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Intermediate-term results after cidofovir treatment of pediatric laryngeal papillomas

Gheorghe DC, Epure Veronica, Borangiu A

ENT Clinic, M.S. Curie Hospital University of Medicine and Pharmacy “Carol Davila” Bucharest, Romania


Correspondence

Ass Prof Dan-Cristian Gheorghe
ENT Clinic, M.S.Curie Hospital
University of Medicine and Pharmacy “Carol Davila”
Bd. C Brancoveanu 20
Bucharest, Romania
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Abstract

Objectives: To evaluate the efficacy of cidofovir intralesional injections for treatment of laryngeal papillomas in children. Methods: Nineteen patients with known recurrent laryngeal papillomas have been submitted to the cidofovir protocol, between 2008 and 2013. Cidofovir has been injected into the larynx, with the patient under general anesthesia, and suspension microlaryngoscopy. The procedure was repeated every 2 weeks till either no more papillomas were observed or no papillomas regressions were noticed. The concentration of cidofovir that we used was 7,5 mg/ml. When needed, partial surgical excision of the papillomas was done before cidofovir injections. Conclusions: Cidofovir decreases the recurrence rate and severity of papillomatosis in almost all patients. Still the rate of complete disappearance with no recurrence on medium term follow-up is low. Previous surgical interventions on the papillomas tend to represent a negative prognostic factor on the response of papillomas to cidofovir.

Keywords: cidofovir, intralesional injection, juvenile laryngeal papillomatosis, surgical papiloma excision, suspension laryngoscopy.


Introduction

Recurrent respiratory papillomatosis is a disease characterized by an intractable course of continuously growing laryngeal tumors, that produce airway obstruction and suffocation if left untreated [1, 2]. Classically, it was considered a self limited disease, disappearing after puberty [2]. Still, the actual evidence shows that laryngeal papillomas continue growing even after that moment, making the patient prone to respiratory distress and vocalizing handicap. The evolution of the disease is characterized by periods with different growth rate of the laryngeal papillomas. The mainstay of treatment remains surgical debulking either by laser [3], microdebrider [4, 5] or cold instruments [6]. Adjuvant therapies directed at preventing further papilloma growth have been under trial [7], none with convincing results. Vaccines have also been tried, with results needing further evaluation [8].

We studied the use of cidofovir, as local infiltrations in juvenile recurrent respiratory papillomatosis. The substance is a nucleoside analog, used as an antiviral agent (cytomegalovirus) in patients with acquired immunodeficiency syndrome. Some studies suggested that it may be useful when used as infiltrations in laryngeal papillomas [9, 10]. We used cidofovir in 19 pediatric patients with disease ranging from 6 months to 5 years follow-up, in order to evaluate its efficiency in treating laryngeal papillomatosis.

Patients and methods

In 2007, we concluded a small uncontrolled study for observing the evolution of the disease after laryngeal infiltrations with cidofovir. The results showed a decrease in the number of needed surgical procedures on recurrent papillomas. Hence, we inferred the need for larger data.

The protocol of the actual study used data from some papers that suggested a higher dosage and shorter infiltration intervals of cidofovir injections into the larynx [11] could yield better results. We included in the study 19 patients that had been diagnosed with laryngeal papillomas, by biopsy and HPV DNA typing by polymerase chain reaction. We did not repeat the HPV testing on disease-free mucosa or residual papillomas. All of the patients agreed to participate and signed an informed consent. Ethical Committee approval was obtained before the study was begun.

The severity of the disease was appreciated after the Derkay anatomical score system [12], assessed at every endoscopic examination, by 2 surgeons. The procedure of cidofovir infiltration was carried out only by the main author. Laryngeal infiltrations were performed every 2 weeks in each patient until either no more papillomas were observed or no papilloma regression was noticed.

The patients were operated under general anesthesia, with spontaneous ventilation. Suspension direct laryngoscopy was performed and bulky laryngeal papillomas were removed with laryngeal forceps. Bleeding was controlled by aspiration and topical vasoconstricting agents (adrenaline). Then, the laryngeal remnants of the papilomas were infiltrated using a long fine needle with a solution of cidofovir (Vistide) containing 7,5 mg/ml, till the surface of mucosa turned slightly pale and a small edema of the region appeared. We always took care that the laryngeal lumen retained a good size, compatible with a normal breathing after the intervention, in order that no intubation was needed postoperatively. The evaluation of the papillomas was done at every cidofovir session injection and at 9 months from the last administration. The results were classified as: complete remission = severity score 0; partial remission = severity score lower than at start of treatment; resistant disease = score higher than the initial one.

Results

Nineteen patients received the protocol already described, between 2008 and 2013. Their mean age was 4,42 years (range 2 to 10 years). The male female ratio was 1,1:1. One patient did not sustain any other surgery before her first Cidofovir infiltration. Thus, her treatment consisted of cidofovir infiltration begun from the diagnosis of her disease. The typing of the papilloma DNA showed HPV11 in 16 cases and HPV6 in 3 cases. Between the patients enrolled in the study, 5 (26,3%) had a complete remission of papillomas after a mean of 3,4 cidofovir infiltrations. Of these patients, only 2 remained disease free after 9 months follow-up (10,5%). 13 patients (68,4%) showed a partial remission by significant low scores at the end of the laryngeal infiltrations; score dropped from 22 to 5,4 after a mean of 5,8 injections (Table 1). One patient presented a slowly progression of the papillomas in spite of cidofovir therapy (resistant disease). Eleven patients (57,8%) showed recurrent disease 9 months after completing the cidofovir treatment but with Derkay score better than before Cidofovir treatment. In 6 patients (31,5%), the 9 months score was slightly greater than at beginning of the study. One of these also had pharyngeal papillomas.

