Zafirlukast (Accolate): A New Treatment for Capsular Contracture
From Aesthetic Surgery Journal, the Official Publication of the American Society for Aesthetic Plastic Surgery
by S. Larry Schlesinger, MD; Richard Ellenbogen, MD; Michael N. Desvigne, MD; Steven Svehlak, MD; and Robert Heck, MD
Background: Capsular contracture after breast augmentation or reconstructive breast surgery is a difficult problem. Previous studies have suggested that alteration of the inflammatory response could have a role in reducing the incidence of capsular contracture. Objective: We report a series of patients with Baker class III or IV capsular contracture who underwent treatment with zafirlukast. rlukast.
Methods: Patients received a regimen of zafirlukast 20 mg by mouth 2 times daily for 3 months.
Results: In many cases, dramatic softening of the breast capsule was evident after 1 to 3 months of treatment.
Conclusions: Zafirlukast appears to effectively soften early capsular contracture and may prevent the formation of capsular contracture in those patients at risk. (Aesthetic Surg J 2002;22:329-336.) Implantation of a silicone elastomer outer shell filled with either saline solution or silicone gel is an accepted, safe, and effective method of augmenting or reconstructing the breast mound. A difficult problem often encountered after implant placement is that of capsular contracture.
Capsular contracture has been defined as a thickened periprosthetic scar engulfing the implant that results in a hard, distorted, often painful, breast.’ It is not a complication but an exaggeration of a normal physiological response after breast augmentation. The “normal” physiological response that occurs after implant placement is an inflammatory foreign body reaction that results in a collagen capsule surrounding the implant.2 The factor or factors determining the severity of this response are not completely understood. Many local factors have been believed to produce an increased inflammatory response, such as hematoma, infection, trauma, and silicone implant leakage. To date, we have not always found a specific cause in each case of capsular contracture encountered. However, most investigators agree that the degree of contracture is associated with an acceleration or prolongation of the inflammatory process. Examination of histologic specimens elicits the myofibroblast as a culprit. In particular, it appears that the phases of fibroblast proliferation and collagen deposition are exaggerated in cases of capsular contracture, as shown by the increased capsular collagen content found in patients who underwent capsulectomy for severe (Baker class III or IV) contracture.
The incidence of capsular contracture reported has been quite variable (2% to 30%). The use of textured implants placed submuscularly has lessened the incidence.3,4 Additionally, several studies in recent years have suggested methods to help decrease the risk of capsular contracture.5-8 These discussions, although helpful, still leave the question of what causes capsular contracture unanswered. Ersek2 attempted to alter the physiological response in patients with evidence of capsular contracture by treating these individuals with localized steroid irrigation. He reported a remarkable improvement in 165 patients over 6 months with continued improvement up to 18 months. This study demonstrated that the degree of contracture could be reduced by altering the body’s immunologic response. In another study, Miller et a19 used an animal model of 90 Sprague-Dawley rats to show that an alteration in the immunologic response resulted in a change in the capsule thickness, cellular component, and collagen organization of the periprosthetic capsule. The problem with such treatment is that the risks of steroid use are not insignificant. Most surgeons avoid the use of steroids (either systemic, intraluminal, or pocket irrigation) because of the potential long-term complications. However, the theoretical gain from immunomodulation has merit, particularly if immunomodulation can target the key inflammatory reaction responsible for producing an exaggerated fibrotic response.
