the protocol, she received 5 applications of Cidofovir. Recurrences were controlled for 11 months when a small lesion focus appeared in the vestibular fold. As Cidofovir was not available at the moment, we decided to wait and see. She has been followed up every month for the past 5 months and the lesion focus showed discreet growth in size but it is still asymptomatic. The child has had no symptoms for 1 year and 4 months. The material for performing the typing test is also stored at the Molecular Biology laboratory.

Child number 5, female, 9 years, born and living in Sao Paulo, had already undergone 3 previous surgeries in intervals of 3 months between procedures. After her inclusion in the protocol, she received 5 applications of Cidofovir and remained free of recurrences for 12 months. Later, she showed a small lesion in the vestibular face of the right vocal fold. Then, we started a new 3-application cycle. However, as the patient did not show up for the third application, she only received two. At the same time, as she did not regularly comply with follow-up schedules, she has been excluded from the protocol. She remained in the follow-up program as an outpatient and has had no recurrence for a whole year. Currently, she showed a small lesion in the right vocal fold, which is still asymptomatic. The material collected for HPV typing is also stored in the Molecular Biology laboratory.

In all five children, we had good control of recurrent lesions when we compared the intervals between surgeries before and after the use of the medication.

No child showed any type of change in the laboratorial exams and no local or systemic side effect with the local injection of Cidofovir.

DISCUSSION

Several authors have demonstrated positive results with the use of Cidofovir in RLP patients. Pransky et al. in 1999 and 200020,21 were the first researchers to demonstrate results in pediatric patients. In their first study, they had a series of 5 children and used Cidofovir in an initial concentration of 2.5mg/ml with maximum dosage of 1mg/kg. During the study, they increased the concentration to 5mg/ml, in applications of 1 to 2 ml, and the total dosage they used ranged from 2.5 to 10 mg, in intervals of 2-3 weeks. In their second study, they added 5 more children in their series and maintained the same concentration (5mg/ml), but they administered 2 to 4 ml per application and performed at least 4 applications in intervals of 2 weeks. They also recommended previous debulking. Snoeck16 and Willian22, on the other hand, presented different methodologies: they performed local application of Cidofovir without any debulking (lesion removal). Snoeck, who was a pioneer in the use of Cidofovir for RLP, recommended a concentration of 2.5mg/ml and applied the medication until the lesions disappeared, but he only studied the adult population.

Although there are some studies with the use of Cidofovir, the methodology published in the literature varies a lot and there is no consensus regarding the ideal dose to be used, the number of applications and the interval between applications. Besides, some authors favor local application only on the lesions, whereas other authors associate the lesions exeresis with local application of the medication.

In our series, we have been using Cidofovir for almost 4 years and have had excellent results in adults25. In these patients the procedure was to perform surgical removal of the lesions and administer 18mg of Cidofovir, and new applications only when lesion relapses occurred.

When we started using the medication in children, we observed that the results were not as positive as the results previously observed in adults. Then, we started to use a protocol based on the one used by Pransky, in which we applied Cidofovir at least 4 times in intervals of 2 weeks. But the concentration and the doses we used (7.5mg/ml up to 3 ml) were higher than those recommended in the literature. We agreed with Pransky methodology regarding the association of lesions removal with Cidofovir application, especially in the pediatric population where the diameter of the upper airways is smaller, thus, with higher risk of obstruction.

In our outcomes with these 5 children we have observed good recurrence control when we compared the intervals between surgeries before starting the treatment and after the use of the medication. Before the applications of Cidofovir, these 5 children had recurrences in shorter intervals (1 to 3 months), which required surgical procedures. After their inclusion in the protocol, there was a change in the disease evolution in the 5 children, as they remained free of recurrences during at least one year. Moreover, the recurrences in patients numbers 4 and 5 could only be noticed due to our strict follow-up because these patients remained asymptomatic. Milczuk, in 200323, also had positive outcomes in 4 children who were treated with Cidofovir.

