Effects of Singulair (Montelukast) Treatment for Capsular Contracture

Breast Surgery Effects of Singulair (Montelukast) Treatment for Capsular Contracture Catherine K. Huang, MD; and Neal Handel, MD Aesthetic Surgery Journal 30(3) 404 410 2010 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: http://www.sagepub.com/ journalspermissions.nav DOI: 10.1177/1090820X10374724 www.aestheticsurgeryjournal.com Abstract Background: Capsular contracture (CC) is one of the most common complications of breast augmentation surgery. Leukotrienes are implicated in the inflammatory cascade and have been postulated to be involved in the formation of CC. Therefore, leukotriene antagonists Accolate and Singulair have been prescribed by plastic surgeons off-label to treat and prevent CC. To date, there are no studies investigating the efficacy of Singulair on CC. Objective: The authors retrospectively review a series of patients treated with Singulair to determine whether it improves CC after breast implant surgery. Methods: Nineteen patients treated with Singulair by the senior surgeon (NH) after implant placement from March 2006 to November 2009 were included in this study. Follow-up on Singulair efficacy was obtained by a combination of office chart review and standardized telephone questionnaire. Results were characterized as improvement, improvement, no change, or worse. Results: Seventeen patients presented with CC resulting from a variety of breast operations. Two patients who had a history of recurrent CC were prescribed Singulair prophylactically immediately after surgery. Twenty-one breasts with existing CC were included in the total. Two (11%) patients became worse, three (16%) patients had no change, five (26%) improved, seven (37%) ly improved, and two (11%) were prevented from having CC formation. Conclusion: Our preliminary study shows that Singulair improves CC. Breasts with mild CC (Baker score < III) appeared to have better improvement with Singulair compared to those with more severe contracture (Baker score III and IV). Singulair is well tolerated with minimal side effects and can be administered to patients after breast implant surgery to improve CC. Keywords capsular contracture, Singulair, breast augmentation, breast implants, complications Capsular contracture (CC) is one of the most frequent and troublesome complications of cosmetic breast augmentation. It is widely held that newer generation implants result in lower contracture rates than their predecessors. 1 However, even with modern devices, there is a significant incidence of CC. Cumulative six-year data reported to the Food and Drug Administration (FDA) by Mentor Corporation revealed that 7.7% of patients receiving saline implants and 9.8% of patients receiving cohesive silicone gel implants for augmentation developed Baker III or IV contracture. Often, correction of CC requires reoperation. The cause of CC is multifactorial; etiological factors that may contribute include implant surface texture, 2,3 anatomic placement, 4 bacterial contamination with formation of biofilms, 5 and intraoperative complications such as hematomas. Any of these factors may contribute to activation or prolongation of the inflammatory response, resulting in an exaggerated foreign body reaction around the implant. 6 Leukotrienes namely, LTC 4, LTD 4, and LTE 4 are implicated in the inflammatory cascade and have been postulated to play a role in the development of CC. Histologic analysis of contracted (Baker score II-IV) capsules revealed up-regulation of one of the leukotriene receptors (cyslt1), as compared to controls. 7 There are two leukotriene antagonists zafirlukast (Accolate; AstraZeneca Pharmaceuticals, Wilmington, Delaware) and montelukast (Singulair; Merck & Co, West Point, Pennsylvania). Accolate inhibits all three leukotrienes and Singulair inhibits LTD 4, which is the most active of the leukotrienes. 8,9 Accolate and Singulair are both FDA approved for the treatment of asthma. In 2002, Schlesinger et al 10 proposed the application of Accolate to treat and prevent CC after breast augmentation; since then, some plastic surgeons have adopted off-label prescription of these drugs either to prevent or to treat contracture. From the Division of Plastic and Reconstructive Surgery, David Geffen School of Medicine at University of California, Los Angeles, California. Corresponding Author: Neal Handel, MD, FACS, 13400 Riverside Drive, Suite #101, Sherman Oaks, CA 91423, USA. E-mail: drhandel@aol.com