The Development of Zafirlukast
In 1979, the term “leukotrienes” was given to a family of lipid mediators that were derived from their cell source (leukocytes). Specifically, identification of “the slow-reacting substance of anaphylaxis” led to identification of several additional inflammatory mediators.1° Arachidonic acid, a constituent of cell membranes, is released by phospholipase A2 in response to a number of biologic signals. Once released, arachidonic acid can follow at least 2 metabolic pathways. One of these is the 5-lipoxygenase pathway, which gives rise to the cysteinyl leukotrienes (LTC4, LTD4, and LTE4). These potent mediators have been shown to cause an eosinophyllic influx. After identification of these inflammatory mediators, efforts were made to develop a structurally similar analog that could modulate and perhaps halt the inflammatory process.11
In November 1996 the Food and Drug Administration approved the use of zafirlukast (Accolate; AstraZeneca Pharmaceuticals, Wilmington, DE), a leukotriene receptor antagonist (LTRA), for the treatment of asthma. This class of drugs has the unique ability to prevent asthma symptoms rather than treating an attack once it occurs. In vitro studies have demonstrated that zafirlukast inhibits the eosinophilic influx and contractile activity of smooth muscle in all 3 leukotrienes (LTC4, LTD4 and LTE4) in both humans and laboratory animals. Additionally, studies have shown that in sheep, zafirlukast also suppresses the eosinophilic response, resulting in a decrease in bronchial “hyperresponsiveness.” From November 1996 through 1998, zafirlukast tablets were prescribed more than 4 million times. Zafirlukast 20 mg administered by mouth 2 times daily is indicated for the preventative and long-term treatment of asthma in adults and children 12 years of age or older. Generally, it is well tolerated, although reported side effects may include headache (12.9%) and nausea (3.1%).12-14
A Link to Capsular Contracture
A series of accidents contributed to the discovery of zafirlukast’s effects on capsular contracture. In 1996 a local pharmacist, who was of Spanish descent, mentioned to the senior author (S.L.S.) that since he started his asthma medication, he noted a significant improvement in his previously pigmented scars. He said the medicine was a new type of antiinflammatory agent, zafirlukast. The senior author began using zafirlukast to help minimize hyperpigmentation seen after laser resurfacing in Asian and darker-skinned patients. Then in 1998, he saw a patient in whom a capsular contracture (Baker III) developed after an elective breast augmentation was performed 2 months earlier. She explained that she did not want to go through any additional surgery. She had already been taking vitamin E and performing breast massage daily. It was at that moment that he considered zafirlukast, thinking that perhaps by working on the early inflammatory process, zafirlukast might affect the later stages that lead to capsular contracture. After 1 month of therapy, the breasts softened. After 3 months, the patient returned to Baker class I. The senior author continued to selectively prescribe zafirlukast to those patients in whom capsular contracture developed and who did not desire surgery.
Another author (R.E.) first heard of the effectiveness of zafirlukast for treating capsular contracture from the senior author. Before he could begin using it in his own practice, he found confirmation of its effectiveness from a patient who was scheduled to undergo an open capsulectomy for a Baker class IV unilateral capsular contracture.
This patient had already undergone surgery for severe capsular contracture that then recurred within 60 days. When she presented for surgery, the surgeon was unable to determine which side required the procedure. The patient then informed him that in the interim since her last visit, the breast capsule had softened significantly after her primary care physician had initiated treatment with zafirlukast, 20 mg by mouth, for her asthma.
The authors report a series of cases in which zafirlukast was given for capsular contracture after breast augmentation or reconstruction. In these cases, the medication was prescribed only after capsular contracture was noted and documented by a physician. In many cases, after a therapeutic trial of zafirlukast 20 mg by mouth, twice daily for 3 months, the patients and surgeon appreciated a dramatic improvement of the contracture, defined by the softening and improved appearance of the breast. In some cases, patients who otherwise would have undergone surgical intervention were treated successfully with zafirlukast.
A 33-year-old white woman with bilateral hypomastia presented for augmentation mammaplasty. The patient was a nonsmoker without significant medical history and with no previous breast surgery. The examination showed small breasts bilaterally with no ptosis. Before surgery, the patient received the antibiotic cefazolin 2 g.
The patient underwent bilateral transaxillary endoscopic subpectoral augmentation with Mentor Contour profile saline solution—filled, smooth 450-cc implants (Mentor Corp., Santa Barbara, CA) (right, 490 cc; left, 480 cc). JP 7-mm drains (Allegiance Healthcare Corp., McGaw Park, IL) were inserted.
As part of her postoperative care, the patient received cephalexin 500 mg by mouth, 4 times daily for 7 days, and an Ace wrap band. The drains were removed on postoperative day (POD) 3, and the sutures were removed on POD 5. The patient also received vitamin E and breast massage.
The breasts remained soft until 4 years and 2 months later, when Baker class III capsular contracture developed in the left breast. The right breast remained soft (Baker class I). The patient was placed on zafirlukast 20 mg by mouth 2 times daily. One month after initiation of treatment, the left breast was softer . Three months after treatment began, the left breast was Baker class I, and remained so at 4 months after initiation of treatment.
