ORIGINAL ARTICLE
Steroid-eluting sinus implant for in-office treatment of recurrent nasal polyposis: a prospective, multicenter study Franc¸ois Lavigne, MD1 , Steven K. Miller, MD2 , Andrew R. Gould, MD3 , Brent J. Lanier, MD4 and J. Lewis Romett, MD5
Background: Treatment options for chronic rhinosinusitis with recurrent polyposis (CRSwNP) aer endoscopic sinus surgery (ESS) are limited, and include frequent use of systemic steroids and revision surgery. A bioabsorbable, steroid-eluting implant was studied for its ability to dilate sinuses obstructed by polyps and provide localized, controlled steroid delivery to reestablish sinus patency. This study assessed the initial feasibility, safety, and efficacy of steroid-eluting implants placed in the office seing in patients who were candidates for revision ESS. Methods: Prospective, multicenter study enrolling 12 patients who had prior ESS but experienced recurrent polyposis refractory to medical therapy. Implants were placed bilaterally under topical anesthesia in-office. Follow-up through 6 months included endoscopic grading, patientreported outcomes (22-item Sino-Nasal Outcomes Test [SNOT-22]) and need for revision ESS. Results: Implants were successfully inserted in 21 of 24 (88%) ethmoid sinuses, resulting in 11 evaluable patients. No serious adverse events occurred. Within 1 month, mean bilateral polyp grade was reduced from 4.5 at baseline to 2.3 (p = 0.008) and sustained through 6 months (2.33;
1 Department of Otolaryngology, Centre hospitalier de l’Universite ´ de Montreal Notre-Dame, Montreal, Canada; ´ (CHUM), Hopital ˆ ´ Quebec, ´ 2 Intermountain ENT, Salt Lake City, UT; 3 Advanced ENT & Allergy, Louisville, KY; 4 Central California ENT, Fresno, CA; 5 Colorado ENT & Allergy, Colorado Springs, CO
Correspondence to: Francois Lavigne, MD, FRCSC, Department of Otolaryngology, Centre hospitalier de l’Universite´ de Montreal ´ (CHUM), Hopital Notre-Dame, 1560 Sherbrooke St. E., Montreal, H2L 4M1, ˆ ´ Quebec, ´ Canada; e-mail: [email protected] Funding sources for the study: Intersect ENT provided funding for the investigation as well as administrative and logistical support in coordinating the study across the study sites. Potential conflict of interest: F.L. is a consultant, advisory board member, and minor shareholder at Intersect ENT. None of the other authors have anything to report. Received: 8 August 2013; Revised: 19 January 2014; Accepted: 23 January 2014 DOI: 10.1002/alr.21309 View this article online at wileyonlinelibrary.com.
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p = 0.008). Mean SNOT-22 score was significantly improved from 2.19 at baseline to 0.90 within 1 month (p = 0.001) and sustained to 6 months (1.03; p = 0.012). Sixtyfour percent of patients were no longer revision ESS candidates at 6 months. Conclusion: The study provided initial clinical evidence of the feasibility, safety, and efficacy of in-office steroideluting implant placement in CRS patients with recurrent polyposis aer ESS. Although further studies are needed, the results suggest this therapy may provide a safe and effective, office-based option for the treatment of obstrucC 2014 ARS-AAOA, LLC. tive polyposis.
Key Words: sinusitis; nasal congestion; nasal polyps; inflammation; functional endoscopic sinus surgery; FESS; corticosteroid; mometasone furoate; drug-eluting implant; bioabsorbable How to Cite this Article: Lavigne F, Miller SK, Gould AR, Lanier BJ, Rome JL. Steroid-eluting sinus implant for in-office treatment of recurrent nasal polyposis: a prospective, multicenter study. Int Forum Allergy Rhinol. 2014;4:381–389.
C
hronis rhinosinusitis with nasal polyposis (CRSwNP) is a distinct subtype of CRS with an estimated prevalence of 3% to 5%, with a greater burden of symptoms and a higher relapse rate after treatment, making this subtype more costly to manage.1, 2 Options for the management of CRSwNP are aggressive medical treatment, surgery, and combinations thereof. Patients who have been managed both medically and surgically but continue to present with recurrent polyposis and CRS symptomatology represent 1 of the otolaryngologist’s most perplexing and challenging patient populations. This recidivism leads to repeated rounds of corticosteroid therapy, off-label strategies for attempting to deliver medications to the sinus anatomy, or multiple revision surgeries. Although endoscopic sinus surgery (ESS) is now widely accepted for the treatment of inflammatory diseases of the paranasal sinuses, and particularly for patients with
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CRSwNP who have failed to respond to medical therapy, recurrence rates for patients with significant polyposis are higher than the general ESS population. Wynn and Har-El3 reported that 70 of 118 (60%) patients who underwent ESS for significant polyposis developed recurrent polyposis, and 55 (47%) were indicated for another revision ESS. Only 32 (58%) of those indicated for revision ESS elected to undergo the procedure again, illustrating the conundrum facing patients with CRSwNP, and reinforcing the need for development of additional therapeutic options for this population. The safety and efficacy of localized, controlled steroid delivery to the sinus mucosa from a bioabsorbable sinus implant have been demonstrated in the perioperative setting in 3 clinical studies and a meta-analysis.4–7 The present study evaluated the technical feasibility of in-office insertion of a steroid-eluting sinus implant and its initial safety and efficacy. The sinus implant used in this study was designed to dilate sinuses reobstructed by polyps and provide localized, controlled steroid delivery for 3 months to reestablish sinus patency. The study was conducted in CRSwNP patients who were candidates for revision surgery due to recurrent sinus polyposis and symptomatology that were refractory to medical therapy.
Patients and methods Device description A steroid-eluting sinus implant was supplied by Intersect ENT (Menlo Park, CA) for investigational use, and at the time of this manuscript was not for sale in the United States nor approved by the U.S. Food and Drug Administration (FDA). The implant has a self-expanding, non-obstructive design (Fig. 1) composed of a biodegradable polymer that allows it to adjust to fit in a previously-operated sinus cavity. This product is similar in concept to the previously R studied mometasone furoate–eluting implant (PROPEL steroid-eluting sinus implant; Intersect ENT), with some unique differences to allow for treatment of polyp patients. In order to dilate an obstructed sinus cavity, the implant has greater radial strength owing to its arched design. The arched design also aids in retention by maintaining strength and apposition in the cavity as polypoid tissue recedes. The rounded tip of the implant facilitates in-office insertion and placement in a polyp-filled cavity. The polymer matrix contains 1350 μg of mometasone furoate and provides for gradual release of the drug over 3 months. The combination of these attributes allows the implant to create and maintain an opening in the sinus both mechanically and medically.
