Office-based treatment of laryngeal papillomatosis with percutaneous injection of

DINESH K. CHHETRI, MD, JOEL H. BLUMIN, MD, NINA L. SHAPIRO, MD, and GERALD S. BERKE, MD, Los Angeles, California

OBJECTIVE: Our aim was to report our experience otolaryngologist. The technique is quick and safe with office-based treatment of severe laryngeal and can be performed in the office setting. Green papillomatosis with percutaneous injection of cldo­ et al ' described a "point-touch technique" for the fovir in a case series of 5 patients. injection of botulinum toxin for the treatment of STUDY DESIGN AND SETTING: We conducted a ret­ spasmodic dysphonia. The senior author (G.S.B.) rospective review of a case series in a tertiary ac­ ademic care voice disorders clinic. Adult patients routinely uses this technique for botulinum toxin with of the and anterior and collagen injections. Knowledge of laryngeal commissure received percutaneous injection using anatomy based on external landmarks is an essen­ a point-touch technique. Clinical improvement or tial component in this technique to properly direct remission of the papillomatosis was noted. the needle. A flexible nasopharyngoscope con­ RESULTS: Before initiation of office treatments, pa­ nected to a video monitor is also necessary to tients required direct and CO laser 2 improve the precision of the placement of laryn­ ablation of papillomas on average every 2.8 geal augmentation agents. months. There were no complications related to the Recurrent respiratory papillomatosis is the most injection technique. During a treatment period of 7 to 16 months (mean 12 months), a significant re­ common benign of the . It occurs duction in the volume of papillomatosis was in both juvenile and adult forms. The standard achieved in all patients. One patient received 2 treatment for this disease consists of repeated mi­

treatments and another received 1 treatment in the crosuspension direct laryngoscopy and CO 2 laser operating room for final clearance of papillomas. ablation of papillomatous growths under general CONCLUSION: Office-based treatment of adult pa­ anesthesia. Numerous publications have recently tients with anterior laryngeal papillomatosis using reported the efficacy of intralesional injection of percutaneous injection of cidofovir reduces the the cidofovir (Gilead Sciences, Fos­ need for repeated direct laryngoscopy and laser ter City, CA) in the treatment of laryngeal papil­ ablation under general anesthesia. SIGNIFICANCE: Percutaneous injection treatment lomas.>> Cidofovir is a cytosine nucleotide analog with cidofovir is a useful adjunct to direct laryngos­ that is approved for treatment of copy and laser ablation in the treatment of laryn­ (CMV) retinitis in human immunodeficiency vi­ geal papillomatosis. (Otolaryngol Head Neck Surg rus infected patients. It is administered parenter­ 2002; 126:642-648.) ally in these patients. It suppresses CMV through selective inhibition of viral DNA synthesis. After Percutaneous injection of the larynx is a useful entry into a cell, the drug undergoes phosphoryla­ technique in the armamentarium of skills of an tion and its active metabolite, cidofovir diphos­ phate, selectively inhibits CMV DNA poly­ From the Division of Head and Neck Surgery, UCLA School of merases. Incorporation of cidofovir into the Medicine. growing DNA chain results in reduction in the rate Presented at the Annual Meeting of the American Academy of viral DNA synthesis. The long intracellular of Otolaryngology Head and Neck Surgery, Denver, CO, September 9-12, 200 I. half-life of cidofovir and its metabolites allows for Reprint requests: Gerald S. Berke, MD, Division of Head and infrequent dosing." Cidofovir has also been shown Neck Surgery, UCLA School of Medicine, 10833 Le Conte to be effective against a broad range of DNA Ave, ChS 62-132, Los Angeles, CA 90095; e-mail, , including human . 2,8 [email protected]. Van Cutsem et aF first reported the successful Copyright © 2002 by the American Academy of Otolaryn­ gology-Head and Neck Surgery Foundation, Inc. treatment of 1 adult with hypopharyngeal papillo­ 0194-599812002/$35.00 + 0 23/1/125604 mas with intralesional cidofovir. Subsequently, doi: 10.1067/mhn.2002.125604 Snoeck et aP reported successful treatment in 16