The patient was a 19-year-old white woman with bilateral hypomastia and no history of previous breast surgery. She smoked 1 pack of cigarettes per day. The examination showed small breasts bilaterally without ptosis. Before surgery the patient received the antibiotic cefazolin 2 g.
The patient underwent bilateral transaxillary endoscopic subpectoral breast augmentation with Mentor Contour Profile saline solution—filled 350-cc implants (right, 380 cc; left, 380 cc). JP 7-mm drains were inserted.
As part of her postoperative care, the patient was treated with an Ace wrap band. The drains were removed on POD 3, and the sutures were removed on POD 5. The patient also received vitamin E and breast massage.
Two weeks after operation, bilateral Baker class III capsular contractures developed. The patient was given zafirlukast (Accolate) 20 mg by mouth 2 times daily, for 3 months. Two months after initiation of treatment, both breasts were significantly softer (Baker class II). After 3 months of treatment, both breasts were Baker class I, and she was taken off medication. At the patient’s most recent follow-up examination, S months after she was taken off medication, both breasts remained Baker class I.
The patient was a 42-year-old white woman with bilateral hypomastia and mild breast ptosis. She had a history of eczema but was otherwise healthy. The patient was a nonsmoker with no history of previous surgery to the breasts. The examination showed bilateral hypoplastic breasts with grade II ptosis. Before surgery, the patient received cefazolin 2 g.
The patient underwent Benelli mastopexy with subpectoral augmentation with Mentor smooth round 200-cc implants (right, 200 cc; left, 210 cc). JP 7-mm drains were inserted. Suction-assisted lipoplasty of the hips, abdomen, back, and axilla was also performed.
After operation the patient was treated with cephalexin as in case 1 and a Warner bra (Warner’s, New York, NY). Drains were removed on POD 3, and the sutures were removed on POD 6. PDS deep sutures (Ethicon, Inc., Somerville, NJ) required removal because of “spitting.”
Three months after operation, redness developed at the left nipple that was believed to be a “reaction to a suture.” At S months after operation, a lump developed on the right breast that required surgical excision. The lump was identified as an inclusion cyst. The patient was placed on cephalexin therapy. Five days later, she noted increasing firmness of both breasts. Two weeks later, after a local infection developed at the right nipple, she was taken off cephalexin and placed on wide-spectrum antibiotics. One month later (7 months after operation) all incisions were healed, but severe capsular contracture (Baker class IV) was evident in both breasts that required surgical intervention. Before the second procedure the patient was given cephazolin 2 g.
The second procedure was an open capsulotomy and implant exchange with PIP High Profile 230-cc implants (PIP America, Santa Barbara, CA). JP drains were placed.
After operation, once again the patient was treated with cephalexin and a Warner bra. The drains were removed on POD 3, and the sutures were removed on POD 6. The patient also received vitamin E and breast massage.
Twenty days after operation, the patient noted increasing firmness of both breasts. The patient continued breast massage and vitamin E therapy. At 4 months after operation, severe capsular contracture of the left breast developed (Baker class IV). The right breast remained soft (Baker class I). The patient was placed on zafirlukast, 20 mg by mouth 2 times daily. One month after initiation of treatment, the left breast was much improved (Baker class I).
A 39-year-old Hawaiian woman was diagnosed with infiltrating ductal carcinoma in the left breast in June 2000. She underwent a modified radical mastectomy with immediate reconstruction with placement of a tissue expander. Pathologic study revealed 1 of 12 nodes positive for tumor, stage III disease. After operation, the patient received chemotherapy (doxorubicin, cyclophos-phamide, paclitaxel) and was also placed on a study protocol for trastuzumab. In February 2001, she underwent exchange of the tissue expander for a McGhan textured saline-filled implant placed submuscularly. Six weeks after implant placement, the patient received local radiation therapy to the left breast (5000 rads total).
Immediately after radiation therapy, she noted redness and blistering of the skin surrounding the left breast. Three weeks after therapy, the patient noted hardening of the left breast mound. This quickly progressed to a Baker class IV capsular contracture at 5 weeks after radiation therapy. The patient was treated initially with breast massage and vitamin E therapy without relief. She was referred by her surgical oncologist and reconstructive surgeon for possible treatment options.
