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Topical Mitomycin Application After Laryngotracheal Reconstruction
A Randomized, Double-blind, Placebo-Controlled Trial
Christopher J. Hartnick, MD;
Benjamin E. J. Hartley, MD;
Peter D. Lacy, MD;
James Liu, MD;
Judy A. Bean, PhD;
J. Paul Willging, MD;
Charles M. Myer III, MD;
Robin T. Cotton, MD
Arch Otolaryngol Head Neck Surg. 2001;127:1260-1264.
ABSTRACT
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Objective To explore the effect of mitomycin treatment on the pediatric airway
following laryngotracheal reconstruction.
Design Randomized, double-blind, placebo-controlled trial.
Patients Children aged 2 to 17 years with subglottic or upper tracheal stenosis
undergoing laryngotracheal reconstruction at a single, tertiary care, children's
hospital.
Intervention At the time of extubation or stent removal, the children underwent bronchoscopy
and 0.4 mg/mL (2 mL of a 0.2-mg/mL solution of either mitomycin or an equal
volume of isotonic sodium chloride was directly applied to the subglottic
region for a single application of 2 minutes. These children then underwent
interval endoscopy at 2 weeks, 6 weeks, and 3 months postoperatively for assessment
of their airways.
Results Granulation tissue was graded on a scale of 0 (none) to 4 (near-total
or total occlusion). Videotapes of endoscopies were independently observed
and graded by 3 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, interim analysis was performed by a Data Safety and Monitoring Committee.
At this time, 13 children had been randomized to the mitomycin-treated arm
of the study and 11 children to the placebo-treated arm. A 2-tailed Fisher
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 2 populations were almost identical.
Conclusion We cannot reject the null hypothesis that a single topical dose of mitomycin
exerts an equal benefit as does isotonic sodium chloride when applied to the
pediatric airway after laryngotracheal reconstruction.
INTRODUCTION
THE ISSUE of restenosis following pediatric laryngotracheoplasty or
cricotracheal resection is a difficult and challenging problem. Many techniques
including postoperative stenting and the use of the carbon dioxide laser have
been employed to address this complication; however, the incidence of restenosis
following these airway procedures persists at 20% to 40% depending on the
initial grade of the stenosis.1 It follows
that the incidence of granulation tissue following operative repair for grade
3 and 4 lesions may well be significantly higher than this quoted figure.
Mitomycin is an antineoplastic antibiotic derived from Streptomyces caespitosus; it acts as an alkylating agent to inhibit
DNA synthesis as well as to inhibit cell division and fibroblast proliferation.
Mitomycin represents one possible nonsurgical means of reducing postoperative
granulation and scar tissue formation.
Mitomycin has been used for some time by opthalmologists to reduce scarring
following surgery for glaucoma. Its efficacy and safety have been shown in
numerous animal and clinical trials.2-4
At a cellular level, Khaw et al5 have shown
the demonstrable effects of mitomycin on cell proliferation and cellular morphology.
In the field of otolaryngology, topical administration of mitomycin has been
shown to delay the closing time of maxillary antrostomies in the rabbit model.6 Specifically regarding the issue of laryngotracheal
stenosis and postoperative scar formation, there have been several studies
that have addressed the issue. Ward and April7
looked retrospectively at a series of 70 patients who underwent some type
of laryngotracheal reconstruction and identified 5 cases in which restenosis
had been a significant issue requiring multiple surgical procedures without
resolution. They administered mitomycin topically just after laser excision
at a dose of 0.2 mg/mL for a period of 2 minutes. They reported that the amount
of scarring after this topical administration of mitomycin was significantly
reduced and that 3 of the 5 patients were able to be decannulated and remained
so to an end point of 2 years in the case of at least 1 patient. Of issue
in this study is that it is a single-arm study in which the initial stage
of stenosis is not clearly stated and, therefore, the exact effect of mitomycin
is difficult to measure.
Rahbar et al8 described another single-arm
study in which they administered mitomycin topically after endoscopic laser
treatment for posterior glottic or subglottic stenosis, or both, and noted
improvement of symptoms and airway diameter. They administered either mitomycin
in a dose of 0.4 mg/mL or isotonic sodium chloride for a duration of 2 to
4 minutes. Their outcome measurement was based on the resolution of patients'
symptoms and on an increase in the size of the airway. Again, this is a single-arm
study in which the effects of mitomycin are difficult to quantify; moreover,
the outcome measurement of airway size is qualitative and difficult to assess
critically.
Eliashar et al9 have examined the role
of mitomycin on laryngotracheal stenosis in the dog model by iatrogenically
injuring the canine larynx or trachea and then administering topical mitomycin,
0.2 mg/mL. They found that over a 21-day postoperative period, a single dose
of mitomycin significantly reduced the amount of laryngotracheal stenosis.
