Mitomycin C in the Endoscopic Treatment of Laryngotracheal Stenosis: Systematic Review and Proportional Meta-Analysis

Queiroga, Thereza L. O.; Cataneo, Daniele C.; Martins, Regina H. G.; Reis, Tarcisio A.; Cataneo, Antônio J. M.

doi:10.1055/s-0039-1700582

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International Archives of Otorhinolaryngology

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Systematic Review • Int. Arch. Otorhinolaryngol. 24 (01) • Jan-Mar 2020 • https://doi.org/10.1055/s-0039-1700582 copy

Mitomycin C in the Endoscopic Treatment of Laryngotracheal Stenosis: Systematic Review and Proportional Meta-Analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Introduction

Mitomycin C is a natural antibiotic that has been used to inhibit the proliferation of ﬁbroblasts in scar tissue.

Objective

To evaluate the effectiveness and safety of topical Mitomycin C as an adjuvant in the endoscopic treatment of laryngotracheal stenoses.

Data synthesis

A systematic review of experimental or observational studies that have evaluated the treatment of laryngotracheal stenoses with the use of topical Mitomycin C was performed. Databases researched: LILACS, PubMed, Embase, Cochrane and Web of Science. Outcomes: resolution (symptom-free time ≥ one year), number of procedures required, and complications resulting from the procedure. A total of 15 studies (involving 387 patients) were selected. Mitomycin C was administered to every patient in 11 studies, and in 4 other studies, the patients were separated into 2 groups, 1 receiving mitomycin C, and the other not. The resolution of the stenosis evaluated in 12 studies in which the patients received mitomycin C was of 69% (95% conﬁdence interval [95%CI]: 61-76%; I2 = 17.3%). A total of 52% of the patients (95%CI: 39-64%, 11 studies; I2 = 64.7%) were submitted to a single endoscopic procedure, and 48% (95%CI: 36-61%, 11 studies; I2 = 64.7%) were submitted to more than 1 procedure. Complications (mediastinal and subcutaneous emphysema, dysphonia, laceration or vocal fold paralysis and acute light obstruction) were reported in 9% of the patients (95%CI: 3-18%, 9 studies; I2 = 79.8%).

Conclusions

The evidence suggests that mitomycin C is an effective and safe option in the endoscopic treatment of laryngotracheal stenosis.

Keywords:
laryngotracheal stenosis; mitomycin C; systematic review; dilation; endoscopic treatment