Study design A prospective, multicenter, nonrandomized study was conducted at 4 private otolaryngology clinics in the United States between November 2011 and May 2012. The study protocol and informed consent form were reviewed and
IRB-approved for all study centers. All study patients provided written informed consent prior to study entry. Table 1 provides the schedule of assessments. Adult patients were included if they were at least 18 years old, had been diagnosed with chronic sinusitis and had undergone prior bilateral ethmoidectomy more than 90 days earlier. Patients had endoscopically confirmed recurrent ethmoid sinus obstruction due to polyposis or significant mucosal edema that was refractory to medical therapy. Polyposis was graded on a scale of 0 to 4. Patients were required to have at least grade 2 polyps on 1 side. Patients were required to be candidates for revision sinus surgery, defined as having a symptom burden consisting of 2 or more of the prominent symptoms of chronic sinusitis despite ongoing treatment with intranasal steroids, having received oral steroids within 6 months prior to enrollment, and having a known history of repeated oral steroid use for recurrent sinusitis. Patients were excluded if they had known history of intolerance to corticosteroids, an oral-steroid dependent condition (eg, chronic obstructive pulmonary disease [COPD]), history of immune deficiency, insulin dependent diabetes, clinical evidence of either acute bacterial sinusitis or invasive fungal sinusitis, or had previously undergone ESS and experienced a cerebrospinal fluid (CSF) leak or ocular complication in a prior ESS procedure. Leading up to the implant placement procedure, patients were required to have been continually using a topical steroid spray and were required to continue that regimen during the study follow-up period. Prior to enrollment, there was a 2-week restriction on the use of oral steroids or topical steroid irrigations. After implant placement, no oral steroids were allowed during the first 30 days unless medically necessary. Topical steroid irrigations were restricted for the first 90 days. Patients were permitted to continue stable regimens of orally-inhaled steroids and sinus-related medications (eg, Singulair [montelukast], leukotriene inhibitors [eg, Zileuton], immunotherapy, etc.) throughout the 90-day follow-up interval. Use of antibiotics was allowed at any time if sinus infection was suspected. The study implants were placed in the office setting using topical/local anesthesia consisting of spraying the nasal cavity with 4% lidocaine (or equivalent) and oxymetazoline nasal decongestant, followed by middle meatal placement of cottonoids or pledgets soaked in 4% lidocaine and decongestant solution. Local injection of the sinus tissue and nasal septum was permitted as necessary to ensure patient comfort. After the procedure, patients were encouraged to use saline sprays or irrigations as needed during follow-up. Follow-up visits involved endoscopic examination and grading, monitoring for adverse events, and completion of the 22-item Sino-Nasal Outcomes Test (SNOT-22; see Table 1). During the follow-up period, the implants were left in place to gradually soften and reabsorb, and could be removed at the discretion of the physician. Implant remnants remaining by day 60 were removed.
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FIGURE 1. Steroid-eluting sinus implant and endoscopic photographs from a study patient before and after placement. (A) Sinus implant, general view. (B) Left ethmoid sinus obstructed by polyposis before placement. (C) Same sinus immediately after placement. (D) Same sinus after 30 days. (E) Same sinus after 90 days.
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TABLE 1. Study schedule of assessments Assessments
Screening
Implant
Day 7
Day 14
Day 21
Day 30
Informed consent, medical history, and physical
X
Assess whether patient indicated for revision ESS
X
SNOT-22
X
X
X
X
X
Concomitant medications
X
X
X
X
X
Day 45
Day 60
Day 90
Month 6
X X
X
X
X
X
X
X
Review of adverse events
X
X
X
X
X
X
X
X
X
Endoscopic grading by clinician
X
X
X
X
X
X
X
X
X
ESS = functional endoscopic sinus surgery; SNOT-22 = 22-item Sino-Nasal Outcomes Test.
Safety was assessed by monitoring for device-related adverse events.
could range from 0 to 5. Patients were also asked about their perceptions of the in-office procedure and whether they would choose to have it again.
Endoscopic assessments Device performance and sinus evaluations were assessed by endoscopic examination. The evaluations were instantaneous on the day of each study visit and all endoscopic examinations were recorded. Prior to participation, clinicians participated in a training session on endoscopic grading that included photographic examples. A standardized case report form, containing endoscopic parameters that have been previously studied, was used for the endoscopic grading (Fig. 2).4–7 The percentage of stent remaining was also visually estimated at each time point.
Patient reported outcomes Patients were asked to assess their sinusitis symptoms using the SNOT-22. The scores were analyzed in a normalized manner, meaning that the total possible score for a patient
Surgical and medical interventions Clinicians reassessed patients using the same methodology as was done at study entry to determine whether they still met the criteria for revision surgery at 6 months. The criteria included whether the patients reported at least 2 of the hallmark chronic rhinosinusitis (CS) symptoms (nasal obstruction/blockage, postnasal discharge, thick nasal discharge, altered sense of smell/taste, facial pain/pressure) despite ongoing use of their topical intranasal spray, and had endoscopic findings consisting of persistent obstructive mucosal edema or bilateral polyposis (with 1 side being at least grade 2). The planned analysis related to medical interventions consisted of adverse event reporting and tabulation of
FIGURE 2. Representative endoscopic grading form. VAS for percent ethmoid sinus obstruction (not to scale in figure) is anchored as 0 = no obstruction and 100 mm = complete obstruction of ethmoid sinus by polyps/mucosal edema. Polyps graded as 0 = none; 1 = small amount of NPs confined to MM (clinically insignificant, not requiring treatment); 2 = expanded amount of NP confined to MM; 3 = NP extending beyond MM, within sphenoethmoid recess but not totally obstructing, or both; 4 = NP completely obstructing nasal cavity. Adhesions are graded as 0 = none; 1 = small but nonobstructing; 2 = obstructing but easily separated; 3 = dense and obstructing and separation is difficult; 4 = severe with complete adhesion of the middle turbinate to lateral nasal wall. MM = middle meatus; NP = nasal polyps; VAS = visual analogue scale.
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TABLE 2. Baseline demographics and clinical
the number of patients requiring some high-dose form of steroid therapy during the follow-up period.
characteristics* Age, years, mean (minimum, maximum)
Data analysis All data were entered into a validated database. Descriptive statistics and graphical summaries were used to summarize the data. For categorical variables, counts, percentages, and exact 95% confidence intervals using Clopper-Pearson’s method were calculated. For continuous variables, means, standard deviations (SDs), and 95% confidence intervals for the mean assuming a normal distribution were calculated. The Wilcoxon signed-rank p values for changes from baseline are presented, unless otherwise specified. Values of p 4
1 (8)
n = 12. Presented on a by-sinus count. ESS = functional endoscopic sinus surgery; SD = standard deviation. *
a
was removed at approximately 10 weeks. Twelve of the 23 implants were removed at day 60, per the study protocol. The majority of patients (8/11; 72.7%) described the sensation of pain/pressure during the implant placement procedure as mild or moderate. Nine of 11 patients (81.8%)
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FIGURE 4. Mean bilateral polyp grade at baseline before implant and through 6 months following placement. Error bars are 95% confidence intervals. All changes from baseline are statistically significant.
