Eur Arch Otorhinolaryngol DOI 10.1007/s00405-014-3055-x

Laryngology

Use of cidofovir in HPV patients with recurrent respiratory papillomatosis M. Grasso · M. Remacle · V. Bachy · S. Van Der Vorst · G. Lawson 

Received: 24 December 2013 / Accepted: 7 April 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract Recurrent respiratory papillomatosis is a viralinduced disease, associated with exophytic epithelial lesions affecting the upper airways. Problem of treatment is the high recurrence of papilloma growth after surgical removal; therefore, adjuvant therapy schemes have been established. We used cidofovir, 7.5 mg/ml, in adjuvant therapy in the past years. Out of 31 adult patients treated with the drug, 26 (83.9 %) are at the moment in complete response. 19 (73 % of pts with CR) of those 26 patients were cured with a number of injections between 1 and 4 (mean 2.5). We did not see any clinical manifestation of renal toxicity or neutropenia (superinfection) necessitating a blood test. Six patients presented dysplasia during the treatment with the drug, while six patients had dysplasia prior to cidofovir injection. Due to recurrent nature of the disease and the high number of mechanical and laser surgeries required we treated one tracheal stenosis, two scarred larynx, and two glottic synechiaes. There is still an ongoing discussion within the European Laryngological Society about the effectiveness and possible side effects of this drug. Results show promising long-term effects of adjuvant use of cidofovir, without any relevant side effects.

Keywords  Cidofovir · Recurrent respiratory papillomatosis · Larynx

M. Grasso  Otorhinolaryngology Section, Department of Sensorial Organs, “Sapienza” University of Rome, Rome, Italy

Materials and methods

M. Grasso (*)  via San Silverio 15, 00165 Rome, Italy e-mail: [email protected] M. Remacle · V. Bachy · S. Van Der Vorst · G. Lawson  Department of Otorhinolaryngology, University Hospital of Louvain de Mont-Godinne, Yvoir, Belgium

Introduction Recurrent respiratory papillomatosis (RRP), caused by a human papilloma virus (HPV), is a rare, sometimes debilitating disease, compromising voice and airway, and characterized by a variable course of disease, potentially leading to multiple surgical procedures. Therapy focuses usually on surgical removal of the epithelial lesions to keep the airway open and the voice satisfactory. Till now, there is no curative therapy for the virus infection in itself. As recurrent surgery alone has proven to be insufficient in many cases, adjuvant therapy is increasingly being used. One of the mainstays of adjuvant therapy is the administration of intralesional cidofovir (Vistide) [1]. The purpose of this retrospective study was to assess the capacity of combined surgical ablation of laryngeal papilloma and laryngeal cidofovir injection in adult onset RRP to reach a complete response with no signs of recurrence. We conducted the analysis of the adult population affected by RRP and treated in our Department.

Between August 1999 and December 2012, 31 patients, 6 females and 25 males, were treated with combined surgical ablation and intralaryngeal cidofovir injection. At the beginning of the treatment there ages were from 24- to 82-years (mean 46). All of the group was over the age of 12 and, therefore, classified as adult-onset recurrent respiratory papillomatosis (AORRP) (Table 1). Previous

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Table 1  Clinical data of treated patients Pt no

Sex

Age at beginning of cidofovir (years)

Previous treatment

Total no of sessions No of injec- Cumulative tions dose (mg) of previous treatments

Period of injections (months)

Remission

Relapse freetime (months)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

M M M M M M M M M M M F M M M M M M

40 62 43 32 43 43 35 31 50 66 55 39 47 30 82 61 51 68

2 2 2 1 2 2 2 2 2 1,2 2 2 2 2 2 2 1,2 2

7 2 2 1 1 1 1 1 1 9 1 1 1 1 1 3 3 1

14 8 7 2 2 3 8 4 4 13 4 3 1 1 6 4 1 2

97.9 120 105 75 60 112.5 210 75 159.9 474 90 45 15 7.5 180 120 18.75 45

30 11 11 8 11 30 42 7 27 45 4 11 0 0 92 21 0 2

Complete Complete Complete Complete Complete Partial Complete Complete Complete Complete Complete Complete Complete Complete Partial Complete Complete Complete

