Injection Laryngoplasty Outcomes in Irradiated and Nonirradiated Unilateral Vocal Fold Paralysis

The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Injection Laryngoplasty Outcomes in Irradiated and Nonirradiated Unilateral Vocal Fold Paralysis Joseph Chang, BS; Mark S. Courey, MD; Soha A. Al-Jurf, CCC-SLP; Sarah L. Schneider, CCC-SLP; Katherine C. Yung, MD Objectives/Hypothesis: To evaluate the effect of radiation therapy on voice outcome and duration of effect of calcium hydroxylapatite (CaHA) injection laryngoplasty in unilateral vocal fold paralysis (UVFP) patients. Study Design: Retrospective case series. Methods: UVFP patients treated with CaHA injection laryngoplasty at the University of California San Francisco Voice and Swallowing Center were identified. Demographic information, history of irradiation to the larynx, and time to additional medialization procedures were obtained. Examinations at presentation and follow-up were analyzed for laryngostroboscopic parameters and CAPE-V scores. Results: Four nonirradiated and five irradiated patients underwent a total of six and nine injection laryngoplasties, respectively. Time to additional procedures was longer in irradiated patients (P 5 0.02). Prior to injection, nonirradiated patients had more severe glottic insufficiency (P 5 0.007, 0.002) than did irradiated patients. Postinjection, irradiated patients demonstrated improvement in overall voice quality, breathiness, and loudness, while nonirradiated patients demonstrated improved overall quality, breathiness, pitch, and loudness. Voice quality was not statistically different between patient groups. Conclusion: CaHA injection laryngoplasty improved voice quality in both irradiated and nonirradiated patients. Nonirradiated patients experience greater vocal improvement compared to irradiated patients. Vocal cord stiffness due to radiationinduced changes may be responsible for the lack of improvement in pitch. Time to additional procedures was longer in irradiated patients and may be secondary to effects of prior radiation on graft resorption. Vocal fold medialization with CaHA injection remains a safe and efficacious treatment for UVFP in both irradiated and nonirradiated patients. Key Words: Laryngoplasty, vocal fold injection, unilateral vocal fold paralysis, calcium hydroxylapatite, radiation, voice, glottic insufficiency. Level of Evidence: 4. Laryngoscope, 124:1895 1899, 2014 INTRODUCTION Vocal fold injection augmentation to treat glottic insufficiency, first described by Brunings 1 in 1911, is a well-established procedure. Due to immunologic reactions with the originally described injectable, newer materials such as calcium hydroxylapatite (CaHA) have been developed and have been shown to be safe and effective long-term options. 2,3 In addition to injection augmentation, Type I thyroplasty 4 and reinnervation 5 have also been shown to be effective in the treatment of patients with unilateral Additional Supporting Information may be found in the online version of this article. From the School of Medicine (J.C.), and Department of Otolaryngology Head and Neck Surgery (M.S.C., S.A.A-J., S.L.S., K.C.Y.), University of California, San Francisco, San Francisco, California, U.S.A Editor s Note: This Manuscript was accepted for publication January 24, 2014. Presented at the Triological Society 2014 Combined Sections Meeting in Miami Beach, Florida, U.S.A., January 10 12, 2014. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Katherine C. Yung, MD, UCSF Voice and Swallowing Center, 2330 Post Street, 5th Floor, San Francisco, CA 94115. E-mail: kyung@ohns.ucsf.edu DOI: 10.1002/lary.24622 vocal fold paralysis (UVFP). However, due to lack of experience with reinnervation and personal experience with increased rates of rejection and chondronecrosis in irradiated patients undergoing type I thyroplasty, we offer injection laryngoplasty as the safest option to patients with a history of laryngeal irradiation. While injection laryngoplasty has been shown to improve mean phonation time in irradiated larynges, 6 it is unknown whether the local radiation effect to the larynx has a detrimental effect on the resultant voice improvement or the duration of improvement. Conceivably, radiation would be expected to have a negative effect on voice results; therefore, patients who have undergone radiation to the neck have been excluded from many previous studies on injection laryngoplasty. 