Nevertheless, we observed that we had to have several applications to obtain good response and patients 1, 2 and 3 - who have received 9 to 10 Cidofovir applications, achieved better outcomes and were free of disease for more than 14 months.

We believe that these children - maybe because they have a more aggressive type of recurrent laryngeal papillomatosis - need heavier doses and higher number of Cidofovir applications than adults do. The dosage used in our protocol is a little higher than the doses described in literature up to now20,21,23,24. These patients needed more than one 3-application cycle to achieve good control of recurrences. However, these children did not have any type of changes in their laboratorial exams, clinical pathology analysis and also did not show any local or systemic side effect, as in accordance to other cases in the literature 15,16,20,21,26. The only study described in the literature that reports side effects with local use of Cidofovir was published by Bienvenu27 in 2002. This was the report of a case study with an immunodepressed patient, with previous chronic renal failure who developed an extensive acuminate condyloma and who was, then, submitted to local application of Cidofovir in gel 4% for 12 continuous days. Although there was lesion involution, on the 19th day the patient developed acute renal failure. The author underlined that the patient had received a higher dose than those described by other authors and had genital excoriations during treatment and, in addition, suffered from chronic renal failure. Considering all previous conditions affecting this patient, we do not believe that this case should be relevant when analyzing the side effects in the local use of Cidofovir.

Although HPV typing by Molecular Biology (PCR) is part of the protocol, due to budget limitations, we were only able to obtain the typing for patients 1 and 3. The material from the other patients has been collected and is stored for further typing as soon as possible.

Based on the preliminary outcomes, we consider Cidofovir as a promising therapy to control recurrent laryngeal papillomatosis in children with aggressive form of the disease. The protocol in use allowed us to standardize the dose, to choose the proper moment to perform new applications, and also to have close observation to check possible recurrences. Nevertheless, our follow-up is not long enough to report any cure. This is a new therapy (little bit more than 5 years); thus, we must have strict follow-up of these patients and develop study protocols with larger number of patients and longer follow-up periods. Bearing in mind this purpose, we continue to develop this protocol in our service and to include new patients.

REFERENCES

1. Cummings CH, Fredrickson JM et al. Otolaryngology Head & Neck Surgery. Mosby. Third Edition Copyright ©; 1998.

2. Kashima HK, Leventhal B et al. Sites of Predilection in Recurrent Respiratory Papillomatosis. Ann Otol Rhinol Laryngol 1993; 102: 580-3.

3. Bauman NM; Smith RJ et al. Recurrent Respiratory Papillomatosis. Pediatr Clin North Am 1996; 43: 1385-401.

4. Doyle DJ, Henderson LA et al. Changes in Human Papillomavirus Typing of Recurrent Respiratory Papillomatosis Progressing to Malignant Neoplasm. Arch Otolaryngol Head Neck Surg 1994; 120: 1273-6.

5. Gaylis B, Hayden RE. Recurrent Respiratory Papillomatosis: Progression to Invasion and Malignancy 1991; 12: 104-12.

6. Pignatari SSN, Smith EM, Shive C et al. Detection of human papillomatosis infection in diseased and nondiseased sites of the respiratory tract in recurrent respiratory papillomatosis patients by DNA hybridization. Oto-rhino-laryngol 1992; 101: 408-12.

7. Doyle DJ, Gianoli GJ et al. Recurrent Respiratory Papillomatosis: Juvenile versus Adult Forms. Laryngoscope May 1994; 104: 523-7.

8. Hartley C, Hamilton J et al. Recurrent Respiratory Papillomatosis - The Manchester Experience, 1974-1992. The Journal of Laryngology and Otology 1994; 108: 226-9.

9. Aguado LD, Pinero BP et al. Acyclovir in the Treatment of Laryngeal Papillomatosis. Int J Pediatr Otorhinolaryngol 1991; 21: 269-74.

10. Endres DR, Burke D et al. Acyclovir in The Treatment of Recurrent Respiratory Papillomatosis. Ann Otol Rhinol Laryngol 1994; 103: 301-5.