84 36 86 10 4 2 25 69 35 9 55 5 44 1 1 1 1 34

19 20 21 22 23 24 25 26 27 28 29 30

M F M M M F M M M M F F

46 34 45 45 32 30 32 38 25 65 38 81

2 1,2 1 2 2 2 2 2 2 2 2 2

1 3 5 5 1 3 4 3 3 5 7 1

1 2 4 7 1 1 4 3 2 5 2 2

15 75 204.9 120.75 37.5 33.75 135 120 225 120 142.5 7.5

0 2 10 52 0 0 22 No data 8 7 31 1

Complete Partial Complete Complete Complete Complete Complete Complete Complete Complete Complete Partial

16 1 6 6 1 61 11 No data 29 9 4 1

31

F

24

2

1

2

20.25

3

Partial

1

Previous treatment 1 pince/microdebrider, 2 laser CO2

treatments included mechanical procedures, as cold steel forceps or microdebrider, and lasers of different wavelengths as CO2, diode or Holmium-yag lasers. We used cidofovir as only adjuvant therapy. At the beginning of the procedure, extension of the lesions in the upper and lower airway is assessed with 0° and 70° telescopes. Biopsies of lesions were performed to identify HPV type by polymerase chain reaction techniques and in situ hybridization. All the patients received at least one laser-assisted treatment before cidofovir. Cidofovir injections alone were proposed in case of localization of the papillomatosis in specific area more risky for surgery (anterior commissure, crico-arytenoid articulation).

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The procedure begins with the ablation of the lesions using the CO2 scanning technology [2], allowing the beam to run on a predefined circle of usually 0.5–2 mm. In single or repeat mode, every pass of the beam along the circle is used to ablate in the mean range 100 μ with the CW mode and a power of 10 W. In case of extensive lesions above or under the vocal folds, the continuous delivery of the beam is used. When approaching the folds, the mode is switched to the repeat or single pulse mode, allowing to stop the delivery of the beam when the epithelium is ablated and the superficial part of the lamina propria visible. When using the repeat mode, a delay of 0.20 s is used allowing a very good precision in ablation.

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Localized bleeding must be controlled and carbonization cleaned to allow a proper absorption of the laser energy by the targeted lesion. After full ablation of the papilloma, cidofovir with a concentration of 7.5 mg/ml is injected into the subepithelial space, not only where the papilloma lesions were visible but all over the larynx as HPV viruses can be present in the apparently normal epithelium surrounding the lesions. Papilloma extending to the anterior commissure is only injected with cidofovir without laser ablation to avoid any risk of anterior glottic synechia. We are used to inject the cidofovir for all our cases. In young adults we start immediately giving the drug; we believe that the disease is less aggressive than in children and that combining cidofovir and surgical ablation the disease could be controlled after a few procedures, what is much more difficult to accomplish in children. The patient is preferably ventilated with a laser-proof tube instead of a high-frequency jet ventilation as blood drops could possibly spread all over the air pressure of the jet-ventilation. However, jet ventilation can be useful for reaching the trachea or the posterior glottis. Lesions that extended to the trachea can be ablated using a broncho laser [3] or since this is available the CO2 wave-guide (CO2 LWG; Lumenis, Santa Clara, CA) [4]. Narrow band imaging [5] and contact endoscopy [6] can help to identify suspected lesions. The cidofovir was being provided in bottles of 5 ml, while the remaining dose after injection was given to the patient by aerosol. Patients were controlled biologically preoperatively for renal function and neutropenia. Pre and postop blood samples were taken from a vast majority of patients. Postoperative care is based on voice rest (for 10 days), aerosoltherapy with saline solution to avoid laryngeal dryness, antibiotics for 2–3 days (amoxicillin—clavulinic acid 2 g/day) and proton pump inhibitors to prevent granuloma formation (pantazol 40 mg twice/day) until the healing is completed. Follow-up was based on stroboscopy and when this was available in our department, narrow-band imaging, with flexible video endoscope or rigid telescope, at 2 weeks and 1 month after surgery, and then every 6 months for 3 years. Patients are advised to come earlier in case of voice change. A new procedure is proposed in case of recurrence. Speech therapy is advised for voice recovery after the healing is completed. Eight of the 31 patients received Gardasil® (Merck & Co., USA) vaccine for HPV. Vaccination even in case of clinical superinfection is said to decrease the risk of recurrence.