Author (year) and country	Type of study (period studied)	Total number of patients (type of stenosis)	Concentration of MMC (time of application)	Intervention performed	Follow-up	Primary outcome: symptom-free time ≥1 year/total	Secondary outcomes
Author (year) and country	Type of study (period studied)	Total number of patients (type of stenosis)	Concentration of MMC (time of application)	Intervention performed	Follow-up	Primary outcome: symptom-free time ≥1 year/total	Number of procedures required	Complications
Rahbar et al⁵5 Rahbar R, Shapshay SM, Healy GB. Mitomycin: effects on laryngeal and tracheal stenosis, bene?ts, and complications. Ann Otol Rhinol Laryngol 2001;110(01):1-6. Doi: 10.1177/000348940111000101 https://doi.org/10.1177/0003489401110001... (2001), United States	Case series (January 1998–December 1999)	15 (10 subglottic, 3 glottic, 2 tracheal)	0.4 mg/mL (4 minutes)	Radial incision with CO2 laser + dilation + MMC	6–29 months; < 1 year = 1 pat; 1–2 years = 10 pat; > 2 years = 4 pat	11/15	1 proc = 9 pat; > 1 proc = 6 pat (2 = 5; 3 = 1)	Tracheostomies (3)Poor quality voice (3)
Perepelitsyn and Shapshay⁶6 Perepelitsyn I, Shapshay SM. Endoscopic treatment of laryngeal and tracheal stenosis-has mitomycin C improved the outcome? Otolaryngol Head Neck Surg 2004;131(01):16-20. Doi: 10.1016/j. otohns.2004.03.001 https://doi.org/10.1016/j... (2004), United States	Case-control (1990–1997 without MMC; 1997–2001 with MMC)	20 without MMC (3 glottic, 17 subglottic); 16 with MMC (8 glottic, 8 subglottic)	0.4 mg/mL (4 minutes)	Only CO2 laser or laser with MMC or laser with corticoid	Without MMC = 25.2 months; with MMC = 5 to 70 months	Without MMC: 5/20; with MMC: 12/16	2.35 per patient	Zero
Nouraei et al⁷7 Nouraei SA, Singh A, Patel A, Ferguson C, Howard DJ, Sandhu GS. Early endoscopic treatment of acute in?ammatory airway lesions improves the outcome of postintubation airway stenosis. Laryn- goscope 2006;116(08):1417-1421. Doi: 10.1177/000348940611 500105 https://doi.org/10.1177/000348940611... (2006), United Kingdom	Case series (2003–2005)	31, but 11 were recent, (20 late stenoses)	1 mg/mL (3 minutes)	Radial incision with CO2 laser + dilation + MMC	15.4 ± 1.8 months	14/20	1 proc = 9 pat; > 1 proc = 11 pat	not reported
Schweinfurth⁸8 Schweinfurth JM. Endoscopic treatment of severe tracheal stenosis. Ann Otol Rhinol Laryngol 2006;115(01):30-34. Doi: 10.1177/00034 8940611500105 https://doi.org/10.1177/00034... (2006), United States	Case series (does not mention period)	20 (degree 1 = 1; degree 2 = 3; degree 3 = 10; degree 4 = 6)	1 mg/mL (5 minutes)	Incision with CO2 laser + dilation + MMC	Mean of 16 months (5 to 27 months)	15/20; tracheostomy (2), tracheal resection (3), death (1)	1 proc = 15 pat; > 1 proc = 5 pat (2 = 4; 3 = 1)	Tracheostomy (2) Dysphonia (4)
Simpson and James⁹9 Simpson CB, James JC. The ef?cacy of mitomycin-C in the treat- ment of laryngotracheal stenosis. Laryngoscope 2006;116(10): 1923-1925. Doi: 10.1097/01.mlg.0000235934.27964.88 https://doi.org/10.1097/01.mlg.000023593... (2006) United States	Case-control (January 1999–December 2004)	36 (24 subglottic, 5 glottic, 3 supraglottic, 4 combined); 29 with MMC and 7 without MMC	2 groups; 0.4 mg/mL: 22 patients; 1 mg/mL: 7 patients (5 minutes)	CO2 laser + dilation or CO2 laser + dilation + MMC	37.4 months	Mean symptom-free time without MMC: 4.9 months; with MMC: 23.2 months	With MMC: 1 proc = 24 pat; > 1 proc = 5 pat (2 = 4; 3 = 1); Without MMC: 2 proc = 2 patients; ≥3 proc = 5 patients	not reported
Ubell et al¹⁰10 Ubell ML, Ettema SL, Toohill RJ, Simpson CB, Merati AL. Mitomy- cin-c application in airway stenosis surgery: analysis of safety and costs. Otolaryngol Head Neck Surg 2006;134(03):403-406. Doi: 10.1016/j.otohns.2005.10.057 https://doi.org/10.1016/j.otohns.2005.10... (2006), United States	Case series (August 2001–August 2005)	50 (3 supraglottic, 13 glottic, 15 subglottic, 5 tracheal, 14 combined)	0.4 mg/mL (Does not mention time of application)	CO2 laser + dilation + MMC	Not reported	Not reported	1.86/patient	Fungal infection (1)