A second administration of mitomycin was of no additional benefit.
Three randomized controlled studies examining the effects of mitomycin
on the airway have been undertaken previously in animal models. Correa et
al10 used a canine model in which they created
radial incisions to the subglottic region and treated these incisions with
either a 1% solution of mitomycin with a single application for 5 minutes
or with a control where no application was administered. They were able to
confirm statistically that dogs treated with mitomycin exhibited a larger
airway with decreased collagen and scar formation. Spector et al11
also used a canine model and created laser incisions to the glottis of 16
dogs. Compared with controls, a single application of 1% mitomycin for an
application of 3 minutes significantly reduced the amount of postoperative
granulation tissue. However, Coppit et al12
used a pig model and examined the effect of mitomycin compared with a control
after single-stage laryngotracheal reconstruction and stenting. They administered
0.5 mg/mL of mitomycin over 2 minutes for a total of 2 applications of mitomycin
per animal. They found that there was no statistically significant difference
in the amount of inflammatory tissue between the mitmoycin-treated and the
control pigs.
This study represents the next step in the investigation of mitomycin
and its effect on the airway. Whereas there have been single-arm human clinical
studies, the only randomized controlled studies to date have involved animals.
By establishing a randomized, double-blind, placebo-controlled study, we hope
to be able to shed light on the human paradigm of mitomycin as it affects
the airway.
PATIENTS, MATERIALS, AND METHODS
INCLUSION AND EXCLUSION CRITERIA
All children younger than 18 years who had grades 3 and 4 Myer-Cotton
stage laryngotracheal stenosis when undergoing either laryngotracheoplasty
or cricotracheal resection with postoperative stenting were enrolled in the
study during the period of the study (September 1, 1999, to September 1, 2000).
Male and female patients and all minorities were equally enrolled. The sole
criterion was the severity of laryngotracheal stenosis and that the type of
surgery require some form of postoperative stenting whether that be from a
suprastomal stent, a T-tube, or an endotracheal tube. Patients who have had
previous endolaryngeal topical application of mitomycin were excluded from
this study.
PROTOCOL
The parents or primary caregivers of patients enrolled in the study
were each informed of the study and were enrolled after signing an institutional
review board–approved informed consent (IRB 99-7-16). When the stent
was removed (any form of stent), all children received an intravenous dose
of 0.5 mg/kg of dexamethasone acetate (Decadron); this dose was repeated at
postoperative days 2 and 4 for all patients. Patients then received either
a single topical application of 0.4 mg/mL of either mitomycin for 2 minutes
or isotonic sodium chloride. The surgeon was blinded to the type of topical
medication applied; the solution consisted of 1 of the 2 agents (mitomycin
or control) that were prepared and numbered in advance and then chosen according
to a random number generation list provided by the pharmacy.
The postoperative follow-up consisted of the routine follow-up for children
operated on at Children's Hospital Medical Center, Cincinnati, Ohio. The children
underwent interval laryngoscopy and bronchoscopy at 2 weeks, 6 weeks, and
3 months after the stents were removed. At each interval evaluation, the amount
of granulation tissue and the airway diameter were recorded. The following
0- to 4-point scoring system was used for rating the amount of granulation
tissue: 0, none; 1, single focus of granulation tissue; 2, multiple small
foci, polyps; 3, moderate polypoid tissue; and 4, near-total or total occlusion
with granulation tissue. The airway diameter was graded according to the Myer-Cotton
grading system.13
INTERIM ANALYSIS
The study was designed so that, at the 1-year mark, an independent Data
Monitoring and Safety Committee whose members were chosen by the Children's
Hospital Medical Center statistician (J.A.B.) would review the data for adverse
outcomes, as well as to identify whether there was a valid reason to end the
study early.
STATISTICAL ANALYSES
Interobserver Agreement for Granulation Tissue Grading Scale
The grading system for assessment of endoluminal granulation tissue
was established and the 3 pediatric otolaryngology fellows (C.J.H., B.E.J.H.,
and P.D.L.) who would be involved in all of the postoperative endoscopies
each independently reviewed 36 videotapes of postoperative endoscopies and
assigned scores to each according to the amount of granulation tissue. There
was disagreement among the 3 fellows only on 3 of the 36 endoscopies for an
overall interobserver agreement of 91.6%. For the 3 cases in which there was
disagreement, the disparity was never greater than 1-grade difference in opinion.