FIGURE 3. Disposition of study patients.
then described the sensation of pain/pressure after the implant placement procedure as none or minimal. Ten of 11 patients (90.9%) were either satisfied or very satisfied with the convenience of the office implant procedure in comparison to having another sinus surgery, and 10 of 11 patients (90.9%) described the recovery process as satisfactory or very satisfactory. Ten of 11 patients (90.9%) were satisfied or very satisfied with their overall experience with the procedure. When asked how the procedure compares to other in-office medical procedures (eg, dental), 6 of 11 patients (54.5%) said it was about the same. Nine of 11 patients (81.8%) said they would have the procedure again and 8 of 11 (72.7%) said they would recommend it to a family member or friend.
Safety No serious adverse events were reported during the study. Two device-related adverse events (nasal irritation on 1 side and ocular irritation with dryness and tearing on 1 side) were reported by the patient in whom the implants had been placed incorrectly. Both events resolved without sequelae after in-office removal of the implants. The protocol required that all patients continue the use of their topical steroid spray during the follow-up period through at least the day 90 time point. Two patients were prescribed additional higher-dose forms of steroids during the study follow-up period. The patient that had received the study implant on only 1 side had persistent polyposis and mucosal edema on the untreated side at day 21 and received a course of oral prednisone for 1 week. Another patient received the study implants bilaterally and responded well to the treatment. The patient was prescribed budesonide irrigations twice daily at approximately 4 months
due to recurrent rhinorrhea and asthma symptoms despite widely patent sinuses. In both patients, the SNOT-22 scores and bilateral polyp grades actually increased (worsened) slightly after these steroids were commenced. In order to analyze the sensitivity of the study conclusions to these 2 interventions, efficacy outcomes were analyzed both with and without inclusion of these patients’ post-steroid data points. All changes from baseline in bilateral polyp grades, percentage of ethmoid sinus obstruction, and SNOT-22 scores remained statistically significant using both analysis methods. In the results presented below, efficacy data at time points after steroid prescription were excluded for these 2 patients.
Efficacy Mean bilateral polyp grade at baseline was 4.50 ± 1.65 (Fig. 4). Within the first week, the mean bilateral polyp grade had been reduced to 2.80, representing a change from baseline of −1.70 (p = 0.0039). At days 30, 60, 90, and 6 months the mean bilateral polyp grades were 2.30, 2.10, 2.00, and 2.33, representing changes from baseline in mean bilateral polyp grade of −2.20, −2.40, −2.50, and −2.10 at these time points, respectively. All changes from baseline were statistically significant (p ࣘ 0.0078). The mean percentage of ethmoid sinus obstruction at baseline was 66.37% ± 29.41% and was reduced to 27.84% ± 32.81% at 6 months (p < 0.0007; Fig. 5). The average SNOT-22 score changed from 2.19 ± 1.03 at baseline to 1.48 ± 0.67 by day 7 (Fig. 6), representing a reduction of −0.71 (p = 0.0273). At days 30, 60, 90, and month 6 the average score was 0.90, 0.83, 0.74, and 1.03, respectively, representing changes from baseline of −1.28, −1.23, −1.32, and −0.99 at these time points. All changes from baseline were statistically (p ࣘ 0.0117) and clinically significant.10 The nasal blockage score was significantly (p ࣘ 0.0076) reduced from 3.45 at baseline to 1.82, 1.64, 1.20, 1.00, and 1.89, representing changes
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FIGURE 5. Mean percent ethmoid sinus obstruction at baseline before implant and through 6 months after placement. Error bars are 95% confidence intervals. All changes from baseline are statistically significant.
FIGURE 6. Mean total SNOT-22 scores at baseline before implant and through 6 months after placement. Error bars are 95% confidence intervals. All changes from baseline are statistically significant. SNOT-22 = 22-item Sino-Nasal Outcomes Test.
from baseline of −1.64, −1.82, −2.10, −2.30, and −1.33 at days 7, 30, 60, 90, and month 6, respectively. At month 6, bilateral polyp burden was reduced in 10 of the 11 (90.9%) evaluable patients, and 7 of the 11 patients (63.6%) were no longer considered to be candidates for revision sinus surgery based on the surgeon’s endoscopic evaluation and symptomatic improvement. One patient elected to have revision sinus surgery during the 6-month follow-up.
Discussion The results of the study demonstrated procedural technical success, patient tolerability, and initial significant clinical outcomes, suggesting that the drug-eluting sinus implant may provide an in-office treatment option for CRSwNP patients indicated for repeat surgery.
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Current treatment options for CRSwNP include topical steroid sprays, off-label use of topical steroid irrigations or drops, steroid injection into polyps, systemic steroids, and ESS to remove polyps and diseased mucosa. Regardless of the treatment, polyps have a strong tendency to reoccur, and therefore repeated courses of these medications and repeat ESS is often needed. Each of these treatment options and their repeated use present various concerns for patients and their managing otolaryngologists. Topical steroid sprays lack systemic side effects, but they do not sufficiently reach the middle meatus from which polyps originate11 and they have not been rigorously studied in postsurgical patients with recurrent polyposis. Use of topical steroid drops for 12 weeks in surgical candidates has been shown to reduce the need for sinus surgery compared to placebo, but more than one-half of treated patients still required surgery, and application of the steroid drops required awkward head-hanging positions to be performed daily by patients.12 Short courses of systemic steroid treatment have resulted in subjective and objective improvements with reduction in polyposis, but the effect is shortlived and recurrence is seen within 1 to 5 months.13, 14 Oral corticosteroids, especially with repeated use, pose systemic risks including aseptic necrosis of the femoral head, calcium demineralization, osteoporosis, posterior cataract formation, mood changes, and increases in blood glucose levels.15, 16 Vaidyanathan et al.17 studied oral steroids for 2 weeks followed by steroid drops for 2 months and then topical sprays for 4 months, as compared to placebo followed by steroid drops and then topical sprays. Although overall improvements were observed in the treatment group in both subjective and objective measures, the results were not statistically significantly different between groups after the first 10 weeks. Poor patient compliance can also compromise the effectiveness of any of these steroid regimens. This study was designed to evaluate the technical feasibility, safety, and efficacy of office-based insertion of a drug-eluting sinus implant in this patient population. It confirmed the tolerance of the implants in the sinus cavity, because they were not felt by patients once implanted. The implants are designed to provide long-term local steroidal therapy deep within the middle meatal/ethmoid sinus anatomy. We hypothesized that the design of the implant would physically dilate sinuses obstructed by polyps and mucosal edema, allowing for aeration and drainage, and would then maintain a physical opening in the sinus both medically and mechanically. The mechanical dilative pressure exerted by the implant compresses polyps, often breaking the membranous surface stroma, which may allow penetration of the steroid. The selection and engineering of the bioabsorbable polymers used to fabricate the implant provide a radial, dilating force that compresses polypoid tissue and medializes the middle turbinate, which are functions that allow the implant to be retained in the sinus anatomy to serve as a drug delivery platform. The longterm controlled delivery of the corticosteroid is intended to reduce polyposis and help to restore the sinus cavity to