Roediger et al¹¹11 Roediger FC, Orloff LA, Courey MS. Adult subglottic stenosis: management with laser incisions and mitomycin-C. Laryngoscope 2008;118(09):1542-1546. Doi: 10.1097/MLG.0b013e318179247a https://doi.org/10.1097/MLG.0b013e318179... (2008), United States	Case series (October 2004–January 2008)	15 subglottic	0.5 mg/mL (3 minutes)	CO2 laser + dilation + MMC	Mean of 18 months (3 to 39 months)	10/15	1 proc = 6 pat; > 1 proc = 9 pat (2 = 6; 3 = 2; 4 = 1)	Acute Lumen Obstruction (1)
							1 proc = 12 pat;2 proc = 14 pat
							1 proc = 4 pat;2 proc = 3 pat
							With MMC: 1 proc = 3 pat;> 1 proc = 7 pat (2 =2; 3 = 5);without MMC: > 1 proc = 2 pat(5 = 1; 7 = 1)
							> 2 proc = 29 pat;≤2 proc= 51 pat;220 procedures;interval between procedures: 405 days;more distal stenosis = more frequent procedures
Smith and Elstad³3 Smith ME, Elstad M. Mitomycin C and the endoscopic treatment of laryngotracheal stenosis: are two applications better than one? Laryngoscope 2009;119(02):272-283. Doi: 10.1002/lary.20056 https://doi.org/10.1002/lary.20056... (2009), United States	Case series (does not mention period)	26 subglottic	0.5 mg/mL (5 minutes)	1st - CO2 laser + dilation + MMC; 2nd - CO2 laser + dilation + (MMC or placebo)	5 years	21/26	1 proc = 6 pat;> 1 proc = 9 pat (2 = 6; 3 = 2; 4 = 1)	Zero
							1 proc = 12 pat;2 proc = 14 pat
							1 proc = 4 pat;2 proc = 3 pat
							With MMC: 1 proc = 3 pat;> 1 proc = 7 pat (2 =2; 3 = 5);without MMC: > 1 proc = 2 pat(5 = 1; 7 = 1)
							> 2 proc = 29 pat;≤2 proc= 51 pat;220 procedures;interval between procedures: 405 days;more distal stenosis = more frequent procedures
Madan et al¹²12 Madan K, Agarwal R, Aggarwal AN, Gupta D. Utility of rigid bronchoscopic dilatation and mitomycin C application in the management of postintubation tracheal stenosis: case series and systematic review of literature. J Bronchology Interv Pulmo- nol 2012;19(04):304-310. Doi: 10.1097/LBR.0b013e3182721290 https://doi.org/10.1097/LBR.0b013e318272... (2012), India	Case series (July 2009–August 2011)	7 (degree III)	0.4 mg/mL (2 minutes in each quadrant)	Dilation + MMC	27 days	1/7	1 proc = 6 pat;> 1 proc = 9 pat(2 = 6; 3 = 2; 4 = 1)	not reported
							1 proc = 12 pat;2 proc = 14 pat
							1 proc = 4 pat;2 proc = 3 pat
							With MMC: 1 proc = 3 pat;> 1 proc = 7 pat (2 =2; 3 = 5);without MMC: > 1 proc = 2 pat(5 = 1; 7 = 1)
							> 2 proc = 29 pat;≤2 proc= 51 pat;220 procedures;interval between procedures: 405 days;more distal stenosis = more frequent procedures
Gouveris et al¹³13 Gouveris H, Karaiskaki N, Koutsimpelas D, Chongolwatana C, Mann W. Treatment for adult idiopathic and Wegener-associated subglottic stenosis. Eur Arch Otorhinolaryngol 2013;270(03): 989-993. Doi: 10.1007/s00405-012-2240-z https://doi.org/10.1007/s00405-012-2240-... (2013), Germany and Thailand	Case-control (does not mention period)	12 subglottic (7 degree II and 5 degree I); 10 with MMC and2 without MMC	5 mg (10 minutes)	CO₂ laser + MMC or only CO₂ laser	With MMC: 7 to 72 months; without MMC: 18 to 115 months	8/10 with MMC; 2/2 without MMC	1 proc = 6 pat;> 1 proc = 9 pat(2 = 6; 3 = 2; 4 = 1)	not reported
							1 proc = 12 pat;2 proc = 14 pat
							1 proc = 4 pat;2 proc = 3 pat
							With MMC: 1 proc = 3 pat;> 1 proc = 7 pat (2 =2; 3 = 5);without MMC: > 1 proc = 2 pat(5 = 1; 7 = 1)
							> 2 proc = 29 pat;≤2 proc= 51 pat;220 procedures;interval between procedures: 405 days;more distal stenosis = more frequent procedures
Parker et al¹1 Parker NP, Bandyopadhyay D, Misono S, Goding GS Jr. Endoscopic cold incision, balloon dilation, mitomycin C application, and steroid injection for adult laryngotracheal stenosis. Laryngoscope 2013;123(01):220-225. Doi: 10.1002/lary.23638 https://doi.org/10.1002/lary.23638... (2013), United States	Case series (March 2000–December 2010)	80 (does not mention the type)	1 mg/mL (4 minutes)	Cold incision + balloon dilation + MMC application + steroid injection; open surgery = 8	2.9 years	Not reported	1 proc = 6 pat;> 1 proc = 9 pat(2 = 6; 3 = 2; 4 = 1)	Dyspnea (2) Subcutaneous emphysema (1) Laceration of vocal fold (1) Temporal vocal fold paralysis (1)