3,4 To our knowledge, there have been no previous studies comparing outcomes after vocal fold injection between irradiated patients and nonirradiated patients. The primary aims of our study are to evaluate the benefit of injection laryngoplasty with CaHA (Radiesse Voice, Merz Aesthetics, San Mateo, CA) in irradiated patients with UVFP in terms of voice outcome and longevity, as well as compare the effects of CaHA injection augmentation between irradiated and nonirradiated patients. 1895

TABLE I. Patient Demographics. Group *Patient Age Gender Race UVFP Etiology Method Time Since RT (months) Follow-up (months) Next Tx nonrt 1a 79 M Other Primary Lung Ca FL 1.6 Repeat injection 1b 79 M Other Primary Lung Ca FL 3.6 Type I thyroplasty 2a 13 F Caucasian NF1 MDL 7.9 Repeat injection 2b 14 F Caucasian NF1 MDL 3.1 None 3 78 M Asian Papillary Thyroid Ca MDL 6.7 Type I thyroplasty 4 39 F Caucasian Iatrogenic MDL 9.8 none RT 5a 57 M Caucasian Iatrogenic MDL 159 16.3 Repeat injection 5b 59 M Caucasian Iatrogenic MDL 175 8.5 Repeat injection 6a 44 F Caucasian Papillary Thyroid Ca MDL 2.7 24.0 Repeat injection 6b 46 F Caucasian Papillary Thyroid Ca MDL 21 14.9 Repeat injection 7a 79 M Caucasian Iatrogenic MDL 8.3 10.1 Repeat injection 7b 80 M Caucasian Iatrogenic MDL 18 8.3 Repeat injection 7c 81 M Caucasian Iatrogenic MDL 27 1.0 None 8 52 F Asian Iatrogenic MDL 2.6 17.3 None 9 60 M Asian Papillary Thyroid Ca MDL 1.9 26.9 None Time to additional procedures was statistically longer in irradiated patients compared to nonirradiated patients, 13.7 and 5.0 months, respectively (P 5 0.02). All other patient characteristics were not statistically different (Student s t test, a < 0.05). Ca 5 cancer; F5 female; FL 5 flexible laryngoscopy; M 5 male; MDL 5 microdirect laryngoscopy; NF1 5 peripheral nerve sheath tumor secondary to neurofibromatosis I; nonrt 5 nonirradiated patient group; RT 5 irradiated patient group; Tx 5 treatment. *Patients who underwent multiple procedures are designated with a, b, and c. Negative times indicate completion of radiation therapy following injection laryngoplasty. In cases where patients received an additional treatment, follow-up time is considered time to the next treatment. MATERIALS AND METHODS After approval was obtained from the University of California at San Francisco (UCSF) Committee on Human Research, a retrospective case series of patients treated with CaHA (Radiesse Voice) injection laryngoplasty for UVFP between 2007 and 2012 at the UCSF Voice and Swallowing Center was performed. Patients with and without a history of external beam radiation to the larynx were included. Exclusion criteria included history of injection laryngoplasty with Teflon or concomitant injection with non-caha fillers, high vagal injury, recovery of vocal cord motion, and less than 6 months follow-up of the first injection. Voice quality and laryngeal function were determined from archived recordings. Examinations were divided into preoperative, 1-month, 3-month, 6-month, 12-month, and last follow-up groups based on temporal proximity. Voice and laryngostroboscopy recordings were independently evaluated by two speech language pathologists and two laryngologists, respectively, each blinded to patient identity as well as treatment outcome. Laryngostroboscopy recordings were graded according to a system proposed by Rosow and Sulica. 7 Twelve different parameters were evaluated (glottic insufficiency, salivary pooling, ventricular contraction, volitional arytenoid adduction, vocal process contact, arytenoid stability and position, and vocal fold bowing, tone, atrophy, shortening, and height mismatch) according to a dichotomous rating system. Perceptual voice quality was evaluated using CAPE-V scoring, which includes overall voice quality, roughness, breathiness, strain, pitch, and loudness. Recordings with the most improved overall voice quality were selected as the postoperative time point for voice quality calculations. Because mild disorder spans 25 points in the CAPE-V system, preoperative and postoperative voice values within half of this range, 12.5 