Huang and Handel 405 Most research on the efficacy of leukotriene antagonists has been with Accolate. Two recent studies in a rat model showed that administration of Accolate in the presence of textured silicone implants resulted in a statistically significant decrease in mean capsule thickness when compared to controls. 11,12 There was, however, no difference in capsule thickness with smooth implants. 12 In a prospective study that measured mammary compliance, Scuderi et al 13 found an increase in breast compliance of up to 24% after six months in patients treated with Accolate compared to controls. In another study, Reid et al 14 found that 55% of patients with CC had resolution of symptoms and 24% had partial reduction of symptoms after taking Accolate for six months. In recent years, however, the use of Accolate has largely been abandoned because of potential adverse effects on the liver. In 2003, Gryskiewicz 9,15 described 867 adverse events reported by the Center for Drug Evaluation and Research, including 66 cases of hepatitis or liver failure (two requiring liver transplants) and 12 deaths. His editorial in Plastic and Reconstructive Surgery recommended strongly against the use of Accolate because of these potentially harmful side effects. 15 As a consequence, Singulair has become popular as an alternative leukotriene antagonist for treatment of CC. However, there are no published studies investigating the efficacy of Singulair in treating or preventing CC. METHODS This study included 19 breast implant recipients treated with Singulair by the senior surgeon (NH) between March 2006 and November 2009; 17 of these patients presented to the clinic with CC and two were treated prophylactically because of a history of CC. Four of the 17 patients with CC had had bilateral contracture, for a total of 21 breasts treated for existing CC (defined as Baker score II or greater). All patients were informed of possible risks associated with the off-label application of Singulair. Patients were prescribed 10 mg of Singulair for 90 days and instructed to massage their breasts twice daily. Follow-up of patient compliance and treatment results was obtained by a combination of chart review and a standardized telephone questionnaire. Patient race and age were noted, along with the indication for surgery and previous breast implant history. Implant size, type, position (submammary vs subpectoral), and operative incision were recorded. Breast firmness was assessed by the senior surgeon (NH) according to the Baker classification. The time interval from implantation to contracture was determined, as was the time that elapsed between development of contracture and initiation of Singulair treatment. It was also noted whether patients had subsequent revision surgery. Telephone interviews were used to determine the actual duration and dose of Singulair taken by the patient and whether the patient noted improvement, no change, or worsening of contracture. Statistical analysis was performed by the UCLA Department of Biomathematics. Improvement was analyzed with the Wilcoxon signed rank test. To assess whether Baker grade affected response, each breast (n = 21) was placed into a low Baker score group (score greater than I and less than or equal to II) or a high Baker score group (score III or IV). Outcome of the treatments was assigned as follows: 0 = worsened, 1 = no change, 2 = improved, and 3 = ly resolved. The nonparametric Kruskal-Wallis test for ordered outcome determined whether implant position (submammary vs subpectoral) had any statistical correlation. RESULTS From March 2006 to November 2008, the senior author selected 