Results Table  1 shows clinical data of patients treated with CO2 laser ablation and cidofovir. Papillomatous lesions were mostly located (Table 2) in the glottic larynx in 28 cases (90.3 %), with supraglottic extension in 18 cases (58 %)

and subglottic spread in 12 cases (38.7 %). In two cases (6.4 %) there was a secondary involvement of trachea in patients with previous involvement of larynx, located in the upper and in the middle third part. One patient was found with papillomas in the hypopharynx. In one patient we found papillomas in the soft palate (left palatal arc) as the only finding. The base of tongue was the only place involved in one patient. No papillomas were found in the lower third and in the tracheal carena and none in the esophagus, bronchi and lungs. The most common types of HPV detected were HPV 6/11 in 7 cases (22.5 % of patients) and HPV 16 in 2 cases (6.4 % of patients). In one patient biopsies showed absence of HPV. HPV typing was not performed for the other case; systematic typing is only performed since 2008. Due to the recurrent nature of the disease, patients underwent several procedures (from 1 to 9, mean of 2.6). Cidofovir was injected into the larynx at the bases of papillomata after excision of lesions. Quantity of injected cidofovir by surgery ranged from 0.1 to 10 ml. The minimal dose of 0.1 ml was used for a small papilloma involving the vocal fold. Out of 31 adult patients, 26 (83.9 %) are presently in complete response, after a period of treatment from 0 (only one injection need) to 52 months (mean 14.4), with a number of injections between 1 and 14 (mean 4.2) and a dose between 7.5 and 225 mg, whereas 474 mg (given for patient number 10) was used exceptionally for a wide extension to larynx and the upper third of trachea (mean 110.25; SD 96). The follow up ranged between 1 and 86 months (mean 25.7). 19 (73 % of pts with CR) of those 26 patients were cured with a number of injections between 1 and 4 (mean 2.5), in a mean period of time of 7.7 months (0–27), with a dose between 7.5 and 225 mg, given for patient number 27 (mean 84 mg, SD 64.5), and with a mean dose of 30 mg for each injection. Conversely, five patients (16.1 %) reported a partial response and show actually a residual disease, after a mean period of treatment of 25.6 months (1–92), with a mean number of injections of 3 (2–6), and a dose between 7.5 and 180 mg (mean 78.75 mg), using a mean dose of 30 mg for each injection. They actually show a short relapse-free time, from 1 to 2 months. In one patient the overall cumulative dose was higher than the recommended 300 mg. Patient number 10 received 474 mg in 13 injections reaching a complete response in a period of 45 months, indicating a long period of time for application. Moreover, no side effects could be observed in this patient, except for a progression discussed below. We did not see any clinical manifestation of renal toxicity or neutropenia (superinfection) necessitating a postoperative blood test. None of the patients had skin changes, high body temperature, abnormal blood morphology, changed kidney, and coagulation parameters. Patients did not complain of breathing or swallowing problems. We can describe the evolution of the