11. Kiroglu M, Cetik F et al. Acyclovir in the Treatment of Recurrent Respiratory Papillomatosis: A Preliminary Report. American Journal of Otolaryngology 1994; 15: 212-4.

12. McGlennen RC, Adams GL et al. Pilot Trial of Ribavirin for the Treatment of Laryngeal Papillomatosis. Head & Neck nov/dec 1993; 504-13.

13. Ostrow R, Forslund K, et al. Ribavirin Inhibits Wart Growth in Rabbits Infected with Cottontail Rabbit Papillomavirus. Antiviral Res 1992; 17: 99-113.

14. Kurtzman G, Pickel M et al. Phosphonate Nucleoside Analogs Are Potent Anti-papillomavirus Agents in Animal Models. 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, October 1993. Abstract n1593.

15. Snoeck R, Wellens W et al. Treatment of severe recurrent laryngeal papillomatosis by local injections of (S)-1-(3-hydroxy-2-phosphonylmethoxy-propyl) cytosine (cidofovir). In: Programs and Abstracts of the Ninth International Conference on Antiviral Research; May 19-24, 1996; Fukushima, Japan.

16. Snoeck R et al. Treatment of Severe Laryngeal Papillomatosis with Intralesional Injections of Cidofovir. Journal of Medical Virology 1998; 54: 219-25.

17. Snoeck R, Ranst MV et al. Treatment of anogenital Papillomavirus Infections with an Acyclic Nucleoside Phosphonate Analogue. The New England Journal of Medicine 1995; 333(4): 943-4.

18. Bielamowicz S, Villagomez V et al. Intralesional Cidofovir Therapy for Laryngeal Papilloma in an adult Cohort. Laryngoscope 2002; 112: 696-9.

19. Christensen ND, Han R et al. Combination Treatment with Intralesional Cidofovir and Viral-DNA Vaccination Cures Large Cottontail Rabbit Papillomavirus-Induced Papillomas and Reduces Recurrences. Antimicrobial Agents and Chemotherapy Apr. 2001, p. 1201-9.

20. Pransky SM et al. Intralesional Cidofovir for Recurrent Respiratory Papillomatosis in Children. Arch Otolaryngol Head Neck Surg; 1999; 125: 1143-8.

21. Pransky SM et al. Intralesional Cidofovir for Recurrent Respiratory Papillomatosis in Children. Arch Otolaryngol Head Neck Surg 1999; 125: 1143-8.

22. Willian RW, Hashemiyoon R et al. Intralesional cidofovir for recurrent laryngeal papillomas: Preliminary report. ENT- Ear, Nose & Throat Journal April 2000.

23. Milczuk HA. Intralesional Cidofovir the Treatment of Severe Juvenile Recurrent Respiratory Papillomatosis: Long-Term Results in 4 Children. Otolaryngol Head Neck Surg 2003; 128(6): 788-94.

24. Chhetri DK, Shapiro NL. A Scheduled Protocol for the Treatment of Juvenile Recurrent Respiratory Papillomatosis with Intralesional Cidofovir. Arch Otol Head Neck Surg 2003; 129: 1081-5.

25. Avelino, MAG. Efeito da aplicação local do cidofovir no controle da papilomatose laríngea recorrente. São Paulo: UNIFESP-EPM, 2003. Dissertação (Mestrado) - Universidade Federal de São Paulo - Escola Paulista de Medicina, 2003.

26. Van Cutsem EV, Snoeck R et al. Successful Treatment of a Squamous Papilloma of the Hypopharynx-Esophagus by Local Injections of (S)-1-(3-Hydroxy-2-Phosphonylmethoxypropyl) Cytosine. Journal of Medical Virology 1995; 45: 230-5.

27. Bienvenu B, Martinez F et al. Topical use of Cidofovir Induced Acute Renal Failure. Brief Communications February 2002; 73(4): 661-2.

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