							1 proc = 12 pat;2 proc = 14 pat
							1 proc = 4 pat;2 proc = 3 pat
							With MMC: 1 proc = 3 pat;> 1 proc = 7 pat (2 =2; 3 = 5);without MMC: > 1 proc = 2 pat(5 = 1; 7 = 1)
							> 2 proc = 29 pat;≤2 proc= 51 pat;220 procedures;interval between procedures: 405 days;more distal stenosis = more frequent procedures
Viveiros et al¹⁴14 Viveiros F, Gomes J, Oliveira A, Neves S, Almeida J, Moura e Sá J. Aplicação tópica de mitomicina-C como adjuvante no tratamento broncoscópico da estenose traqueal pós-entubação. Rev Port Pneu- mol 2013;19(06):276-280. Doi: 10.1016/j.rppneu.2013.06.006 https://doi.org/10.1016/j.rppneu.2013.06... (2013), Portugal	Case series (2006–2012)	11 (9 complex, 2 simple)	0.4 mg/ml (3 minutes)	Dilation with rigid bronchoscope + MMC	27.5 months	6/11	1 proc = 5 pat;> 1 proc = 6 pat(2 = 2; > 2 = 4)	not reported
							1 proc = 6 pat;> 1 proc = 5 pat(2 = 4; 3 = 1)
							With MMC: 2,3/patients;without MMC: 2,0/patients;interval between procedures:375 days with MMC;186 days without MMC
							1 proc = 5 pat;> 1 proc = 17 pat(2 = 8; 3 = 3; 4 = 4; 5 = 2)
Vorasubin et al¹⁵15 Vorasubin N, Vira D, Jamal N, Chhetri DK. Airway management and endoscopic treatment of subglottic and tracheal stenosis: the laryngeal mask airway technique. Ann Otol Rhinol Laryngol 2014; 123(04):293-298. Doi: 10.1177/0003489414525340 https://doi.org/10.1177/0003489414525340... (2014), United States	Case series (2008–2011)	11 (6 subglottic, 2 tracheal, 3 combined)	0.4 mg/mL (4 minutes)	CO2 laser + dilation + MMC	28 months	9/11	1 proc = 5 pat; > 1 proc = 6 pat (2 = 2; > 2 = 4)	not reported
							1 proc = 6 pat;> 1 proc = 5 pat(2 = 4; 3 = 1)
							With MMC: 2,3/patients;without MMC: 2,0/patients;interval between procedures:375 days with MMC;186 days without MMC
							1 proc = 5 pat;> 1 proc = 17 pat(2 = 8; 3 = 3; 4 = 4; 5 = 2)
Reichert et al¹⁶16 Reichert LK, Zhao AS, Galati LT, Shapshay SM. The ef?cacy of mitomycin c in the treatment of laringotracheal stenosis: results and experiences with a dif?cult disease entity. ORL J Otorhinolar- yngol Relat Spec 2015;77(06):351-358. Doi: 10.1159/000439174 https://doi.org/10.1159/000439174... (2015), United States	Case-control (January 2005–May 2013)	37 subglottic; 15 without MMC and 22 with MMC	0.4 mg/mL (4 minutes)	CO₂ laser or CO₂ laser + MMC	10 months	15/22 with MMC; 6/15 without MMC	1 proc = 5 pat; > 1 proc = 6 pat (2 = 2; > 2 = 4)	Zero
							1 proc = 6 pat; > 1 proc = 5 pat (2 = 4; 3 = 1)
							With MMC: 2,3/patients; without MMC: 2,0/patients; interval between procedures: 375 days with MMC; 186 days without MMC
							1 proc = 5 pat; > 1 proc = 17 pat (2 = 8; 3 = 3; 4 = 4; 5 = 2)
Cataneo et al¹⁷17 Cataneo DC, Ximenes AMG, Cataneo AJM. Mitomycin C in the endoscopic treatment of tracheal stenosis: a prospective cohort study. J Bras Pneumol 2018;44(06):486-490. Doi: 10.1590/S1806- 37562017000000423 https://doi.org/10.1590/S1806-... (2018), Brazil	Prospective cohort (2003–2010)	22 (4 subglotic, 14 tracheal, 4 combined)	0.5 mg/mL (2 minutes)	Dilation + MMC	> 1 year	14/22	1 proc = 5 pat; > 1 proc = 6 pat (2 = 2; > 2 = 4)	Mediastinal emphysema (2) Granuloma (1)
							1 proc = 6 pat;> 1 proc = 5 pat(2 = 4; 3 = 1)
							With MMC: 2,3/patients;without MMC: 2,0/patients;interval between procedures:375 days with MMC;186 days without MMC
							1 proc = 5 pat;> 1 proc = 17 pat(2 = 8; 3 = 3; 4 = 4; 5 = 2)

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[1] Address for correspondence Regina H. G. Martins, MD, PhD, Departamento de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Faculdade de Ciências Médicas e Biológicas de Botucatu, Universidade Estadual Paulista, Distrito de Rubião Junior s/n, 18618-970, Botucatu, SP, Brazil (e-mail: Regina.g.martins@unesp.br).