On initial examination, the patient had a Baker class IV capsular contracture of the left breast. She was placed immediately on zafirlukast, 20 mg administered by mouth 2 times daily. Two weeks after the initiation of treatment, both the patient and the physician noted dramatic softening of the breast implant. After 1 month on zafirlukast the pain and distortion had resolved, and the implant was “soft,” approaching a Baker class I. In addition, the patient appreciated a significant improvement in the mastectomy scar, which she described as extremely hard and firm before initiation of zafirlukast therapy.
A 54-year-old Japanese-American woman underwent augmentation mammoplasty in 1986 in which 250-cc silicone implants were placed on each side above the muscle. After operation the patient had no complications. The breasts remained soft for 5 years.
In 1991 the patient noted increasing firmness in both breasts. She received no treatment at that time. Seventeen years after surgery, she presented for possible surgical intervention. On examination, she was noted to have Baker class IV capsular contractures bilaterally. She was placed on zafirlukast 20 mg administered by mouth 2 times daily. Three weeks later, the patient noted some improvement of the softness of both breasts. At 3 months after therapy was initiated, she had improved from Baker class IV to a class III in the right breast and class II on the left.
Capsular contracture is a common problem after placement of breast implants for augmentation or reconstruction. The precise mechanism by which the body produces this response to the implants is unknown. What we do know is that an inflammatory response occurs that results in periprosthetic fibrosis. The severity of this response appears to determine whether a patient will exhibit distortion or a painful periprosthetic scar.
Once capsular contracture develops, the current recommendations for treatment are breast massage, oral vitamin E therapy, and, lastly, surgical intervention.ls However, most surgeons agree that the best treatment for capsular contracture is prevention. It is difficult to predict which patients may have severe contracture. Certainly, a patient with development of a postoperative infection or hematoma would be at risk. Additionally, one might also consider those patients with a history of hypertrophic scarring to be at risk for significant contracture after breast augmentation. This “high-risk” group of women may benefit from prophylactic intervention that would decrease the inflammatory response.
Early intervention and prophylactic intervention appear to be the best means of decreasing the incidence of significant capsular contracture. Historically, surgeons have avoided the use of steroids in the treatment or prevention of capsular contracture because of the inherent risks. However, a more targeted approach that focuses on limiting the inflammatory response may prove more efficacious and safe. LTRAs have proven to be safe and efficacious for the treatment of asthma. Their antiinflammatory characteristics target early cellular-mediated proliferation without producing a generalized immunosuppression.
Possible Mechanisms of Action
The role of the macrophage and the mast cell may be particularly important in the physiological mechanisms by which LTRAs inhibit capsular contracture. Myofibroblasts having the properties of both fibroblasts and smooth muscle cells have been suggested as the cause of excess collagen production and extracellular matrix deposition.16-21 In addition, in 1981 Baker et a122 specifically credited the myofibroblast as the probable cause of capsular contracture. They postulated that drugs that inhibit myofibroblast smooth muscle activity would be beneficial in preventing capsular contracture.
If indeed the myofibroblast is responsible for the exaggerated collagen deposition and the resultant smooth muscle activity postulated in capsular contracture, perhaps immunomodulation at the cellular level can reduce capsular contracture. These mechanisms include inhibition of the macrophage and mast cell response. First by reducing the cellular response of SRS-A (substance of anaphylaxis) (Figure 1, A), the “histamine-like” response generated by eosinophills, mast cells, neutrophils, and lymphocytes will be inhibited. Second, by preventing monocyte activation, cytokine and growth factor release, and the production of superoxide radicals, the inflammatory cascade will be reduced significantly (Figure 1, B).10’23’24
A report by Niessen, et al 18 suggests that the macrophage is a pivotal intermediary between the inflammatory phase and scar formation. The macrophage release of fibroblast activating cytokines, transforming growth factor—(3, platelet-derived growth factor, and interleukins is important in collagen production, organization, and extracellular matrix degradation. Niessen et a118 suggest that all of the cellular and immunologic processes, not just fibroblast activity alone, are important in the formation of excessive scar tissue. The relationship between mast cells and scars is also suggested, as mast cells are found among dermal collagen bundles and are found in higher numbers in hypertrophic versus “normal” scars.23 The mast cell response is characterized by histamine-like activity, which is capable of stimulating collagen formation and is notably increased in keloid tissue. The result is an increase in the collagen matrix found in scar tissue. This response is directly inhibited by LTRAs and would appear to reduce the rate of capsular contracture.