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a normal phenotype over a clinically meaningful period of time, hence alleviating symptoms. The safety profile of the in-office sinus implant placement appears to be favorable, especially when considering the alternatives for this patient population. Only 2 device-related adverse events occurred and both were related to suboptimal placement of the implants. Minor adjustments to the treatment strategy, such as techniques for gauging the space available in the sinus, may eliminate the few placement difficulties encountered. Based on our experience, we expect that most patients will tolerate placement of the implants with use of topical anesthetic spray and placement of pledgets soaked in anesthetic, making the in-office procedure accessible to all otolaryngologists. Overall, the study patients tolerated the procedure well, were not able to feel the implants in the sinuses after placement, and the majority were very satisfied with their symptom improvements. The majority of patients said they would recommend this to a family member or friend. The implant placement success rate was 87.5% and supported high technical feasibility. Short-term results at day 7 appear to support that there was an immediate onset of action, which was sustained though 6 months. The statistically significant reductions in both objective (bilateral polyp grade, percentage of ethmoid sinus obstruction) and subjective outcome measures were observed at this first follow-up visit. Further improvements were observed at day 30 and the results were sustained through 6 months. Two patients were prescribed additional forms of steroid therapy during the follow-up period. Such medical interventions have the potential to confound interpretation of the study results. To address this concern, we analyzed efficacy outcomes both with and without inclusion of the data points after steroid prescription in these patients, and the results and conclusions remained the same. Future studies should employ similar analysis methodologies to assess the sensitivity of conclusions to these types of interventions. Given that all patients enrolled in the study were considered to be surgical revision candidates, the study results are quite promising. Nearly 64% of patients were no longer considered to be surgical candidates by the end of the study, and only 1 patient underwent revision sinus surgery within the 6-month follow-up period. This rate compares favorably to revision rates for ESS reported in the literature, which range from 9% to 13% within 9 months to 1 year.18–20 The 6-month follow-up period is reasonable, given the low-risk, minimally invasive treatment approach. A recent multicenter, longitudinal cohort study concluded that improvements in quality of life (QOL) after ESS do not appear to change between 6 and 20 months, indicating that 6 months is an appropriate follow-up timeframe for clinical study designs incorporating QOL outcomes after ESS.21 Our study used the SNOT-22 measure, which is a validated, disease-specific QOL instrument, and an accepted polyp grading scheme.8 The observed reductions from baseline (2.19) in mean normalized SNOT-22 score between 1 and 6 months ranged from −0.99 to −1.32, surpassing
the threshold of −0.8, which is accepted to be large and clinically meaningful.10 The reductions from baseline in bilateral polyp grade between 1 and 6 months were also clinically significant and ranged from −2.1 to −2.5. These improvements appear to compare favorably to other treatment modalities, both medical and surgical, reported in the literature. Mometasone furoate nasal spray (Nasonex) is currently the only topical steroid spray approved by the FDA for treatment of nasal polyposis. Primary efficacy outcome measures in 2 randomized placebo controlled trials were reported at 1 month: change from baseline in bilateral polyp grade in both studies was −0.96 with twice-daily dosing, and change from baseline in nasal congestion/obstruction was approximately −0.6.22, 23 Hissaria et al.14 reported on a randomized, double-blind, controlled trial in polyp patients comparing 2 weeks of oral prednisolone (50 mg 4 times daily) to placebo. Significant reductions in polyp grade and patient-reported outcomes were observed at 2 weeks. No further follow-up was described and the authors commented that the efficacy of systemic steroids for this indication is variable, ranging from 1 to 6 months. Additionally, the SNOT-22 results were comparable with disease and symptom reductions reported in the surgical literature. Browne et al.24 reported on a national audit conducted in 2256 patients in the United Kingdom that was performed to compare outcomes of all surgical units and surgeons performing ESS to relieve symptoms associated with CRS and nasal polyposis. The mean total preoperative normalized SNOT-22 score was 1.91. At 3 and 12 month follow-up, reductions of −1.16 and −0.65 were observed, respectively. Kuhn et al.25 assessed symptoms in 115 patients using the SNOT instrument before and after traditional ESS with concurrent balloon sinuplasty in patients with CRS. For the 84 patients with a complete dataset, the mean total preoperative SNOT score was 2.3 and the mean change from baseline in total score at 24 weeks was −1.171. The main limitations of our study design were the small sample size, lack of randomization, and lack of a concurrent control group. Therefore the potential contribution of placebo effect cannot be ruled out. Randomized, controlled, blinded clinical studies can address these limitations and provide further clinical evidence of the safety and efficacy of the in-office sinus implant strategy for patients with CRSwNP.
Conclusion The study results suggest that in-office placement of steroideluting sinus implants in patients with CRSwNP has the ability to improve objective and subjective outcome measures, which translated into elimination of the need for surgical revision in 64% of patients in a 6-month period. Although further studies are needed, the results suggest this therapy may provide a clinically effective and safe
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office-based alternative to revision surgery for the treatment of obstructive polyposis.
Acknowledgments We thank the research staff at the study centers for their time and contribution to this research study. We would especially like to acknowledge clinical research coordinators Holly Featherstone, CCRP (Intermountain ENT Special-
ists, Salt Lake City, UT), Kathleen Sheely (Advanced ENT and Allergy, Louisville, KY), JoAnn LoForti, RN (Central California ENT Medical Group, Fresno, CA), and Sharon Woodworth, RN, and Deborah Bothwell, CCRC (Colorado ENT & Allergy, Colorado Springs, CO). Finally, we thank Vicki Schreckengost, MSN, Sally Glauz, and Jennifer Slocum, for the professional support they provided to the clinical sites.
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tivity impairment instrument. Pharmacoeconomics. 1993;4:353–365. Piccirillo JF, Merritt MG, Richards ML. Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg. 2002;126:41–47. Hardy JG, Lee SW, Wilson CG. Intranasal drug delivery by spray and drops. J Pharm Pharmacol. 1985;37:294–297. Aukema A, Mulder P, Fokkens WJ. Treatment of nasal polyposis and chronic rhinosinusitis with fluticasone propionate nasal drops reduces need for sinus surgery. J Allergy Clin Immunol. 2005;115:1017–1023. van Camp C, Clement PA. Results of oral steroid treatment in nasal polyposis. Arch Otolaryngol Head Neck Surg. 1998;124:513–518. Hissaria P, Smith W, Wormald PJ, et. al. Short course of systemic corticosteroids in sinonasal polyposis: a double-blind, randomized, placebo-controlled trial with evaluation of outcome measures. J Allergy Clin Immunol. 2006;118:128–133. Murr AH, Goldberg AN, Vesper S. Fungal speciation using quantitative polymerase chain reaction (QPCR) in patients with and without chronic rhinosinusitis. Laryngoscope. 2006;116:1342–1348. Ferguson BJ, Otto BA, Pant H, When surgery, antibiotics, and steroids fail to resolve chronic rhinosinusitis. Immunol Allergy Clin North Am. 2009;29:719– 732. Vaidyanathan S, Barnes M, Williamson P, Hopkinson P, Donnan PT, Lipworth B. Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids. Ann Intern Med. 2011;154:293–302.