19 patients (21 breasts) who presented with CC for treatment with Singulair. Two patients who had a history of recurrent CC were given Singulair prophylactically immediately after surgery. Follow-up ranged from five to 36 months (mean, 19 months). The mean patient age was 44.2 years. Three patients were Hispanic and 16 were Caucasian. Those patients treated for established contracture had undergone a variety of procedures. Two patients had primary augmentation with, one patient had breast reconstruction with implants for asymmetry after melanoma excision, four patients had an implant exchange, two had capsulotomy to revise the breast implant pocket, and the remaining 10 had secondary revision surgery with (Table 1). Of the 10 patients undergoing revision surgery, four had bilateral silicone implant rupture. Eleven of the patients had undergone previous breast revision. All of the patients except one had Mentor memory gel smooth implants; the additional patient had a Mentor saline implant. The senior author inserted all of the original implants. Twelve patients had moderate-profile silicone implants and six patients had high-profile implants. The average volume was 450 cc. Six patients had their implants placed subpectorally and 13 had them placed in the submammary plane. CC occurred from 10 to 472 days postoperatively (mean, 162 days). A regimen of Singulair was begun immediately upon detection of CC in 16 patients; one patient had CC for 8.5 months before beginning Singulair treatment and two patients used it immediately after surgery prophylactically. Our follow-up data showed that in two (11%) patients, the CC worsened, three (16%) patients had no change, five (26%) improved, and seven (37%) ly resolved. The two (11%) patients who received Singulair prophylactically were prevented from developing CC (Table 2). The four patients who had bilateral CC had the same results bilaterally. Of those four, two patients had no change in both breasts, one patient improved, and one patient worsened. Based on the assumption that CC does not improve without treatment, 16 Singulair significantly improved CC (P <.05). Of the 12 patients who had improvement of their contracture, eight patients noticed improvement within days. Three patients reported that a month elapsed until they noticed improvement and one patient reported improvement after two months. Five patients had revision surgery that involved

406 Aesthetic Surgery Journal 30(3) Table 1. Patient Demographics Patient Age, y Race Indication Previous Surgeries Size Incision Position 1 48 W D2 B, 2 41 W D2 B, 3 39 H A crescent and aug 1981 primary aug 1991 primary aug, 2002, RR None 250 cc B Mentor saline 250 cc 500 cc 4 18 H A Binelli and aug None 400 cc 5 32 W C sec rev B 1993 primary capsulotomy aug, 1993 RR, 600 cc 6 42 W D sec rev bilateral 7 55 W D sec rev bilateral 8 39 W B implant exchange, 9 61 W D sec rev B, 10 51 W D2 B 11 39 W D sec rev surg R partial, L total, 12 55 W D sec rev B, 2003 RR 2004 primary aug 1988 2005 8-10 RR for capsular contracture 1994 primary aug, 2005 RR 1984 primary aug, 2001 RR, 2007 RR 1980s 2007 multiple RR and 1988 primary aug, 1989 RR, 2004 RR, 2005 RR 1977- primary aug, 1995 RR 13 48 W B implant exchange 1986 primary aug, 1992 RR, 2007 RR 14 34 W C capsulotomy 1998 primary aug, 2007 RR 15 46 H B implant exchange, 2004 breast aug 16 51 W E breast 2005 lumpectomy reconstruction after melanoma 17 48 W D sec rev bilateral 18 54 W D2 B 19 38 W B implant exchange, 1991 primary aug 1992 primary aug, 1996 RR 2005 primary aug 550 cc 375 cc 450 cc 700 cc R Mentor MP 300 cc L Mentor MP 325 cc 450 cc 500 cc 550 cc 350 cc 700 cc 350 cc 600 cc 375 cc 275 cc Binelli Vertical Inframmary Inframmary Wise pattern Wise pattern Indications: A = primary aug; B = implant exchange; C = capsulotomy; D = with replacement; D2 = ruptured implant, with replacement; E = reconstructive surgery. Previous surgeries: RR = revision and replacement of breast implants. Size: Mentor MP = Mentor silicone implant moderate plus profile; Mentor HP = Mentor silicone implant high profile.