points, were considered equivalent. Voice data from one patient who underwent repeat injection at 1.6 months was excluded due to assumed undermedialization. Fifteen percent of samples were repeated to calculate interrater and intrarater reliability. Intrarater reliability was calculated using Spearman s rho (rs) for laryngostroboscopic evaluations and Pearson s r (r) for voice evaluations. Interrater reliability was determined using quadratic kappa for laryngostroboscopic evaluations and ICC for voice evaluations. Values of r or rs less than 0.5, 8 kappa values below 0.4, 9 and ICC below 0.6 were considered poor. 10 Fisher s exact test and Student t test were used to determine statistical significance. When graders ratings cannot be combined, values from both graders are reported together. Only results that are both statistically significant and reproducible between graders are reported below as statistically significant. RESULTS Patient Characteristics Four nonirradiated and five irradiated patients underwent a total of six and nine laryngoplasties (Table I). Two of the four nonirradiated patients underwent repeat injections at 1.6 and 7.9 months, while three of the five irradiated patients underwent a total of six repeat injections between 8.3 and 24 months following initial injection. Because each injection laryngoplasty was considered a separate entry in the data analysis, from here onward subject or patient will refer to individual procedures. No statistically significant differences in age, gender, race, etiology for UVFP, method of injection, or number of injections per subject were found between patient 1896

TABLE II. Proportion of Abnormal Stroboscopic Parameters. Glottic Insufficiency Salivary Pooling Time Point nonrt RT P Value nonrt RT P Value Preoperative Grader 1 100% 22% *0.007 0% 56% 0.04 Grader 2 83% 0% *0.002 17% 56% 0.29 1 month Grader 1 67% 20% 0.24 17% 60% 0.24 Grader 2 67% 0% 0.06 33% 20% 1 3 months Grader 1 67% 0% 0.4 33% 33% 1 Grader 2 33% 0% 1 0% 33% 1 6 months Grader 1 100% 0% 0.4 17% 67% 0.4 Grader 2 83% 0% 1 33% 33% 1 12 months Grader 1 100% 20% 0.4 17% 40% 1 Grader 2 83% 0% 0.4 50% 40% 1 Preoperatively, nonirradiated patients had higher proportions of moderate and severe glottic insufficiency than irradiated patients (Fisher s Exact, P < 0.05). *Statistically significant based on both graders (P < 0.05). nonrt 5 nonirradiated patient group; RT 5 irradiated patient group. groups. Time to additional procedures was 5.0 months in nonirradiated patients and 13.7 months in irradiated patients (P 5 0.02), with a range of 1.6 to 7.9 months and 8.3 to 24.0 months, respectively. There were no complications recorded in either patient group. Interrater and Intrarater Reliability Among the laryngostroboscopic parameters, only glottic insufficiency (rs 5 0.93 and 0.93; kappa 5 0.80) and salivary pooling (rs 5 1 and 0.75; kappa 5 0.58) had acceptable interrater and intrarater reliability values. Of the voice parameters, overall quality (r 5 0.92 and 0.87; ICC 5 0.87), roughness (r 5 0.91 and 0.97; ICC 5 0.85), breathiness (r 5 0.99 and 0.76; ICC 5 0.79), and loudness (r 5 0.91 and 0.69; ICC 5 0.74) had acceptable interrater and intrarater reliability. Laryngostroboscopic Parameters Preoperatively, irradiated patients had less severe glottic insufficiency than did nonirradiated patients. One-hundred percent and 83% of irradiated patients had mild to absent (vs. moderate to severe) glottic insufficiency compared to 22% and 0% of nonirradiated patients (P 5 0.007, 0.002), as per graders 1 and 2, respectively (Table II). There were no statistically significant improvements in laryngostroboscopic parameters compared to baseline values. Voice Parameters There were no statistically significant differences between irradiated and nonirradiated groups in either preoperative or postoperative voice parameters (Table III). However, both irradiated and nonirradiated patients demonstrated improvement in overall voice quality, breathiness, and loudness compared to preoperative values based on the 12.5-point threshold. Nonirradiated patients, but not irradiated patients, also demonstrated improvement in pitch (Fig. S1). There were no clear improvements in roughness or strain that were reproducible between graders in