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18. Hoffman DF, May M, Mester SJ. Functional endoscopic sinus surgery—experience with the initial 100 patients. Am J Rhinol. 1990;4:129–132. 19. Jakobsen J, Svendstrup F. Functional endoscopic sinus surgery in chronic sinusitis—a series of 237 consecutively operated patients. Acta Otolaryngol Suppl. 2000;543:158–161. 20. Tran KN, Beule AG, Singal D, Wormald PJ. Frontal ostium restenosis after the endoscopic modified Lothrop procedure. Laryngoscope. 2007;117:1457– 1462. 21. Soler ZM, Smith TL. Quality-of-life outcomes after endoscopic sinus surgery: How long is long enough? Otolaryngol Head Neck Surg. 2010;143:621–625. 22. Stjarne P, Mosges R, Jorissen M, et.al. A randomized controlled trial of mometasone furoate nasal spray for the treatment of nasal polyposis. Arch Otolaryngol Head Neck Surg. 2006;132:179–185. 23. Small CB, Hernandez J, Reyes A, et.al. Efficacy and safety of mometasone furoate nasal spray in nasal polyposis. J Allergy Clin Immunol. 2005;116:1275– 1281. 24. Browne J, Hopkins C, Slack R, et al. The National Comparative Audit of Surgery for Nasal Polyposis and Chronic Rhinosinusitis. August 2003. London: Clinical Effectiveness Unit, Royal College of Surgeons of England. http://www.rcseng.ac.uk/publications/docs/nationalcomparative - audit - of - surgery - for - nasal - polyposisand-chronic-rhinosinusitis-final-report. Accessed February 5, 2014. 25. Kuhn FA, Church CA, Goldberg AN, et al. Balloon catheter sinusotomy: one-year follow-up—outcomes and role in functional endoscopic sinus surgery. Otolaryngol Head Neck Surg. 2008;139:S27-S37.
Steroid-eluting sinus implant for in-office treatment of recurrent nasal polyposis: a prospective, multicenter study Franc¸ois Lavigne, MD1 , Steven K. Miller, MD2 , Andrew R. Gould, MD3 , Brent J. Lanier, MD4 and J. Lewis Romett, MD5
Background: Treatment options for chronic rhinosinusitis with recurrent polyposis (CRSwNP) aer endoscopic sinus surgery (ESS) are limited, and include frequent use of systemic steroids and revision surgery. A bioabsorbable, steroid-eluting implant was studied for its ability to dilate sinuses obstructed by polyps and provide localized, controlled steroid delivery to reestablish sinus patency. This study assessed the initial feasibility, safety, and efficacy of steroid-eluting implants placed in the office seing in patients who were candidates for revision ESS. Methods: Prospective, multicenter study enrolling 12 patients who had prior ESS but experienced recurrent polyposis refractory to medical therapy. Implants were placed bilaterally under topical anesthesia in-office. Follow-up through 6 months included endoscopic grading, patientreported outcomes (22-item Sino-Nasal Outcomes Test [SNOT-22]) and need for revision ESS. Results: Implants were successfully inserted in 21 of 24 (88%) ethmoid sinuses, resulting in 11 evaluable patients. No serious adverse events occurred. Within 1 month, mean bilateral polyp grade was reduced from 4.5 at baseline to 2.3 (p = 0.008) and sustained through 6 months (2.33;
1 Department of Otolaryngology, Centre hospitalier de l’Universite ´ de Montreal Notre-Dame, Montreal, Canada; ´ (CHUM), Hopital ˆ ´ Quebec, ´ 2 Intermountain ENT, Salt Lake City, UT; 3 Advanced ENT & Allergy, Louisville, KY; 4 Central California ENT, Fresno, CA; 5 Colorado ENT & Allergy, Colorado Springs, CO
Correspondence to: Francois Lavigne, MD, FRCSC, Department of Otolaryngology, Centre hospitalier de l’Universite´ de Montreal ´ (CHUM), Hopital Notre-Dame, 1560 Sherbrooke St. E., Montreal, H2L 4M1, ˆ ´ Quebec, ´ Canada; e-mail: [email protected] Funding sources for the study: Intersect ENT provided funding for the investigation as well as administrative and logistical support in coordinating the study across the study sites. Potential conflict of interest: F.L. is a consultant, advisory board member, and minor shareholder at Intersect ENT. None of the other authors have anything to report. Received: 8 August 2013; Revised: 19 January 2014; Accepted: 23 January 2014 DOI: 10.1002/alr.21309 View this article online at wileyonlinelibrary.com.
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p = 0.008). Mean SNOT-22 score was significantly improved from 2.19 at baseline to 0.90 within 1 month (p = 0.001) and sustained to 6 months (1.03; p = 0.012). Sixtyfour percent of patients were no longer revision ESS candidates at 6 months. Conclusion: The study provided initial clinical evidence of the feasibility, safety, and efficacy of in-office steroideluting implant placement in CRS patients with recurrent polyposis aer ESS. Although further studies are needed, the results suggest this therapy may provide a safe and effective, office-based option for the treatment of obstrucC 2014 ARS-AAOA, LLC. tive polyposis.
Key Words: sinusitis; nasal congestion; nasal polyps; inflammation; functional endoscopic sinus surgery; FESS; corticosteroid; mometasone furoate; drug-eluting implant; bioabsorbable How to Cite this Article: Lavigne F, Miller SK, Gould AR, Lanier BJ, Rome JL. Steroid-eluting sinus implant for in-office treatment of recurrent nasal polyposis: a prospective, multicenter study. Int Forum Allergy Rhinol. 2014;4:381–389.
C
hronis rhinosinusitis with nasal polyposis (CRSwNP) is a distinct subtype of CRS with an estimated prevalence of 3% to 5%, with a greater burden of symptoms and a higher relapse rate after treatment, making this subtype more costly to manage.1, 2 Options for the management of CRSwNP are aggressive medical treatment, surgery, and combinations thereof. Patients who have been managed both medically and surgically but continue to present with recurrent polyposis and CRS symptomatology represent 1 of the otolaryngologist’s most perplexing and challenging patient populations. This recidivism leads to repeated rounds of corticosteroid therapy, off-label strategies for attempting to deliver medications to the sinus anatomy, or multiple revision surgeries. Although endoscopic sinus surgery (ESS) is now widely accepted for the treatment of inflammatory diseases of the paranasal sinuses, and particularly for patients with
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CRSwNP who have failed to respond to medical therapy, recurrence rates for patients with significant polyposis are higher than the general ESS population. Wynn and Har-El3 reported that 70 of 118 (60%) patients who underwent ESS for significant polyposis developed recurrent polyposis, and 55 (47%) were indicated for another revision ESS. Only 32 (58%) of those indicated for revision ESS elected to undergo the procedure again, illustrating the conundrum facing patients with CRSwNP, and reinforcing the need for development of additional therapeutic options for this population. The safety and efficacy of localized, controlled steroid delivery to the sinus mucosa from a bioabsorbable sinus implant have been demonstrated in the perioperative setting in 3 clinical studies and a meta-analysis.4–7 The present study evaluated the technical feasibility of in-office insertion of a steroid-eluting sinus implant and its initial safety and efficacy. The sinus implant used in this study was designed to dilate sinuses reobstructed by polyps and provide localized, controlled steroid delivery for 3 months to reestablish sinus patency. The study was conducted in CRSwNP patients who were candidates for revision surgery due to recurrent sinus polyposis and symptomatology that were refractory to medical therapy.