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31

19 20 21 22 23 24 25 26 27 28 29 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

x x

x x x

x

x x x x x x x x x x x

x x x x

x x x x

x x x

x x x x

x x x x x x x x x x x x

X x

x

x

x

x

x x

x x x

x x

x

Patient Supra glottic Glottic larynx Sub glottic larynx larynx

Table 2  Extension of disease

x

x

Trachea 3° upper

x

x

Trachea 3° middle

Trachea 3° lower

X

X

Tracheal Bronchi Tracheo tomy carena stoma

x

x

Hypo pharynx Esophagus

Lungs

x

x

Soft pal- Base of ate tongue

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disease in two groups of patients: the first one with laryngeal papilloma without any dysplasia on first histology, and the second one on whom dysplasia was found prior to cidofovir injection. (1) In the first group we found six patients (19.3 %), followed first for RRP, not for suspicion of carcinoma, who presented dysplasia during the treatment (1 low-grade, 4 moderate, 1 undetermined) after a mean of 101.3 mg of cidofovir (from 55.3 mg in patient number 22 to 136.1 mg in patient number 9), in a mean of 25.6 months (23–30) of treatment, and with a mean of three injections of cidofovir per patient. Five of six patients had no longer dysplasia and were completely cured of laryngeal papilloma. Only one of them (patient number 22), affected by HPV 6/11, progressed from moderate dysplasia to carcinoma in situ after 48 months (after 111.45 mg of cidofovir in 6 injections), whereas patient number 15, who presented low-grade dysplasia without progression, was affected by HPV 16. (2) In the second group we found six patients: the first one (patient number 11), followed for RRP, presented low-grade dysplasia and 1 month later underwent the first administration of cidofovir (90 mg in four injections through 4 months of treatment). After 55 months of follow-up there are no signs of progression. The second one (patient number 10) developed SCC (4-year followup) with a subsequence treatment of total Laryngectomy. The first biopsy from sub glottis and trachea showed papilloma and severe dysplasia. Patient received laser vaporization alone. The second biopsy from same place showed slight dysplasia; cidofovir was then injected with a good local control. During the treatment and follow-up period the patient kept smoking two packs of cigarettes a day and drinking (alcohol and wine 1.5 l per day). Tumor was HPV negative and location was on the arytenoid level infiltrating the cricoid cartilage (different from the site of injection). The total dose of cidofovir was 474 mg (13 injections in 45 months). We had three patients (patient numbers 12,27,30),followed for RRP, who underwent biopsies at the same time of the first administration of cidofovir; results were then positive for low-grade dysplasia. At the end of the treatment they received a mean of 92.5 mg (7.5–225) in a mean of 2, 6 injections (2–3) in a mean of 6.6 months (1–11); at the last follow-up they did not show any progression of dysplasia or malignancies. The last patient of the second group (patient number 13) was treated with a cordectomy type 5a, according to ELS classification of cordectomies [7], for an epidermoid carcinoma; 5 months later he received 15 mg of cidofovir in only one injection, able to control RRP. After 44 months of follow-up there are no signs of recurrence. In the management of patients with histology of laryngeal papilloma and dysplasia we systematically took biopsy before cidofovir treatment. None of the patients had an acute local complication. Twenty-four

hours after cidofovir injection no laryngeal edema or inflammatory changes occurred. Due to recurrent nature of the disease and the high number of mechanical and laser surgeries required, some patients developed complications. We treated one tracheal stenosis with laser CO2 and two applications of contact Mitomycin-C. In two patients with scarred larynx, we administered one hyaluronic acid injection, whereas a medialization thyroplasty with Montgomery implant was necessary for an insufficient glottic closure produced by the previous treatment in another department. Two patients developed a glottic synechia after laser CO2 and underwent laser resection with application of contact Mytomicin-C. Despite the widespread behavior of RRP, no adult patients reached any obstructive respiratory syndrome with dyspnea or respiratory distress caused by papillomas and, thus, none of them was admitted to emergency department. No one needed emergency tracheotomy to stabilize respiratory conditions.