Huang and Handel 407 Table 2. Patient Results Patient Tx Duration, d Side and Baker Grade Result Time to Improvement Revision Surgery? 1 30 R II Completely improved Within days 2 21 L I/II Completely improved Within days 3 60 R II/III, L III/IV No change Yes 4 90 R II Completely improved Within days 5 30 L II Completely improved One month 6 90 L II Completely Improved Two months 7 150 Prevented Prophylactic 8 180 Prevented Prophylactic 9 90 R II Worsened Scheduling 10 90 R II/III, L I/II Improved One month Yes 11 60 L III Improved One month Scheduling 12 10 R III/IV No change Yes 13 90 L IV Improved Within days Yes 14 90 R III, L IV Worsened Yes 15 60 R II, L IV No change Scheduling 16 90 L III/IV Improved Within days Scheduling 17 90 R III Improved Within days Scheduling 18 180 R I/II Completely improved Within days 19 90 L II Completely improved Within days Tx duration = time in days that Singular was administered. Completely improved = return to Baker class I. with implant replacement. One patient without CC had revision surgery for a size change and five patients were scheduling revision surgery for their contracture at the time this article was prepared. Nine patients were happy with their result and did not feel the need for any additional surgery. Of the 21 breasts treated for existing CC, Baker scores ranged from greater than I (but less than II) to IV. Breasts with mild CC (Baker score of less than III) had significantly greater improvement with Singulair than breasts with severe CC (Baker score III and IV; P <.05). All patients who had severe CC underwent revision surgery or were scheduling revision surgery. This was true even in patients who reported improvement of their CC. Statistically, the plane of implant placement did not significantly affect the response to Singulair. DISCUSSION Our results in this preliminary study show that Singulair improves CC. However, because our study was retrospective and we did not have a well-matched population of negative controls, we cannot determine which patient variables predict a better response to Singulair. Unlike Accolate, the adverse event profile of Singulair is comparable to placebo, with the most common side effects being headache (18.4% vs 18.1%), influenza-like symptoms (4.2% vs 3.9%), abdominal pain (2.9% vs 2.5%), cough (2.7% vs 2.4%), and dyspepsia (2.1% vs 1.1%). 16 Only one of our patients reported any side effect (fatigue). All other patients tolerated the treatment without any problems. We were unable to make any correlation between duration of therapy and response to Singulair. Nine (47.4%) of the patients took Singulair for the full 90 days. Seven patients (36.8%) took Singulair for less than 90 days. In four of the patients who discontinued use, CC ly resolved and they stopped the medication because they felt they no longer needed it. Three patients stopped the medication early because they felt it was ineffective and scheduled surgery instead. Three patients (15.8%) took Singulair for more than 90 days. Two of these patients were being treated with Singulair prophylactically. One of them had a history of between eight and 10 revision procedures for CC dating back to 1988. Another had severe bilateral CC prior to surgery. Both of these patients began Singulair immediately after surgery and continued taking it for five and six months, respectively. Follow-up at 21 and 23 months after their surgery revealed that neither had redeveloped CC and both were pleased with their result. The third patient who took Singulair for more than 90 days continued it for six months because she felt the drug improved her CC and she elected to extend the duration of therapy. We observed that breasts with mild CC (Baker score of less than III) had a greater likelihood of improvement than those with more severe contracture (Baker score III and IV). The exact molecular mechanism behind CC is not ly understood, although it is generally agreed that an inflammatory response causes periprosthetic scar formation. Leukotriene receptor antagonists are known to alter the inflammatory cascade and likely aid in the prevention of fibrosis associated with CC. 7,13 Perhaps Singulair is capable of ameliorating the lesser degrees of inflammation and fibrosis found in low-grade CC, but less likely to remodel the well-formed fibrotic capsule associated with