642 Otolaryngology- Head and Neck Surgery Volume 126 Number 6 CHHETRI et 01 643

of 17 adults with laryngeal papillomas, and Wil­ son et al- reported a phase I trial with successful treatment of 3 adults with laryngeal papillomas. In all of these studies, intralesional cidofovir injec­ tion was the only modality of treatment and was administered under general anesthesia. Pransky et 5 6 a1 . successfully combined concurrent laser abla­ tion and mechanical debulking with intralesional cidofovir in treating children with severe recurrent laryngeal papillomas. These reports demonstrated that cidofovir was effective against respiratory papillomas, but disease relapses should be antici­ pated even with combined therapy. However, re­ current lesions also respond to further treatments with cidofovir. After reviewing the initial reports on the effi­ cacy of cidofovir against respiratory papillomato­ sis, we began offering office-based cidofovir treat­ ments to select adult patients with aggressive Fig 1. Needle placement in the transcartilaginous ap­ proach for percutaneous injection. laryngeal papillomatosis. The purpose was to ap­ ply the percutaneous laryngeal injection technique to treat laryngeal papillomatosis with cidofovir. This in tum could minimize the necessity and The neck is palpated to identify the outline of the larynx. The superior and inferior borders of the thyroid cartilage and the frequency of operative laser laryngoscopy. Pa­ cricoid cartilage can be marked on the neck skin using a tients were selected based on accessibility of the surgical marking pen. A flexible nasopharyngoscope (P3; papillomas to the percutaneous technique. Here Olympus, Los Angeles, CA) is passed through the anesthe­ we report our experience to date with this tech­ tized into the hypopharynx until the larynx is nique. visualized. The image is viewed on a video monitor. The cutaneous needle injection site is prepared with alco­ MATERIALS AND METHODS hol swabs. The injection is administered with a I-mL syringe Patient Selection and a 1'/4-inch 27-gauge needle. Transcartilaginous injection is performed unless the laryngeal cartilage is ossified, in Adult patients with laryngeal papillomatosis were selected which case the injection is performed through the cricothy­ based on the severity of disease and accessibility of papillo­ roid membrane. The location of the anterior commissure is mas to the percutaneous technique. Cidofovir treatment was estimated as midway between the thyroid notch and the offered if the frequency of operative laser ablation of papil­ inferior border of the thyroid cartilage. For transcartilaginous lomas was approaching every 2 to 3 months. Only those approach, the needle is inserted 5 mm lateral and 5 mm patients with symptomatic papillomas of the vocal cords and inferior to this point (Fig 1). Passage of the needle through the anterior commissure were offered percutaneous injection be­ cartilage can be felt as a slight give or "loss of resistance" as cause injection of other areas of the larynx is difficult with the needle passes through the inner thyroid perichondrium. this technique. The drug, injection method, and potential Proper needle positioning is achieved by pointing and ad­ serious risks were carefully discussed with each patient, and vancing the needle submucosally toward the papillomas and cr~­ fully informed consent was obtained. A baseline serum confirming the position through the nasopharyngoscope be­ atinine level was checked to establish normal renal status m fore injection. For transmembrane injection, the needle is all patients before treatment. All patients were otherwise placed just under the edge of the thyroid cartilage, approxi­ healthy nonsmokers without comorbidities. mately 1.5 em from the midline, and on going through the membrane, the needle is bent 45° to 70° and then directed Injection Technique superiorly and medially toward the lesiogs (Fig 2). The injection method has been descnibe dprevious . 1y..19 The needle tip should be directed submucosally toward the The patient is seated in an eXaminati~n ~hair..The nose and papillomatous areas and can be visualized on the monitor are topically anesthetized WIth lidocaine 2% spray. when the vocal fold "tents up" with pressure from Otolaryngology­ Head and Neck Surgery 644 CHHETRI et 01 June 2002

Table 1. Patient demographics

Patient Age (y) OR frequency*

I 21 Every 2 mo 2 62 Every 3 mo 3 62 Every 4 mo 4 49 Every 3 mo 5 28 Every 2 mo Average 44.4 Every 2.8 mo

*OR Frequency indicates how often patients require surgical inter­

vention (microsuspension direct laryngoscopy and CO 2 laser abla­ tion) for laryngeal papillomatosis before initiation of percutaneous treatment.