Discussion Recurrent respiratory papillomatosis, primarily caused by human papillomas virus, is characterized by exophytic, wart-like lesions primarily involving the epithelium mucosae of the respiratory tract. RRP is a benign disease, although it can potentially threaten life with rare mortality secondary to airway obstruction, and tends to recur potentially spreading throughout the respiratory tract [8, 9]. The role of the quadrivalent HPV vaccine, Gardasil® (Sanofi Pasteur MSD), or the bivalent HPV vaccine, Cervarix® [10] (GSK) with their effects persisting for at least 5 years, is still empirical in the prevention of RRP [11]. But it seems to decrease the risk of recurrence and the aggressivity of the virus. In the Norwegian subpopulations the overall incidence rates of RRP is 0.17 per 100,000 in juveniles and 0.54 in adults, with a male preponderance. The median age at onset was 4 years for children and 34 years for adults [12]. The prevalence of this disease is likely variable between 1 and 4 per 100,000. Adult patients may have been exposed during sexual contact, or with multiple partners, or through orogenital contacts [8]. In literature, as well as in our series, HPV types 6 and 11 are the most common in RRP [13]. Patients with HPV11 and patients younger than 3 years of age at RRP diagnosis are prone to reach higher severity scores at endoscopic debridement, more frequent operative debridement procedures per year, a greater requirement for adjuvant therapy, and greater likelihood of tracheal disease with tracheotomy [14]. A study of Rabah et al. [15] found that HPV-11 infection confers a more aggressive course to

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recurrent respiratory papillomatosis and can lead to the development of bronchogenic squamous cell carcinoma with some patients dying of disease. Although RRP is a benign disease, in fewer than 1 % of cases there is the risk of malignant transformation. A review of Cook revealed cases of malignant transformation in young adult men with a history of papillomatosis (positive for HPV 11) since childhood [16]. Although HPV type 11 is most frequently associated with malignant change of RRP [17], HPV type 6 may also contribute to play an equally important role in RRP carcinogenesis [18] as well as HPV 16 [19]. The most successful adjuvant drugs used are interferon, various virostatics (e.g., acyclovir, valacyclovir, and cidofovir), indole3-carbinol [20], and unsedated office-based photoangiolytic laser surgery (UOLS) [21]. Cidofovir is an antiviral agent, registered for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Since 1998 the drug has been used to treat patients with RRP [1]. Its mechanism of action consists of decreasing the efficiency of DNA transcription following incorporation into the growing DNA chain [22]. The administration should remain below safe limits of dosing (3 mg/kg) and volume [23] even if some studies reported higher doses in individual cases [24]. We respected the safe dosage for the full group of patients except for patient number 10 who received the highest dose used in our Department (474 mg). In the past few years, many studies published promising results about the adjuvant intralesional use of cidofovir. The optimum dose of cidofovir has still not been established. Different concentrations, used in the literature, ranged from 2.5 to 15 mg/ ml [24–28]. The concentration of 7.5 mg/ml used in this study showed efficacy and safety, causing few side effects, reaching an high rate of complete response after few injections, and reducing the number and the rate of recurrence in AORRP, whereas in earlier onset disease the results of literature confirmed an higher aggressiveness of RRP in children [29]. The average cumulative dose used was 110.25 mg (7.5–225), whereas in one patient 474 mg was used exceptionally. A mean of 3 ml (0.1–10), corresponding to 22.5 mg (0.75–75), was injected per session, providing for a sufficient post-operative lumen of the glottis. Analyzing the outcome of intralesional cidofovir in our study, 83.9 % of adult patients are at the moment in complete remission, what is a higher rate of response to therapy than reported in actual literature [24, 25, 27]. Cidofovir showed safety and efficiency although its use remains off label. We all know that surgery alone is insufficient and cidofovir is a good addition to control the disease, what was clinically safe in our series. The only prospective double-blind randomized controlled trial showed a significant improvement in the Derkay severity score between the cidofovir and placebo group but failed to show significant benefit in number of procedures performed [30]. A Cochrane of Chadha