Sample Size Calculations
The main outcome measure chosen for statistical evaluation was the average
granulation grade at the third and fourth visits. The grades were dichotomized
according to clinical relevance; it was hypothesized that patients with grades
0 through 2 would not require further open reconstructive surgery, whereas
patients with grades 3 or 4 would need further surgery. The power for statistical
calculations was established at 0.8%; the  level was .05. We hypothesized
that 70% of the patients treated with placebo and 30% of the patients treated
with mitomycin would be graded as grade 3 or 4 for an overall treatment difference
of 40%. Given these parameters, the sample size needed was calculated to be
23 patients per arm.
Outcome Analysis
Using the dichotomized, binomial variables as described earlier, a 2-tailed
Fisher exact test analysis was chosen for analysis. If there was a statistically
significant difference between the 2 populations, a Mantel-Haenszel test for
trend was chosen to shed more light on this difference between the populations.
RESULTS
Over the first year of the study, 24 patients were enrolled. Their diagnoses
consisted of posterior glottic, subglottic, or upper tracheal stenosis. Twenty-two
of the 24 had acquired an abnormal condition; 2 children had congenital subglottic
stenosis. Eighteen of the 24 patients underwent single-stage laryngotracheal
reconstruction or cricotracheal resection. All 18 patients received endotracheal
tubes as interim stents. The remaining 6 patients had an assortment of stents
placed that consisted of either an above stoma stent (or, in 1 case, a glottic
keel). The demographics for all 24 patients are given in Table 1.
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Demographics of 24 Pediatric Patients Who Received Mitomycin or Placebo
Treatment After Laryngotracheal Reconstruction*
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At the 1-year mark, the Data Monitoring and Safety Committee reviewed
the data for all 24 patients. The dichotomous results, using the Fisher 2-tailed
exact test, for patients receiving either mitomycin or placebo were as follows:
(1) those with an average granulation grade of 3 or 4 and mitomycin treated,
3 patients; placebo treated, 1 patient; (2) those with an average granulation
grade of 0 through 2 and mitomycin treated, 11 patients; placebo treated,
10 patients. A Fisher 2-tailed exact test was performed and calculated as
1.00. The Data Monitoring and Safety Committee advised that the trial should
be stopped because the distributions between the 2 patient populations were
almost identical.
COMMENT
In designing this randomized, double-blind, placebo-controlled trial,
the goal was to establish a working paradigm where the potential confounding
factors would be evenly distributed between the 2 populations. Focusing on
pediatric airway reconstructions in which a stent was involved seemed to be
a reasonable model because there was a definable starting point for each case
when the stent was removed. The initial diagnoses were fairly uniform as were
the surgical reconstructive procedures. Table 1 illustrates how the various procedures and choice of stents
were distributed evenly between the mitomycin-treated and control groups.
The decision of an outcome parameter to be observed and monitored for
statistical analysis was made with the knowledge that many of the possibilities
would be directly influenced by the initial pathologic condition, the type
of surgery, or the type of graft chosen. For this reason, we decided not to
use operation-specific or overall extubation or decannulation rates as an
outcome measure. We also decided that although there was a semiquantitative
means of assessing the size of the airway, still this end point was influenced
more by the surgical procedure than by the use or avoidance of mitomycin treatment.
Short of histopathologic analysis, the development of postoperative granulation
tissue relative to the application of either mitomycin or placebo seemed a
reasonable outcome parameter as previously cited work has focused on the effect
of mitomycin on this development. The creation and validation of a grading
scale facilitated statistical analysis.
About the administration of mitomycin itself, the dosage, length of
application time, and amount of applications were each chosen by reviewing
the literature for established benchmarks. Mitomycin has been applied to the
human and animal airway in dosages of 0.1 to 10 mg/mL.7, 9-10,12
In the human clinical model, previous literature has documented dosages from
0.1 to 0.4 mg/mL. We chose a dosage of 0.2 mg/mL as it was the dosage that
had been used in the only previously reported on application following laryngotracheal
reconstruction.7
The duration of topical application has also varied in the literature
from 1 to 5 minutes.7, 9-12
Most of the citations referenced used an application time of 2 to 3 minutes;
we chose a 2-minute application time to be a conservative but effective time
frame.
Neither dosage nor application time has been studied in any form of
titration study, therefore the choices were made by comparing different studies.
The number of applications of mitomycin for maximum effectiveness has been
investigated, at least in a preliminary fashion, by Eliashar et al.9 As they found that a second application of mitomycin
yielded no more results than a single application, we decided to limit the
number of applications to 1.
Given the negative findings documented by this study, the choices made
about dosage, application time, and number of applications all must be regarded
as possible factors that, if altered, may well have changed the study's outcome.