408 Aesthetic Surgery Journal 30(3) Baker score III or IV contracture. Three of the patients with severe contracture (Baker III or IV) felt that their contracture improved with Singulair, but all three proceeded to schedule or undergo revision surgery. Future studies should include prospective, randomized double-blind studies with negative controls. Patients might be placed into one of four groups primary augmentation ±, implant exchange, revision surgery with capsulotomy, and revision surgery with. Only patients with silicone gel implants would be included to eliminate implant filler as a variable. Patients in each of these four groups should be randomized to receive 90 days of Singulair treatment. Each patient s age, race, implant position, incision, time to contracture, and duration of treatment would be recorded. Degree of CC should be assessed using the Baker Scale at multiple intervals one week, one month, six months, one year, and possibly three years by at least two independent plastic surgeons blinded to whether or not the patients received treatment. A patient questionnaire could obtain follow-up data on patients who did not return for physician examination. Statistical analysis should be employed to determine whether Singulair significantly reduces the risk of developing CC and whether there are specific patient factors associated with treatment response. Because CC can develop after many years, long-term followup studies are warranted to determine the extended efficacy of Singulair. CONCLUSIONS Our article presents preliminary findings on the off-label use of Singulair for CC. The drug is well tolerated with minimal side effects; therefore, we recommend its application in patients with CC. There was a greater response in breasts with mild CC, so a course of Singulair should be started early. Because it prevented recurrence in two patients with previous severe contracture, we recommend prophylactic prescription in patients with a history of recurrent contracture. In patients who already have moderately advanced CC, Singulair is unlikely to reverse symptoms to the degree that revision can be avoided. Disclosures The authors declared no conflicts of interest with respect to the authorship and/or publication of this article. Funding The authors received no financial support for the research and/or authorship of this article. REFERENCES 1. Jewell ML, Jewell JL. A Comparison of outcomes involving highly cohesive, form-stable breast implants from two manufacturers in patients undergoing primary breast augmentation. Aesthetic Surg J 2010;30:51-65. 2. Wong CH, Samuel M, Tan BK, et al. CC in subglandular breast augmentation with textured versus smooth breast implants: a systematic review. Plast Reconstr Surg 2006;118:1224-1236. 3. Spear SL, Elmaraghy M, Hess C. Textured-surface salinefilled silicone breast implants for augmentation mammaplasty. Plast Reconstr Surg 2000;105:1542-1552. 4. Vasquez B, Given KS, Houston GC. Breast augmentation: a review of subglandular and submuscular implantation. Aesthetic Plast Surg 1987;11:101-105. 5. Burkardt BR, Eades E. The effect of Biocell texturing and povidone-iodine irrigation on CC around saline-inflatable breast implants. Plast Reconstr Surg 1995;96:1317-1325. 6. Carpaneda CA. Inflammatory reaction and CC around smooth silicone implants. Aesthetic Plast Surg 1997;21: 110-114. 7. D Andrea F, Nicoletti GF, Grella E, et al. Modification of cysteinyl leukotriene receptor expression in CC: preliminary results. Ann Plast Surg 2007;58:212-214. 8. Holgate ST, Bradding BM, Sampson AP. Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy. J Allergy Clin Immunol 1996;98:1-13. 9. Gryskiewicz JM. Investigation of Accolate and Singulair for treatment of CC yields safety concerns. Aesthetic Surgery J 2003;3:98-101. 10. Schlesinger SL, Ellenbogen R, Desvigne MN, et al. Zafirlukast (Accolate): a new treatment for CC. Aesthetic Surg J 2002;22:329-335. 11. Spano A, Palmieri B, Palmizi, et al. Reduction of capsular thickness around silicone breast implants by zafirlukast in rats. Eur Surg Res 2008;41:8-14. 12. Bastos EM, Neto MS, Alves MT, et al. Histologic analysis of zafirlukast s effect on capsule formation around silicone implants. Aesthetic Plast Surg 2007;31:559-565. 13. Scuderi N, Mazzocchi M, Rubino C. Effects of zafirlukast on CC: controlled study measuring the mammary compliance. Int J Immunopathol Pharmacol 2007;20:557-584. 14. Reid R, Greve S, Casas L. The effect of zafirlukast (Accolate) on early CC in the primary augmentation patient: a pilot study. Aesthetic Surgery J 2005;25:26-30. 15. Gryskiewicz JM. What doctors aren t being told: using the freedom of information act. Plast Reconstr Surg 2003;113:743-745. 16. Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, Orazio N. Antileukotriene drugs: clinical applications, effectiveness and safety. Current Med Chem 2007;14:1966-1977.