either patient group. Only breathiness in irradiated patients was statistically different between preoperative and postoperative values (P 5 0.01 and 0.01). No other changes from baseline reached statistical significance (Table III). Maximum overall voice improvement was achieved in nonirradiated patients from 1.1 to 4.7 months postinjection, and 0.5 to 17.3 months postinjection in irradiated patients. However, patients were continuing to show improvement at last follow-up in 20% to 40% and 56% to 67% of nonirradiated and irradiated patients, respectively. Time to maximum overall voice improvement was not statistically different (P 5 0.06 and 0.20). DISCUSSION The purpose of this study was to determine whether radiation to the larynx affects the voice outcome and duration of voice improvement following CaHA injection laryngoplasty. In UVFP patients, history of radiation to the neck has been a contraindication to more definitive open laryngeal framework surgery. As a result, injection laryngoplasty is one of the few remaining treatment options. While it is thought that radiation decreases the effectiveness of this procedure, there have been no studies comparing outcomes in irradiated and nonirradiated patient groups. Although a similar proportion of patients underwent multiple treatments (3/5 irradiated and 2/4 nonirradiated patients) the average time to additional procedures was longer in irradiated patients than in nonirradiated patients, 13.7 months versus 5.0 months, respectively (P 5 0.02). This difference in time to additional procedures may be explained by decreased vascularity in irradiated tissue, which may result in decreased absorption of injected CaHA and carrier materials. Additionally, it may also be the case that 1897

TABLE III. Voice Quality Comparisons (P values). Comparisons Overall Roughness Breathiness Strain Pitch Loudness Preoperative vs. postoperative nonrt Grader 1 0.02 0.46 0.03 0.02 0.18 0.05 Grader 2 0.11 0.68 0.13 0.95 0.30 0.25 RT Grader 1 0.05 0.73 *0.01 0.46 0.41 0.01 Grader 2 0.01 0.25 *0.01 0.36 0.04 0.06 RT vs. nonrt Preoperative values Grader 1 0.08 0.80 0.01 0.05 0.24 0.04 Grader 2 0.41 0.68 0.12 0.65 0.33 0.15 Postoperative values Grader 1 0.75 0.23 0.15 0.90 0.70 0.28 Grader 2 0.45 0.90 0.14 0.68 0.39 0.20 Postoperative breathiness in irradiated patients was statistically improved from baseline. There were no other statistically significant differences in voice quality between preoperative and postoperative values or between irradiated and nonirradiated patients at either time point (Student t test, a < 0.05). *Statistically significant according to both graders (P < 0.05). nonrt 5 non-irradiated patient group; RT 5 irradiated patient group. irradiated patients are less anxious to return for additional treatments to improve voice quality. However, the majority of the irradiated subjects continued to demonstrate improvement in voice quality at their last followup. Lastly, since irradiated patients did not have improvement in roughness, pitch, and strain parameters, the benefit in voice quality that they achieve with CaHA injection may be more subtle and thus harder to determine when the injection effect was depleted. A second clinically significant result is that irradiated patients improved in fewer voice parameters. Nonirradiated patients improved in four out of the six measured parameters, including overall quality, breathiness, loudness, and pitch, whereas irradiated patients improved in only three parameters: overall quality, breathiness, and loudness. Improvement in voice parameters approached but did not achieve statistical significance except for improvement in breathiness of irradiated patients (P 5 0.01 and 0.01). This may be a result of our small sample size. Lack of improvement in voice parameters, excluding overall quality, breathiness, and loudness, in irradiated patients seems consistent with baseline radiation-induced vocal fold stiffness. Finally, irradiated patients had less preinjection glottic insufficiency than did nonirradiated patients. Perhaps radiation induced fibrosis is contributing to a more medialized vocal-fold position. This result may explain some of the differences in voice improvement. Because there is less glottic insufficiency in irradiated