ing 5 male patients had an average age of 44.4 years and required an operative microsuspen­ sion direct laryngoscopy/Ctj, ablation of laryn­ geal papillomas an average of every 2.8 months (Table 1). All had symptomatic papillomas of the true vocal cords or the anterior commissure. During a mean treatment period of 12 months (range 7-16 months), an average of 7.2 injec­ \ tions (range 2-12) were administered (Table 2). Fig 2. Needle placement in the transcricothyroid ap­ The average dose of cidofovir was 47 mg (range proach for percutaneous injection. 38-57 mg). No patient received> I mg/kg of cidofovir per dose. All injections were given initially 2 to 4 weeks apart and then at longer the needle tip or a small amount of injection. Once the intervals according to the response of papillo­ location of the tip is visualized, it can be redirected toward the mas. All patients reported a mild stinging sen­ base of the papillomas. The drug is then injected at this time. Proper depth of injection is confirmed by distention of the sation as the medication was administered. epithelium at the base of the lesion. The procedure generally There were no other complications related to the takes <3 minutes to complete. injection. Percutaneous treatment with cidofovir did not Drug Dose and Follow-up completely clear papillomatous lesions in all pa­ The drug is supplied as a clear and colorless solution in tients, although the volume of papillomas receded clear glass vials, each containing 375 mg of anhydrous cido­ by at least 90% in all patients. Two patients (pa­ fovir in 5-mL aqueous solution, at a concentration of 75 tients I and 2) required surgical treatment for mg/mL. Cidofovir is diluted to the desired concentration. To complete clearance of papillomas. The illustrative keep the volume of injection low, we generally diluted the case of patient I is discussed here. Patient 2, who drug I: I with sterile saline for a final concentration of 37.5 mg/mL. Frequency of injections was every 2 weeks initially required a return to the operating room, had what and then extended to longer intervals dependent on the re­ appeared to be complete response of the papillo­ sponse of the lesions to treatment. mas to the injections. However, a small anterior web was uncovered after the papillomas receded, RESULTS and 8 months after starting cidofovir injections, he Six patients were offered office-based treat­ was taken to the operating room to divide the web. ment with percutaneous injection of cidofovir. In the operating room, subglottic papillomas were One male out-of-state patient could not return to discovered, and therefore he instead received CO2 our clinic after the first injection and was ex­ laser ablation of the residual papillomas. At 4 cluded from the following analysis. The remain- months after this surgical intervention, he had not Otolaryngology- Head and Neck Surgery Volume 126 Number 6 CHHETRI et al 645

Table 2. Treatment and follow-up

Total To OR on Larynx at no. of Average Follow-up OR treatment Reason for trip latest Patient injections mg/injection (mo) intervention month to OR" follow-up

I 10 51 16 No NA NA AC lesion 2 12 57 16 Yes II Injection of residual Clear lesions 3 5 38 9 No NA NA Clear 4 8 53 12 Yes 8 AC web Clear 5 2 38 7 No NA NA Clear Average 7.2 47 12

NA. Not applicable; AC. anterior commissure. *Reason for trip to the operating room is discussed in the text. received any more treatments and his laryngo­ required laser ablation of his papillomas approxi­ scopic examination was clear of papillomas. mately every 3 months. He had tried a prolonged course of acyclovir and indole-3-carbinol therapy Patient 1 without success. He expressed a desire for an A 21-year-old man presented with hoarseness alternative treatment modality and was offered and a recent history of vocal cord "polyp" re­ percutaneous treatments with cidofovir. He re­ movaL On examination, a papillomatous lesion ceived 12 percutaneous treatments with cidofovir arising from the anterior larynx was evident (Fig at an average dose of 57 mg over the next 16 3A). Microsuspension direct laryngoscopy re­ months. At 11 months after initiation of percuta­ vealed a papillomatous growth arising from the neous treatments, recurrence of a papillomatous anterior commissure and the right true vocal fold. lesion was observed in the left aryepiglottic fold The papillomas were mechanically debulked and (Fig 4B). Because this area is not easily accessible