Patients and methods Device description A steroid-eluting sinus implant was supplied by Intersect ENT (Menlo Park, CA) for investigational use, and at the time of this manuscript was not for sale in the United States nor approved by the U.S. Food and Drug Administration (FDA). The implant has a self-expanding, non-obstructive design (Fig. 1) composed of a biodegradable polymer that allows it to adjust to fit in a previously-operated sinus cavity. This product is similar in concept to the previously R studied mometasone furoate–eluting implant (PROPEL steroid-eluting sinus implant; Intersect ENT), with some unique differences to allow for treatment of polyp patients. In order to dilate an obstructed sinus cavity, the implant has greater radial strength owing to its arched design. The arched design also aids in retention by maintaining strength and apposition in the cavity as polypoid tissue recedes. The rounded tip of the implant facilitates in-office insertion and placement in a polyp-filled cavity. The polymer matrix contains 1350 μg of mometasone furoate and provides for gradual release of the drug over 3 months. The combination of these attributes allows the implant to create and maintain an opening in the sinus both mechanically and medically.
Study design A prospective, multicenter, nonrandomized study was conducted at 4 private otolaryngology clinics in the United States between November 2011 and May 2012. The study protocol and informed consent form were reviewed and
IRB-approved for all study centers. All study patients provided written informed consent prior to study entry. Table 1 provides the schedule of assessments. Adult patients were included if they were at least 18 years old, had been diagnosed with chronic sinusitis and had undergone prior bilateral ethmoidectomy more than 90 days earlier. Patients had endoscopically confirmed recurrent ethmoid sinus obstruction due to polyposis or significant mucosal edema that was refractory to medical therapy. Polyposis was graded on a scale of 0 to 4. Patients were required to have at least grade 2 polyps on 1 side. Patients were required to be candidates for revision sinus surgery, defined as having a symptom burden consisting of 2 or more of the prominent symptoms of chronic sinusitis despite ongoing treatment with intranasal steroids, having received oral steroids within 6 months prior to enrollment, and having a known history of repeated oral steroid use for recurrent sinusitis. Patients were excluded if they had known history of intolerance to corticosteroids, an oral-steroid dependent condition (eg, chronic obstructive pulmonary disease [COPD]), history of immune deficiency, insulin dependent diabetes, clinical evidence of either acute bacterial sinusitis or invasive fungal sinusitis, or had previously undergone ESS and experienced a cerebrospinal fluid (CSF) leak or ocular complication in a prior ESS procedure. Leading up to the implant placement procedure, patients were required to have been continually using a topical steroid spray and were required to continue that regimen during the study follow-up period. Prior to enrollment, there was a 2-week restriction on the use of oral steroids or topical steroid irrigations. After implant placement, no oral steroids were allowed during the first 30 days unless medically necessary. Topical steroid irrigations were restricted for the first 90 days. Patients were permitted to continue stable regimens of orally-inhaled steroids and sinus-related medications (eg, Singulair [montelukast], leukotriene inhibitors [eg, Zileuton], immunotherapy, etc.) throughout the 90-day follow-up interval. Use of antibiotics was allowed at any time if sinus infection was suspected. The study implants were placed in the office setting using topical/local anesthesia consisting of spraying the nasal cavity with 4% lidocaine (or equivalent) and oxymetazoline nasal decongestant, followed by middle meatal placement of cottonoids or pledgets soaked in 4% lidocaine and decongestant solution. Local injection of the sinus tissue and nasal septum was permitted as necessary to ensure patient comfort. After the procedure, patients were encouraged to use saline sprays or irrigations as needed during follow-up. Follow-up visits involved endoscopic examination and grading, monitoring for adverse events, and completion of the 22-item Sino-Nasal Outcomes Test (SNOT-22; see Table 1). During the follow-up period, the implants were left in place to gradually soften and reabsorb, and could be removed at the discretion of the physician. Implant remnants remaining by day 60 were removed.
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FIGURE 1. Steroid-eluting sinus implant and endoscopic photographs from a study patient before and after placement. (A) Sinus implant, general view. (B) Left ethmoid sinus obstructed by polyposis before placement. (C) Same sinus immediately after placement. (D) Same sinus after 30 days. (E) Same sinus after 90 days.
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TABLE 1. Study schedule of assessments Assessments
Screening
Implant
Day 7
Day 14
Day 21
Day 30
Informed consent, medical history, and physical
X
Assess whether patient indicated for revision ESS
X
SNOT-22
X
X
X
X
X
Concomitant medications
X
X
X
X
X
Day 45
Day 60
Day 90
Month 6
X X
X
X
X
X
X
X
Review of adverse events
X
X
X
X
X
X
X
X
X
Endoscopic grading by clinician
X
X
X
X
X
X
X
X
X
ESS = functional endoscopic sinus surgery; SNOT-22 = 22-item Sino-Nasal Outcomes Test.
Safety was assessed by monitoring for device-related adverse events.
could range from 0 to 5. Patients were also asked about their perceptions of the in-office procedure and whether they would choose to have it again.
Endoscopic assessments Device performance and sinus evaluations were assessed by endoscopic examination. The evaluations were instantaneous on the day of each study visit and all endoscopic examinations were recorded. Prior to participation, clinicians participated in a training session on endoscopic grading that included photographic examples. A standardized case report form, containing endoscopic parameters that have been previously studied, was used for the endoscopic grading (Fig. 2).4–7 The percentage of stent remaining was also visually estimated at each time point.
Patient reported outcomes Patients were asked to assess their sinusitis symptoms using the SNOT-22. The scores were analyzed in a normalized manner, meaning that the total possible score for a patient
Surgical and medical interventions Clinicians reassessed patients using the same methodology as was done at study entry to determine whether they still met the criteria for revision surgery at 6 months. The criteria included whether the patients reported at least 2 of the hallmark chronic rhinosinusitis (CS) symptoms (nasal obstruction/blockage, postnasal discharge, thick nasal discharge, altered sense of smell/taste, facial pain/pressure) despite ongoing use of their topical intranasal spray, and had endoscopic findings consisting of persistent obstructive mucosal edema or bilateral polyposis (with 1 side being at least grade 2). The planned analysis related to medical interventions consisted of adverse event reporting and tabulation of
FIGURE 2. Representative endoscopic grading form. VAS for percent ethmoid sinus obstruction (not to scale in figure) is anchored as 0 = no obstruction and 100 mm = complete obstruction of ethmoid sinus by polyps/mucosal edema. Polyps graded as 0 = none; 1 = small amount of NPs confined to MM (clinically insignificant, not requiring treatment); 2 = expanded amount of NP confined to MM; 3 = NP extending beyond MM, within sphenoethmoid recess but not totally obstructing, or both; 4 = NP completely obstructing nasal cavity. Adhesions are graded as 0 = none; 1 = small but nonobstructing; 2 = obstructing but easily separated; 3 = dense and obstructing and separation is difficult; 4 = severe with complete adhesion of the middle turbinate to lateral nasal wall. MM = middle meatus; NP = nasal polyps; VAS = visual analogue scale.
