Advances in Therapy
Researchers have uncovered some novel therapies for SGS.
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August 2020Intralesional Steroid Injections. A drawback of endoscopic SGS treatment has been stenosis recurrence following surgery, necessitating repeated procedures. As knowledge of the underlying proinflammatory/profibrotic mechanisms of the disease has grown, surgeons have begun to use adjuvant treatments to tamp down the wound-healing response and reduce scarring, Dr. Johns noted. These strategies have included the use of systemic antibiotics; topical and intralesional antineoplastic compounds, such as mitomycin C or fluorouracil; and systemic, inhaled, or intralesional corticosteroids, with mixed results.
“Otolaryngologists have borrowed many of these ideas from dermatology. Dermatologists have been injecting the scars of patients susceptible to keloid development with steroids following excision, which can help reduce the inflammatory response and the severity of keloid recurrence,” Dr. Johns said.
There’s something about the skin graft that seems to turn off the fibroblast process. It may be the mechanical pressure of the graft on the fibroblasts, or the extracellular matrix molecules that are within the superficial layer of dermis, that signal the scar to stop progressing in SGS patients. —Alexander Hillel, MD
A recent study by Bertelsen and colleagues evaluated the effectiveness of serial in-office intralesional steroid injections (ISI) after endoscopic dilation (JAMA Otolaryngol Head Neck Surg 2018;144:203-210). A series of 24 patients with varying causes of stenosis were treated with inhaled corticosteroids for one month and oral trimethoprim/sulfamethoxazole for two to four weeks after endoscopic dilation. During the ISI procedure, which included a series of three to six injections spaced three to six weeks apart, 1 to 2 mL of triamcinolone 40 mg/mL was injected into multiple locations in the region of stenosis. After a mean follow-up of 32 months, 17 patients did not require further surgery after ISI.
“Our goal is to extend the interval between surgeries by focusing our treatment on the underlying inflammatory response that’s causing the stenosis re-formation,” Dr. Johns said. “We need to treat SGS more like an inflammatory disease rather than a clogged pipe.”
ISI also has been used to delay surgery in newly diagnosed iSGS patients. “In my practice, ISI has probably been the most transformative advance for my patients,” Dr. Morrison said. “I have a number of patients who have avoided surgery with steroid injections in the office or, at the very least, have significantly reduced the frequency of surgery.”
Split Thickness Skin Grafts. “One problem with current endoscopic SGS treatment is the inability to truly cut the scar out—that requires an open procedure,” Dr. Hillel noted. Two new minimally invasive surgical approaches focus on selective endoscopic removal of affected mucosa, with epithelial reconstitution with dermal or buccal grafts (JAMA Otolaryngol Head Neck Surg 2017;143:609–613;).
Guri Sandhu, MBBS, MD, a consultant otolaryngologist at the Imperial College in London, developed the Maddern procedure to endoscopically resect SGS. The procedure involves resecting the mucosa and scar of the subglottis and replacing it with a split thickness skin graft to re-line the affected area. The graft is held in place with a stent that’s removed approximately 14 days after the endoscopic procedure. With this approach, the diseased mucosa is removed while avoiding alteration of the cartilage framework.
At the same time that Dr. Sandhu was developing the Maddern procedure, Robert Lorenz, MD, a surgeon in the Head and Neck Institute at the Cleveland Clinic, was working on his own technique, which he termed the retrograde endoscopically assisted cricoid hypertrophic epithelial resection (REACHER) procedure. In a technique otherwise similar to the Maddern procedure, the surgeon instead approaches the scar tissue from below, retrograde, through a temporary tracheal opening. After consultation with Dr. Sandhu in which the feasibility of the transoral approach was validated, Dr. Lorenz abandoned the REACHER procedure in 2015 and began performing a modified Maddern procedure in 2016.
To date, Dr. Lorenz has performed the procedure on 28 patients [in press], of which the last eight surgeries have been performed using buccal mucosa to re-line the trachea. This has eliminated one of the side effects of using thigh tissue. “Thigh skin includes keratin, which subsequently collects in the airway, causing coughing and irritation,” he said. “The use of the buccal mucosa appears to eliminate this problem, thus avoiding the need to resurface the skin graft in later endoscopic laser procedures.”
Dr. Lorenz has trained residents, fellows, and observers in the procedure over the past five years and has focused his upcoming publication on “shortening the learning curve,” especially with the use of the more challenging buccal graft. The greatest benefit of the Maddern procedure over open surgery is eliminating removal of the anterior cricoid cartilage and attached cricothyroid muscle, which causes a drop in fundamental frequency by 10 Hz and decreases inflection in speech, both of which are especially detrimental in this mostly female cohort of patients.
According to Dr. Hillel, Dr. Sandhu’s advancement was placing the skin graft endoscopically. “There’s something about the skin graft that seems to turn off the fibroblast process,” he said, although it isn’t entirely clear how that occurs. “It may be the mechanical pressure of the graft on the fibroblasts, or the extracellular matrix molecules that are within the superficial layer of dermis, that signal the scar to stop progressing in SGS patients.”
“This technique is considerably less invasive than an open resection but will still lead to a permanent and long-lasting improvement in the patient’s airway,” Dr. Lorenz said.
Dr. Morrison agreed. “I think these procedures are providing a more aggressive treatment for our patients, with less morbidity than an open procedure.”
Drug-Eluting Stents. Some of the advancements in surgical approaches to the treatment of iSGS have also targeted the underlying inflammatory process that creates the scar tissue. Dr. Hillel and colleagues have developed a drug-eluting stent that can be placed at the surgical site after the scar is removed to inhibit fibroblast proliferation and collagen production.
In a study led by Dr. Hillel, two biodegradable, drug-eluting stents containing 1.0% rapamycin, which is FDA approved for use in cardiac stents for coronary artery disease, were compared in situ in a mouse model (Biomater Sci. 2019;23:7:1863-1874;). The researchers found that the PLLA-PCL (70% poly-L-lactide and 30% polycarprolactone blend) stent exhibited greater mechanical strength and showed more reliable rapamycin release than the PDLGA (poly-DL-lactide-co-glycolide) stent. The rapamycin stents decreased collagen 1 and fibroblast cell proliferation in vitro and reduced laminar propria thickness in vivo. The potential benefit of the stent was that it could be used in combination with any endoscopic procedures or split-thickness skin grafts, Dr. Hillel noted. “A drug-eluting stent that’s placed for two weeks following resection of a scar might be an option in idiopathic and other types of SGS,” he said.