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Topical mitomycin application after laryngotracheal reconstruction. A randomized, double-blind, placebo-controlled trial.

Prakash, Udaya B. S. M.D.


Mayo Medical Center and Mayo Medical School, Rochester, Minnesota, U.S.A.

Topical mitomycin application after laryngotracheal reconstruction. A randomized, double-blind, placebo-controlled trial.

Arch Otolaryngol Head Neck Surg 2001;127:1260–4. Hartnick CJ, Hartley BEJ, Lacy PD, Liu J, Bean JA, Willging JP, Myer CM III, Cotton RT. Departments of Pediatric Otolaryngology and Biostatistics, Children's Hospital Medical Center, Cincinnati, Ohio, U.S.A.

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This randomized, double-blind, placebo-controlled trial assessed the effect of mitomycin treatment on the pediatric airway following laryngotracheal reconstruction. The study group consisted of children age 2 to 17 years with subglottic or upper tracheal stenosis undergoing laryngotracheal reconstruction at a single tertiary-care children's hospital. Patients who had previous endolaryngeal topical application of mitomycin were excluded from this study. At the time of extubation or stent removal, the children underwent bronchoscopy and direct application of either 0.4 mg/mL mitomycin (2 mL of a 0.2-mg/mL solution) or an equal volume of isotonic sodium chloride to the subglottic region for a single application of 2 minutes. These children then underwent interval bronchoscopy at 2 weeks, 6 weeks, and 3 months postoperatively for assessment of their airways. Granulation tissue was graded on a scale of 0 (none) to 4 (near-total or total occlusion). Videotapes of bronchoscopies were observed independently and graded by three pediatric otolaryngology fellows, with a subsequent interobserver agreement of 91.6%. The results were then dichotomized to represent a single cohort in which further surgical intervention would be required and another separate cohort in which further surgery would not be required. At the 1-year mark, a committee for data safety and monitoring performed interim analysis. The results showed that 13 children had been randomized to the mitomycin-treated arm of the study and 11 children to the placebo-treated arm. A two-tailed Fisher's exact test revealed a value of 1.00. The Data Monitoring and Safety Committee advised that the trial should be stopped because the distributions between the two populations were almost identical. No adverse effects were seen for any of the patients who were treated with mitomycin. The authors concluded that they cannot reject the null hypothesis that a single topical dose of mitomycin exerts an equal benefit as isotonic sodium chloride when applied to the pediatric airway after laryngotracheal reconstruction. The occurrence of restenosis after laryngotracheoplasty or cricotracheal resection is a formidable clinical problem that occurs in 20 to 40% of patients. The options to treat the complication of restenosis include postoperative stent placement, CO2 laser dilatation of stenotic airway segment, rigid bronchoscopic dilatation, or repeat surgery. One of the mechanisms thought to be responsible for the recurrence of stenosis is the high incidence of formation of granulation tissue at the site of surgery. Proliferation of fibroblasts and their recruitment to the site of injury or surgery seems to play a major role in the development of granulation tissue. Several investigators have tested the hypothesis that an agent capable of inhibiting the proliferation and recruitment of fibroblasts to the area of injury or surgery will prevent restenosis. The most popular agent used for this purpose is mitomycin, which is an antineoplastic antibiotic derived from Streptomyces caespitosus. Mitomycin acts as an alkylating agent to inhibit deoxyribonucleic acid synthesis as well as to inhibit cell division and fibroblast proliferation. Mitomycin has been used clinically by ophthalmologists to reduce scar formation after surgery for glaucoma. In one report of five patients, mitomycin was administered topically (just after laser excision of subglottic stenosis) at a dose of 0.2 mg/mL for a period of 2 minutes, and the amount of scarring after this topical administration of mitomycin was reduced markedly in three of the five patients (Int J Pediatr Otorhinolaryngol 1998;44:221–6 ). In a dog model of laryngotracheal stenosis, administration of a single dose of 0.2 mg/mL topical mitomycin reduced markedly the amount of laryngotracheal stenosis, and a second administration of mitomycin was of no additional benefit (Laryngoscope 1999;109:1594–600 ). Two other studies that used dog models have shown that topical mitomycin reduced notably the amount of postoperative granulation tissue (Ann Otol Rhinol Laryngol 1999;108:1053–60, Laryngoscope 1999;109:1125–9 ). However, topical administration of mitomycin in a pig model has shown no significant difference in the amount of inflammatory tissue between the mitomycin-treated animals and the controls (Int J Pediatr Otorhinolaryngol 2000;53:125–35 ). The dose of mitomycin applied to the human and animal airways has varied from 0.1 to 10 mg/mL. In the human clinical model, the documented dosages have varied between 0.1 mg/mL and 0.4 mg/mL. The duration of topical application of mitomycin has also varied from 1 to 5 minutes. However, most of the reports indicate an application time of 2 to 3 minutes. All one can say at this time is that mitomycin represents one possible nonsurgical means of reducing postoperative granulation and scar tissue formation. However, the effectiveness of mitomycin in providing substantial long-term clinical benefit is yet to be documented.

© 2002 Lippincott Williams & Wilkins, Inc.