 

Table 1:Clinical data after application of intralesional Cidofovir

 

Patient

No.

 

Sex

 

Ageat diagnosis

Ageat starting cidofovir

 

Initial score

 

Infiltra- tions

 

Finalscore

 

Treatment duration

 

9months score

1

M

4

6

9

10

1

20weeks

14

2

F

7

14

21

5

6

10weeks

12

3

M

9

15

17

8

1

16weeks

8

4

M

2

2

2

5

5

10weeks

6

5

F

4

4

20

5

0

10weeks

12

6

M

2

2

27

7

10

14weeks

20

7

F

10

14

9

3

3

6weeks

6

8

F

4

5

5

3

0

6weeks

0

9

M

3

5

16

5

8

10weeks

12

10

F

5

6

19

8

5

16weeks

9

11

F

4

4

10

5

6

10weeks

15

12

M

2

3

9

3

0

6weeks

0

13

M

5

7

24

10

6

20weeks

9

14

F

2

5

12

3

0

6weeks

14

15

F

4

5

10

5

4

10weeks

6

16

M

7

9

11

10

2

20weeks

12

17

M

3

6

18

5

8

10weeks

10

18

M

5

8

9

8

6

16weeks

12

19

F

2

3

15

3

0

6weeks

9

 

Discussion

The number of patients from this study does not allow us to draw statistical conclusions. We found a low rate of complete remissions (26,3%), but a high percentage of partial remissions (68,4%). Even if a complete remission was obtained, we observed relapses in a short-medium term. Not all patients responded to the cidofovir treatment (5,2%). It seems that the older the disease and with more previous surgery, the lower was the response to cidofovir. Still, the majority of our patients demonstrated a lower rate of papilloma regrowth, when compared to the disease course prior to enrolling in the study.

It is difficult to decide if there are other prognostic factors involved in the course of the laryngeal disease. Good results have been communicated by other authors that used the same protocol we did [11]. Still, we did not use the same method for excision of the papillomas before injection. That could result in some small papilloma tumors left before local treatment was applied. If this could represent a prognostic factor is difficult to prove. The delay between the diagnosis approach and the cidofovir therapy was large in our patients. That could account for the low success rate and the high number of cases of relapses.

No side effects were observed during our study. The mobility of the vocal folds was never impaired. Some minor cicatriceal changes of the vocal cords have been detected but they existed before cidofovir therapy, as a result of previous surgery. Although we did not follow histologically the possibility of a carcinogenic transformation of the laryngeal papillomas, the endoscopic appearance and the papilloma growth rate had never suggested such evolution. We can not ascertain the role of the anatomical extent of papillomas and the response to cidofovir, due to the difficulty of defining the term. In our study, one case that proved to be resistant to infiltrations had papillomas both in the larynx and the pharynx.

Conclusions

The role of cidofovir in laryngeal papillomatosis remains as an adjuvant. The surgical debulking still stands as the mainstay of therapy. The growth rate of papillomas is lower after local infiltrations with cidofovir. The complete anatomical remission does not necessarily mean the cure of the disease. Relapses are possible. The delay from diagnosis to first treatment and the number of previous surgical debulking could predict poor outcome following cidofovir therapy. Larger number of cases and longer intervals of follow-up are necessary to achieve statistical significance of these data. A greater availability of cidofovir would make further studies easier.

 

 

References

1. Morgan, A.H. and R.P. Zitsch, Recurrent respiratory papillomatosis in children: a retrospective study of management and complications. Ear Nose Throat J, 1986. 65(9): p. 19-28.

2. Derkay, C.S., Recurrent respiratory papillomatosis. Laryngoscope, 2001. 111(1): p. 57-69.

3. Healy, G.B., et al., The use of the carbon dioxide laser in the pediatric airway. J Pediatr Surg, 1979. 14(6): p. 735-40.

4. Patel, N., M. Rowe, and D. Tunkel, Treatment of recurrent respiratory papillomatosis in children with the microdebrider. Ann Otol Rhinol Laryngol, 2003. 112(1): p. 7-10.

5. Schraff, S., et al., American Society of Pediatric Otolaryngology members’ experience with recurrent respiratory papillomatosis and the use of adjuvant therapy. Arch Otolaryngol Head Neck Surg, 2004. 130(9): p. 1039-42.

6. Zeitels, S.M. and R.T. Sataloff, Phonomicrosurgical resection of glottal papillomatosis. J Voice, 1999. 13(1): p. 123-7.

7. Kimberlin, D.W., Pharmacotherapy of recurrent respiratory papillomatosis. Expert Opin Pharmacother, 2002. 3(8): p. 1091-9.

8. Cutts, F.T., et al., Human papillomavirus and HPV vaccines: a review. Bull World Health Organ, 2007. 85(9): p. 719-26.

9. Snoeck, R., et al., Treatment of severe laryngeal papillomatosis with intralesional injections of cidofovir [(S)-1-(3-hydroxy- 2-phosphonylmethoxypropyl)cytosine]. J Med Virol, 1998. 54(3): p. 219-25.

10. Pransky, S.M., J.T. Albright, and A.E. Magit, Long-term follow- up of pediatric recurrent respiratory papillomatosis managed with intralesional cidofovir. Laryngoscope, 2003. 113(9): p. 1583-7.

11. Naiman, A.N., et al., Intermediate-term and long-term results after treatment by cidofovir and excision in juvenile laryngeal papillomatosis. Ann Otol Rhinol Laryngol, 2006. 115(9): p. 667-72.

12. Derkay, C.S., et al., A staging system for assessing severity of disease and response to therapy in recurrent respiratory papillomatosis. Laryngoscope, 1998. 108(6): p. 935-7.