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TABLE 2. Baseline demographics and clinical
the number of patients requiring some high-dose form of steroid therapy during the follow-up period.
characteristics* Age, years, mean (minimum, maximum)
Data analysis All data were entered into a validated database. Descriptive statistics and graphical summaries were used to summarize the data. For categorical variables, counts, percentages, and exact 95% confidence intervals using Clopper-Pearson’s method were calculated. For continuous variables, means, standard deviations (SDs), and 95% confidence intervals for the mean assuming a normal distribution were calculated. The Wilcoxon signed-rank p values for changes from baseline are presented, unless otherwise specified. Values of p 4
1 (8)
n = 12. Presented on a by-sinus count. ESS = functional endoscopic sinus surgery; SD = standard deviation. *
a
was removed at approximately 10 weeks. Twelve of the 23 implants were removed at day 60, per the study protocol. The majority of patients (8/11; 72.7%) described the sensation of pain/pressure during the implant placement procedure as mild or moderate. Nine of 11 patients (81.8%)
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FIGURE 4. Mean bilateral polyp grade at baseline before implant and through 6 months following placement. Error bars are 95% confidence intervals. All changes from baseline are statistically significant.
FIGURE 3. Disposition of study patients.
then described the sensation of pain/pressure after the implant placement procedure as none or minimal. Ten of 11 patients (90.9%) were either satisfied or very satisfied with the convenience of the office implant procedure in comparison to having another sinus surgery, and 10 of 11 patients (90.9%) described the recovery process as satisfactory or very satisfactory. Ten of 11 patients (90.9%) were satisfied or very satisfied with their overall experience with the procedure. When asked how the procedure compares to other in-office medical procedures (eg, dental), 6 of 11 patients (54.5%) said it was about the same. Nine of 11 patients (81.8%) said they would have the procedure again and 8 of 11 (72.7%) said they would recommend it to a family member or friend.
Safety No serious adverse events were reported during the study. Two device-related adverse events (nasal irritation on 1 side and ocular irritation with dryness and tearing on 1 side) were reported by the patient in whom the implants had been placed incorrectly. Both events resolved without sequelae after in-office removal of the implants. The protocol required that all patients continue the use of their topical steroid spray during the follow-up period through at least the day 90 time point. Two patients were prescribed additional higher-dose forms of steroids during the study follow-up period. The patient that had received the study implant on only 1 side had persistent polyposis and mucosal edema on the untreated side at day 21 and received a course of oral prednisone for 1 week. Another patient received the study implants bilaterally and responded well to the treatment. The patient was prescribed budesonide irrigations twice daily at approximately 4 months
due to recurrent rhinorrhea and asthma symptoms despite widely patent sinuses. In both patients, the SNOT-22 scores and bilateral polyp grades actually increased (worsened) slightly after these steroids were commenced. In order to analyze the sensitivity of the study conclusions to these 2 interventions, efficacy outcomes were analyzed both with and without inclusion of these patients’ post-steroid data points. All changes from baseline in bilateral polyp grades, percentage of ethmoid sinus obstruction, and SNOT-22 scores remained statistically significant using both analysis methods. In the results presented below, efficacy data at time points after steroid prescription were excluded for these 2 patients.
Efficacy Mean bilateral polyp grade at baseline was 4.50 ± 1.65 (Fig. 4). Within the first week, the mean bilateral polyp grade had been reduced to 2.80, representing a change from baseline of −1.70 (p = 0.0039). At days 30, 60, 90, and 6 months the mean bilateral polyp grades were 2.30, 2.10, 2.00, and 2.33, representing changes from baseline in mean bilateral polyp grade of −2.20, −2.40, −2.50, and −2.10 at these time points, respectively. All changes from baseline were statistically significant (p ࣘ 0.0078). The mean percentage of ethmoid sinus obstruction at baseline was 66.37% ± 29.41% and was reduced to 27.84% ± 32.81% at 6 months (p < 0.0007; Fig. 5). The average SNOT-22 score changed from 2.19 ± 1.03 at baseline to 1.48 ± 0.67 by day 7 (Fig. 6), representing a reduction of −0.71 (p = 0.0273). At days 30, 60, 90, and month 6 the average score was 0.90, 0.83, 0.74, and 1.03, respectively, representing changes from baseline of −1.28, −1.23, −1.32, and −0.99 at these time points. All changes from baseline were statistically (p ࣘ 0.0117) and clinically significant.10 The nasal blockage score was significantly (p ࣘ 0.0076) reduced from 3.45 at baseline to 1.82, 1.64, 1.20, 1.00, and 1.89, representing changes
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FIGURE 5. Mean percent ethmoid sinus obstruction at baseline before implant and through 6 months after placement. Error bars are 95% confidence intervals. All changes from baseline are statistically significant.
FIGURE 6. Mean total SNOT-22 scores at baseline before implant and through 6 months after placement. Error bars are 95% confidence intervals. All changes from baseline are statistically significant. SNOT-22 = 22-item Sino-Nasal Outcomes Test.
from baseline of −1.64, −1.82, −2.10, −2.30, and −1.33 at days 7, 30, 60, 90, and month 6, respectively. At month 6, bilateral polyp burden was reduced in 10 of the 11 (90.9%) evaluable patients, and 7 of the 11 patients (63.6%) were no longer considered to be candidates for revision sinus surgery based on the surgeon’s endoscopic evaluation and symptomatic improvement. One patient elected to have revision sinus surgery during the 6-month follow-up.
Discussion The results of the study demonstrated procedural technical success, patient tolerability, and initial significant clinical outcomes, suggesting that the drug-eluting sinus implant may provide an in-office treatment option for CRSwNP patients indicated for repeat surgery.