The important role of the macrophage and mast cell in wound healing is generally accepted. However, although their role in the formation of capsular contracture is suggested, it is not completely understood. We believe that both myofibroblast smooth muscle contractility and prolonged collagen deposition may be involved in the development of capsular contracture. If so, reducing the activity of the macrophage and mast cell may prove to be useful. Use of LTRAs to diminish the early inflammatory process led by the macrophage and mast cell may indeed impede further cellular mechanisms, such as myofibroblast activity, fibroblast proliferation, and collagen deposition as depicted in Figure 2. The precise mechanism by which zafirlukast reduces or prevents capsular contracture is not completely clear and deserves further investigation.
Zafirlukast Versus Montelukast
One author (R.E.) discovered that montelukast (Singulair; Merck & Co, West Point, PA), a pharmacologic agent similar to zafirlukast but requiring only a single dose at bedtime, also reduced the incidence of capsular contracture. Its effectiveness came to light after a patient with capsular contracture saw her breast capsule decrease from Baker class III to Baker class I during the 6-week period after she began taking montelukast to treat her chronic rhinitis. The physician began using montelukast both prophylactically and to treat newly established contractures. Although it did not completely eliminate production of a firm capsule, the incidence of contracture fell significantly, and those that did form were easily reduced through early recognition and treatment with closed compression. Moreover, women with Baker. class IV contractures who received montelukast noted subjective improvement with decreased pain and increased upper arm mobility.
The authors compared results after treatment with zafirlukast and montelukast and found that although the mechanisms of action and immediate results attained with both agents were similar, slightly better response rates were obtained in patients treated with zafirlukast. The likely explanation for this difference is that zafirlukast blocked all 3 of the leukotriene receptors whereas montelukast blocked only 1.
Capsular contracture after breast augmentation is not an uncommon problem. The best treatment is prevention. Although we do not completely understand the cause of capsular contracture after breast augmentation or reconstruction, an exaggerated inflammatory response does occur. The role of specific cells such as the macrophage or mast cell is not completely defined but suggested. Alteration of the immunologic response of the macrophages and mast cell with LTRAs may alter the inflammatory cascade just enough to prevent the severe fibrotic reaction that occurs with capsular contracture.
We have noted a statistically significant decrease of the capsular contracture rate from 4% down to 1 % after the introduction of zafirlukast to our practice. The senior author has been treating capsular contracture with zafirlukast for approximately 3 years. We have found that it is very effective in the treatment of capsular contracture detected early (less than 6 months after onset) and as prophylactic treatment in patients considered at high risk. “High risk” is defined as those patients with a history of previous capsular contracture, periprosthetic infection, or hematoma or patients with a propensity to form hypertrophic scar. Additionally, to our surprise, zafirlukast has been used successfully to treat established capsular contracture, including contracture after radiation therapy. In our practice, the need for surgical intervention to treat significant capsular contracture (Baker class III or IV) has been significantly reduced since zafirlukast was prescribed. The experience of other authors (R.E., S.S.) is anecdotal but also indicates that zafirlukast dramatically reduced the incidence of capsular contracture after breast augmentation and is effective in softening established capsules, particularly those identified and treated within 6 months. Our experience thus far has shown zafirlukast to be effective after the patient has been taken off therapy, although the length of time it remains effective is uncertain.
For those patients with longstanding (1 year or more) severe capsular contracture (Baker class III or IV), surgery remains the treatment of choice. However, in patients with longstanding contracture who are not surgical candidates or do not desire surgical intervention, zafirlukast has been effective in reducing pain and distortion of the breast capsule.
The precise mechanism by which the LRTAs decrease or prevent capsular contracture warrants further investigation. In addition, longer follow-up results are needed to determine the long-term effect of capsular contracture prevention and treatment. The indications and use of zafirlukast for capsular contracture will be better defined as we learn more. However, we suggest that there is a role for immunomodulation by the LTRAs in the prevention and early treatment of capsular contracture. Specifically, we view zafirlukast as a potential contender as we continue the “fight” against capsular contracture after breast augmentation or reconstruction.