patients, the CaHA injection that medializes the paralyzed vocal fold has a less dramatic effect than does medialization for a larger glottic gap. Limitations of this article include a small sample size and the inability to obtain laryngostroboscopy and voice samples at every time group. Trends that did not reach statistical significance may be valid if this study were better powered. Laryngostroboscopy evaluation is subjective, and a validated scoring system has not been developed. Our study further highlights the difficulty in using laryngostroboscopy for research and comparison purposes. Lastly, selection bias must be considered. Because permanent medialization with a silicone implant is generally offered to nonirradiated patients as a preferred treatment option, the nonirradiated patients who opt for CaHA injection may be patients with poor prognosis (i.e., vocal fold paralysis secondary to lung metastasis). If patients were in weakened medical conditions, this may account for the limited follow-up and perhaps may even restrict improvement in vocal quality after injection due to pulmonary deficiencies. Furthermore, given the small sample size, there is the potential for heterogeneity within the groups to introduce bias including differences in pathology and method of injection augmentation. CONCLUSION UVFP patients who have received radiation to the neck have few options for treatment because open laryngeal framework surgery is generally contraindicated. CaHA injection laryngoplasty is a long-term treatment option. However, it is unknown whether the local radiation effect to the larynx has a detrimental effect on the resultant voice improvement or the duration of improvement and there have been no studies comparing irradiated and nonirradiated patients undergoing injection laryngoplasty. Results from this preliminary study show that CaHA injection in irradiated patients results in the improvement in only overall voice quality, breathiness, and loudness compared to overall quality, breathiness, loudness, and pitch in nonirradiated patients. However, irradiated patients retained benefit from the injection longer than did nonirradiated patients (13.7 vs. 5.0 months respectively; P 5 0.02) and have less severe glottic insufficiency at baseline (P 5 0.007, 0.002). Vocal cord stiffness due to radiation-induced changes may be responsible for the lack of improvement in pitch. Increased length of benefit may be secondary to effects of prior radiation on graft resorption. Although irradiated patients had improvement in fewer parameters than did nonirradiated patients, vocal fold medialization 1898

with CaHA injection remains a safe and efficacious treatment for unilateral vocal fold paralysis in both irradiated and nonirradiated patients. Additional studies will be needed to further investigate the effect of local irradiation on CaHA injection laryngoplasty outcomes. BIBLIOGRAPHY 1. Brunings W. Uber eine neue Behandlungsmethode der Rekurrenslahmung. Verh Veh Laryngol 1911;18:93 151. 2. Carroll TL and Rosen CA. Long term results of calcium hydroxylapatite for vocal fold augmentation. Laryngoscope 2011;121:313 319. 3. Rosen CA, Gartner-Schmidt J, Casiano R, et al. Vocal fold augmentation with calcium hydroxylapatite: twelve-month report. Laryngoscope 2009; 119:1033 1041. 4. Shen T, Damrose EJ, Morzaria S. A meta-analysis of voice outcome comparing calcium hydroxylapatite injection laryngoplasty to silicone thyroplasty. Otolaryngol Head Neck Surg 2013;148:197 208. 5. Aynehchi BB, McCoul ED, Sundaram K. Systemic review of laryngeal reinnervation techniques. Otolaryngol Head Neck Surg 2010;143:749 759. 6. Tirado Y, Lewin JS, Hutcheson KA, Kupferman ME. Office-based injection laryngopasty in the irradiated larynx. Laryngoscope 2010;120:703 706. 7. Rosow DE and Sulica L. Laryngoscopy of vocal fold paralysis: evaluation of consistency of clinical findings. Laryngoscope 2010;120:1376 1382. 8. Zraick RI, Kempster GB, Connor NP, et al. Establishing validity of the consensus auditory-perceptual evaluation of voice (CAPE-V). Am J Speech Lang Pathol 2011;20:14 22. 9. Rosner B. Fundamentals of Biostatistics. Belmont, CA: Duxbury Press; 1995. 10. Fleiss JL. The Design and Analysis of Clinical Experiments. New York, NY: Wiley; 1986. 1899