We chose conservatively in our decisions as to these values, in part because
this was an area of research in which previous titration studies had not been
performed; we were concerned with the possibilities of potential adverse effects
and morbidities from the application of mitomycin. No adverse effects were
seen for any of the patients who were treated with mitomycin. Moreover, the
vast majority of patients who received mitomycin treatment exhibited granulation
with grades of 0 through 2. This would suggest that a single application of
mitomycin at the defined dose, when applied for 2 minutes, is effective in
inhibiting the development of granulation tissue. The problem that confounded
statistical analysis was not the results seen in the mitomycin-treated group,
rather it was those seen in the control population. Ten of the 11 children
treated with placebo exhibited postoperative granulation that was graded as
0, 1, or 2. This suggests that although a significant proportion of children
may develop granulation tissue subsequent to airway reconstruction and stent
placement, this granulation tissue may not be exuberant enough to allow for
this form of comparative study. All patients in the study received a course
of corticosteroids and this may have produced an overall decrease in granulation
tissue formation. The decision was made to offer corticosteroid treatment
for all because corticosteroids are given in an anecdotal fashion according
to the appearance of the airway. It appeared that it would be more reasonable
and ethical to give a short course of corticosteroids to all rather than witholding
it from those who might need it.
The decision to stop the study before the appropriate sample size was
obtained was not made lightly. The use of an independent Data Monitoring and
Safety Committee to review the data at appropriate intervals is a well-established
mechanism for ensuring that no untoward adverse effects are occurring. Interval
analysis also allows for heavily positive findings to be discovered in a timely
fashion; such early findings would spur the argument that it would be unethical
to continue a study and continue to give some population a placebo. Similarly,
if the interval findings show identical or near-identical outcomes where the
distributions are approximate to a level that it is believed that statistically
significant differences cannot be achieved, the argument is raised that it
may be unethical to allow for the possibility of untoward adverse effects
when the outcome of the study is already known. One of the critical points
that frames this decision is a firm knowledge of the nature of the assumptions
that were made to make projections and to calculate sample size initially.
In the case of this study design, we projected that there would be a 40% difference
in the incidence of significant granulation tissue formation postoperatively
between the 2 populations studied. Examining the data shows that the difference
in the incidence of significant granulation tissue formation between the 2
groupings is statistically negligible and this is perhaps the critical reason
why the study's conclusions would not have deviated from the interval projections
if the calculated sample size had been achieved.
After a close review of the data, it becomes clear that although the
dose, application time, number of applications, as well as a host of other
factors may play a role in the outcomes of studies such as this, still the
central deficit that future studies will need to address is to define a model
where the granulation tissue seen within the control population is at a level
high enough so that comparisons can be made when a given therapy significantly
alters the equation and diminishes the amount of granulation tissue. It may
be that future studies in which corticosteroids are not administered to each
patient would allow for an adequate control population and would illuminate
treatment differences specific to mitomycin.
No significant difference in granulation tissue formation was noted
in the only 1 of the 3 randomized trials involving animals in which the effect
of mitomycin after stent placement was examined.12
Models that have illustrated the greatest benefit of mitomycin regarding the
airway have consisted of models in which radial incisions are made with the
carbon dioxide laser, mitomycin is topically applied, and the airway is then
examined prospectively. To answer the question of whether mitomycin affects
granulation tissue and scar tissue formation in the airway, perhaps another
model would be to look at procedures in which discrete laser incisions are
made (eg, arytenoidectomies, cordotomies, or treatment of more minor subglottic
stenosis). A consistent grading system for measuring outcome parameters would
need to be tailored to this study design, and the number of patients required
might well necessitate a multi-institutional effort; however, such a study
holds the potential for enough of a difference between the treated and control
populations to be apparent such that meaningful conclusions could be drawn.
Until such a study is performed, the sole conclusion we can draw from the
findings of our study is that we can reject the null hypothesis established
to frame our study that a single topical 0.2-mg/mL dose of mitomycin exerts
an equal benefit to a dose of isotonic sodium chloride when applied to the
pediatric airway after laryngotracheal reconstruction.
AUTHOR INFORMATION
Accepted for publication March 27, 2001.
Presented in part at the American Society for Pediatric Otolaryngology,
Camelback Mountain, Ariz, May 11, 2001.
Corresponding author and reprints: Christopher J. Hartnick, MD, Havard
Medical School, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary,
243 Charles St, Boston, MA 02114 (e-mail: christopher_hartnick{at}meei.harvard.edu).
From the Departments of Pediatric Otolaryngology (Drs Harnick, Hartley,
Lacy, Liu, Willging, Myer, and Cotton) and Biostatistics (Dr Bean), Children's
Hospital Medical Center, Cincinnati, Ohio. Dr Hartnick is now with Harvard
Medical School, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary,
Boston.
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