CO2 laser ablated. Recurrence was noted within 2 by percutaneous injection, he was brought to the months (Fig 3B). After 6 CO2 laser treatments in operating room for cidofovir injection under the ensuing 9 months, he was referred to a hema­ monitored anesthesia care. Cidofovir was in­ tology oncology consultation, and -a jected in the true vocal folds as well as the treatments were started. He responded minimally aryepiglottic fold percutaneously under moni­ to the interferon therapy and required 10 addi­ tored anesthesia care. Despite overall excellent response of papillomas to percutaneous treatment, tional CO2 laser ablations in the next 22 months. He was then offered percutaneous cidofovir treat­ some myxoid tissue persisted in the anterior third of ments. He received 10 percutaneous treatments both vocal folds (Fig 4C). At 14 months after initi­ with cidofovir at an average dose of 51 mg over ation of office therapy, the patient received mechan­ the next 16 months. Figure 3C is a laryngoscopic ical debulking of these residual lesions and cidofovir view of his larynx 2 months after the last laser injection under general anesthesia. Histopathologic ablation and at the office visit for the second examination of the lesions revealed benign squa­ injection treatment. At his latest visit at 16 mous papilloma with no evidence of dysplasia. At months, his voice was stable and his larynx was his latest follow-up visit 2 months later, the vocal clear of papillomas except for a small stable lesion cords were clear of papillomas and he has not re­ at the anterior commissure (Fig 3D). He has not ceived further treatments (Fig 4D). required operative intervention under general anes­ DISCUSSION thesia since starting percutaneous treatments with Our experience in a small group of 5 adults with cidofovir. severe laryngeal papillomatosis shows a positive Patient 2 response of the papillomas to office-based percu­ A 62-year-old man presented with a 20-year taneous intralesional injection therapy with cido­ history of laryngeal papillomatosis (Fig 4A). He fovir. All patients received laser ablation of pap- Otolaryngology­ Head and Neck Surgery 646 CHHETRI et 01 June 2002

Fig 3. Laryngoscopic examination of patient 1 at initial presentation (A), typical recurrence after microsuspension direct laryngoscopy/C02 ablation (B), at the second injection (C), and at latest follow-up 16 months (D) after initiation of percutaneous treatments with cidofovir. The patient did not require return to the operating room after initiation of office-based therapy. illomas at the onset of percutaneous treatments. eral anesthesia were free of papillomas at the latest The goal was to eliminate the need for laser abla­ follow-up visit and no cidofovir was injected (at 2­ tion under general anesthesia. This was not borne and 4-month postoperative visits, respectively). out in all patients. Although some lesions com­ Candidacy for percutaneous cidofovir injections pletely responded to the therapy, others receded remains in question. We believe it is a useful remarkably but did not completely disappear (Fig adjunct to laser therapy in patients with severe 4). The lesions at the anterior commissure were disease requiring laser ablation every 2 to 3 particularly difficult to eradicate despite the easy months. The morbidity of general anesthesia and access of this area to percutaneous injection (Fig the risks and complications of laser treatment are 3). This may be related to the relatively thin win­ avoided with percutaneous treatment. Complica­ dow of soft tissuebetween cartilage and mucosa at tions of laser therapy include injury to normal this location, which may limit the amount of drug mucosa, laser-induced fire, and the development that can be deposited. Persistent lesions eventually of webs and scars. Percutaneous treatment is per­ required removal via operative intervention under formed in the office and is quick. However, cido­ general anesthesia (Fig 4). Both patients who re­ fovir cannot yet be considered the standard of care quired removal of residual papillomas under gen- in the treatment of respiratory papillomas because Oto - Head and Neck Surgery Volume 126 Number 6 CHHETRI et al 647

Fig 4. laryngoscopic examination of patient 2 at initial presentation (A) and 11 months (B), 14months (C), and 16months (D) after initiation of percutaneous treatments with cidofovir. B, Papillomatous lesions can be seen in the left aryepiglottic fold, which was treated with percutaneous injection of cidofovir under monitored anesthesia care. C, Myxoid persistent lesions can be seen in both vocal folds, which were treated with mechanical debulking. D, The patient's vocal cords are clear of papillomas at the latest follow-up visit. its role remains to be studied in a well-designed opsies were performed 8 and 14 months after prospective trial. Percutaneous treatment is also initiation of percutaneous treatments and after cu­ limited technically to adults with papillomas in­ mulative doses of 420 and 685 mg of cidofovir, volving the vocal cords and anterior commissure. respectively. At the present time, we believe the Supraglottic and subglottic sites are not easily intralesional injection of cidofovir for papilloma­ accessible with this technique, nor would this be tosis is a viable option for patients requiring fre­ feasible in children, who constitute the majority of quent operative laser procedures. However, long­ affected individuals. term follow-up is necessary regarding potential There have been some discussions about poten­ sequelae from this treatment modality. tial carcinogenicity ofcidofovir, although no cases of attributed to laryngeal injection of CONCLUSION cidofovir have been reported.e" There was no Recurrent laryngeal papillomatosis typically evidence of dysplasia in the pathologic specimens has an extended, chronic course and can be frus­ ofeither patient in our study who required surgical trating to treat. Office-based treatment with percu­ intervention to eradicate residual disease. The bi- taneous injection of cidofovir is a useful adjunct to Otolaryngology­ Head and Neck Surgery 648 CHHETRI et 01 June 2002

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