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et al. [31] showed no difference between the cidofovir and placebo groups after a 12-month trial period. Both groups showed a significant reduction in disease extent but no significant change in health-related quality of life. This study was limited by a small sample size and the concentration of cidofovir changed through the trial, from 0.3 mg/ml in children and 0.75 mg/ml in adults, to 5 mg/ml in both adults and children. In 2011, Gilead (the producer of cidofovir) communicated an alarming news concerning very serious side effects of its off-label use, including reports on nephrotoxicity, neutropenia, oncogenicity, and even some fatalities [32]. In our study no patients reported renal toxicity and neutropenia after treatment. The outcome of cidofovir and the side effects of its off-label use in HPV patients with RRP is one the main topics within The European Laryngological Society (ELS), which is the main laryngological organization in Europe (http://www.elsoc.org) [1]. According to Hall et al. [33] dysplasia is common in RRP, but progression of dysplasia, especially with an initial dysplastic grading of benign or mild disease, is rare. The authors identified 27 cases of dysplasia on 54 adult patients (50 %) treated without cidofovir. Nine patients developed a higher dysplastic grade during the course of treatment with only 1 of 9 (11.1 %) developing a squamous cell carcinoma. Comparing our study, we reported five (patient numbers 10,11,12,27,30) cases (16.1 %) of natural onset of dysplasia during the disease without cidofovir (4 lowgrade, 1 severe/ca. in situ) and one (patient number 13) case (3.2 %) of epidermoid carcinoma, properly treated, before the beginning of cidofovir; we even observed the onset of six cases (patient numbers 6,7,9,15,21,22) of dysplasia (1 low grade, 4 moderate, 1 undetermined) on 31 adult patients (19.3 %) after the beginning of cidofovir. 2 (patient numbers 10,22) cases (6.4 %) of dysplasia (1 acquired before and 1 during cidofovir) progressed during cidofovir (1 to ca. in situ, and 1 to epidermoid cancer), and thus stopped the drug. This shows that dysplasia can have a natural progression in adult RRP, and cidofovir does not accelerate or support this process. Patient number 10 was treated with vaporization for a severe dysplasia/ca. in situ before the beginning of cidofovir; he strongly kept smoking and drinking, and then developed on a different place, comparing with the sites of papilloma, an HPV negative epidermoid carcinoma at least micro-invasive (10 months after last injection); alcohol drinking and tobacco smoking are the major risk factors for upper aerodigestive tract cancers [34] and the finding of an HPV negative cancer supports the idea that it was induced by risk factors and not by evolution of papillomas. A review of Broekema et al. [35] reported a 2.7 percentage of patients developing dysplasia, which is concurrent with the incidence of spontaneous malignant degeneration of RRP (2–3 %). Based on this review, it can be concluded that the use of intralesional

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cidofovir does not increase the risk of laryngeal dysplasia. The results of Hoffman HT on histopathologic biopsies done before and after exposure to cidofovir strongly suggest that intralesional cidofovir therapy does not correlate with worsening dysplastic progression [36]. A recent international retrospective study on 635 RRP patients, of whom 275 were treated with Cidofovir, of 16 hospitals from 11 countries worldwide, showed no statistical differences in occurrence of neutropenia or renal dysfunction before and after the administration of cidofovir, neither statistical difference in occurrence of upper airway and tracheal malignancies between the cidofovir and the noncidofovir group [37]. Results of our study show that we can control the disease in young adults affected by recurrent respiratory papillomatosis combining digital scanning CO2 laser ablation, and Cidofovir in few intralesional applications and giving the drug from the beginning of the therapy. In case of scarred larynx we planned hyaluronic acid injections [38], or vocal fold medialization [39] to obtain full glottic closure and produce good quality voice.

Conclusion Combination of Digital scanning CO2 laser ablation and Cidofovir can lead to a complete remission in young adults affected by laryngeal RRP, showing safety and great efficacy after few intralesional applications, mean of 4.2 (1– 14) and decreasing the rate of surgery. Based on our experience this drug is showing promising results to achieve the best possible result and to improve the quality of life in patients with RRP. Cidofovir is well tolerated even after high cumulative doses, but only long surveillance can determine whether RRP patients have increased risk of malignant transformation or not. Further studies are necessary to determine the most appropriate dose, frequency, and duration of therapy. Patients have to be fully informed about the off-label use and possible risks. Conflict of interest  The authors declare no conflict of interest concerning funding sources, relevant patents, financial and business relationship to sponsors, companies related to the research, or the outcome of the studies in the manuscript.

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