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Current treatment options for CRSwNP include topical steroid sprays, off-label use of topical steroid irrigations or drops, steroid injection into polyps, systemic steroids, and ESS to remove polyps and diseased mucosa. Regardless of the treatment, polyps have a strong tendency to reoccur, and therefore repeated courses of these medications and repeat ESS is often needed. Each of these treatment options and their repeated use present various concerns for patients and their managing otolaryngologists. Topical steroid sprays lack systemic side effects, but they do not sufficiently reach the middle meatus from which polyps originate11 and they have not been rigorously studied in postsurgical patients with recurrent polyposis. Use of topical steroid drops for 12 weeks in surgical candidates has been shown to reduce the need for sinus surgery compared to placebo, but more than one-half of treated patients still required surgery, and application of the steroid drops required awkward head-hanging positions to be performed daily by patients.12 Short courses of systemic steroid treatment have resulted in subjective and objective improvements with reduction in polyposis, but the effect is shortlived and recurrence is seen within 1 to 5 months.13, 14 Oral corticosteroids, especially with repeated use, pose systemic risks including aseptic necrosis of the femoral head, calcium demineralization, osteoporosis, posterior cataract formation, mood changes, and increases in blood glucose levels.15, 16 Vaidyanathan et al.17 studied oral steroids for 2 weeks followed by steroid drops for 2 months and then topical sprays for 4 months, as compared to placebo followed by steroid drops and then topical sprays. Although overall improvements were observed in the treatment group in both subjective and objective measures, the results were not statistically significantly different between groups after the first 10 weeks. Poor patient compliance can also compromise the effectiveness of any of these steroid regimens. This study was designed to evaluate the technical feasibility, safety, and efficacy of office-based insertion of a drug-eluting sinus implant in this patient population. It confirmed the tolerance of the implants in the sinus cavity, because they were not felt by patients once implanted. The implants are designed to provide long-term local steroidal therapy deep within the middle meatal/ethmoid sinus anatomy. We hypothesized that the design of the implant would physically dilate sinuses obstructed by polyps and mucosal edema, allowing for aeration and drainage, and would then maintain a physical opening in the sinus both medically and mechanically. The mechanical dilative pressure exerted by the implant compresses polyps, often breaking the membranous surface stroma, which may allow penetration of the steroid. The selection and engineering of the bioabsorbable polymers used to fabricate the implant provide a radial, dilating force that compresses polypoid tissue and medializes the middle turbinate, which are functions that allow the implant to be retained in the sinus anatomy to serve as a drug delivery platform. The longterm controlled delivery of the corticosteroid is intended to reduce polyposis and help to restore the sinus cavity to
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a normal phenotype over a clinically meaningful period of time, hence alleviating symptoms. The safety profile of the in-office sinus implant placement appears to be favorable, especially when considering the alternatives for this patient population. Only 2 device-related adverse events occurred and both were related to suboptimal placement of the implants. Minor adjustments to the treatment strategy, such as techniques for gauging the space available in the sinus, may eliminate the few placement difficulties encountered. Based on our experience, we expect that most patients will tolerate placement of the implants with use of topical anesthetic spray and placement of pledgets soaked in anesthetic, making the in-office procedure accessible to all otolaryngologists. Overall, the study patients tolerated the procedure well, were not able to feel the implants in the sinuses after placement, and the majority were very satisfied with their symptom improvements. The majority of patients said they would recommend this to a family member or friend. The implant placement success rate was 87.5% and supported high technical feasibility. Short-term results at day 7 appear to support that there was an immediate onset of action, which was sustained though 6 months. The statistically significant reductions in both objective (bilateral polyp grade, percentage of ethmoid sinus obstruction) and subjective outcome measures were observed at this first follow-up visit. Further improvements were observed at day 30 and the results were sustained through 6 months. Two patients were prescribed additional forms of steroid therapy during the follow-up period. Such medical interventions have the potential to confound interpretation of the study results. To address this concern, we analyzed efficacy outcomes both with and without inclusion of the data points after steroid prescription in these patients, and the results and conclusions remained the same. Future studies should employ similar analysis methodologies to assess the sensitivity of conclusions to these types of interventions. Given that all patients enrolled in the study were considered to be surgical revision candidates, the study results are quite promising. Nearly 64% of patients were no longer considered to be surgical candidates by the end of the study, and only 1 patient underwent revision sinus surgery within the 6-month follow-up period. This rate compares favorably to revision rates for ESS reported in the literature, which range from 9% to 13% within 9 months to 1 year.18–20 The 6-month follow-up period is reasonable, given the low-risk, minimally invasive treatment approach. A recent multicenter, longitudinal cohort study concluded that improvements in quality of life (QOL) after ESS do not appear to change between 6 and 20 months, indicating that 6 months is an appropriate follow-up timeframe for clinical study designs incorporating QOL outcomes after ESS.21 Our study used the SNOT-22 measure, which is a validated, disease-specific QOL instrument, and an accepted polyp grading scheme.8 The observed reductions from baseline (2.19) in mean normalized SNOT-22 score between 1 and 6 months ranged from −0.99 to −1.32, surpassing
the threshold of −0.8, which is accepted to be large and clinically meaningful.10 The reductions from baseline in bilateral polyp grade between 1 and 6 months were also clinically significant and ranged from −2.1 to −2.5. These improvements appear to compare favorably to other treatment modalities, both medical and surgical, reported in the literature. Mometasone furoate nasal spray (Nasonex) is currently the only topical steroid spray approved by the FDA for treatment of nasal polyposis. Primary efficacy outcome measures in 2 randomized placebo controlled trials were reported at 1 month: change from baseline in bilateral polyp grade in both studies was −0.96 with twice-daily dosing, and change from baseline in nasal congestion/obstruction was approximately −0.6.22, 23 Hissaria et al.14 reported on a randomized, double-blind, controlled trial in polyp patients comparing 2 weeks of oral prednisolone (50 mg 4 times daily) to placebo. Significant reductions in polyp grade and patient-reported outcomes were observed at 2 weeks. No further follow-up was described and the authors commented that the efficacy of systemic steroids for this indication is variable, ranging from 1 to 6 months. Additionally, the SNOT-22 results were comparable with disease and symptom reductions reported in the surgical literature. Browne et al.24 reported on a national audit conducted in 2256 patients in the United Kingdom that was performed to compare outcomes of all surgical units and surgeons performing ESS to relieve symptoms associated with CRS and nasal polyposis. The mean total preoperative normalized SNOT-22 score was 1.91. At 3 and 12 month follow-up, reductions of −1.16 and −0.65 were observed, respectively. Kuhn et al.25 assessed symptoms in 115 patients using the SNOT instrument before and after traditional ESS with concurrent balloon sinuplasty in patients with CRS. For the 84 patients with a complete dataset, the mean total preoperative SNOT score was 2.3 and the mean change from baseline in total score at 24 weeks was −1.171. The main limitations of our study design were the small sample size, lack of randomization, and lack of a concurrent control group. Therefore the potential contribution of placebo effect cannot be ruled out. Randomized, controlled, blinded clinical studies can address these limitations and provide further clinical evidence of the safety and efficacy of the in-office sinus implant strategy for patients with CRSwNP.
Conclusion The study results suggest that in-office placement of steroideluting sinus implants in patients with CRSwNP has the ability to improve objective and subjective outcome measures, which translated into elimination of the need for surgical revision in 64% of patients in a 6-month period. Although further studies are needed, the results suggest this therapy may provide a clinically effective and safe
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office-based alternative to revision surgery for the treatment of obstructive polyposis.
Acknowledgments We thank the research staff at the study centers for their time and contribution to this research study. We would especially like to acknowledge clinical research coordinators Holly Featherstone, CCRP (Intermountain ENT Special-
ists, Salt Lake City, UT), Kathleen Sheely (Advanced ENT and Allergy, Louisville, KY), JoAnn LoForti, RN (Central California ENT Medical Group, Fresno, CA), and Sharon Woodworth, RN, and Deborah Bothwell, CCRC (Colorado ENT & Allergy, Colorado Springs, CO). Finally, we thank Vicki Schreckengost, MSN, Sally Glauz, and Jennifer Slocum, for the professional support they provided to the clinical sites.
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