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2193
A Randomized Trial of a Nonabsorbable
Antibiotic Lozenge Given to Alleviate
Radiation-Induced Mucositis
Scott H. Okuno, M.D.1
Robert L. Foote, M.D.1
Charles L. Loprinzi, M.D.1
Sunil Gulavita, M.D.2
Jeff A. Sloan, Ph.D.1
Julie Earle, R.N.1
Paul J. Novotny, M.S.1
Mary Burk, R.N.1
Albert R. Frank, M.D.3
BACKGROUND. The objective of this study was to determine whether a nonabsorbable antibiotic lozenge could alleviate radiation-induced oral mucositis.
METHODS. Patients scheduled to receive radiation therapy to more than one-third
of the oral cavity mucosa were selected for the study. After stratification, patients
were randomized to receive either a nonabsorbable antibiotic lozenge or a placebo.
Both groups were then evaluated for mucositis by health care providers and selfreport instruments.
RESULTS. Fifty-four patients were randomized to receive the antibiotic lozenge
1
Mayo Clinic and Mayo Foundation, Rochester,
Minnesota.
2
Thunder Bay Regional Cancer Centre, Thunder
Bay, Ontario, Canada, an affiliate of Duluth Community Clinical Oncology Program, Duluth, Minnesota.
3
Nebraska Oncology Group–Creighton University, University of Nebraska Medical Center, and
Associates, Omaha, Nebraska.
and 58 to receive the placebo. There were no substantial differences or trends in
mucositis scores between the two study arms as measured by the health care
providers. However, the mean patient-reported mucositis score and the duration
of patient-reported Grade 3–4 mucositis were both lower in the patients randomized to the antibiotic lozenge arm (P Å 0.02 and 0.007, respectively).
CONCLUSIONS. This prospective, controlled trial provides evidence to suggest that a
nonabsorbable antibiotic lozenge can decrease patient-reported radiation-induced
oral mucositis to a modest degree. Nonetheless, this evidence does not appear to
be compelling enough to recommend this treatment as part of standard practice.
Cancer 1997;79:2193–9. q 1997 American Cancer Society.
KEYWORDS: mucositis, radiation, antibiotic lozenge, head and neck carcinoma,
placebo-controlled trial.
M
ucositis is a major toxicity associated with radiation therapy administered to the oral cavity.1 Mouth soreness and ulceration
can be quite painful, frequently requiring the use of analgesic medications. It may interfere with a patient’s ability to maintain an adequate
Conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic.
Presented at the American Society of Clinical
Oncology Annual Meeting, Philadelphia, PA,
May 18–21, 1996.
Supported in part by Public Health Service grants
CA-25224, CA-37404, CA-15083, CA-35269, CA52352, CA-35101, CA-60276, CA-37417, CA35195, CA-35448, CA-35103, and CA-35415.
Additional participating institutions include: Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa (Martin Wiesenfeld, M.D.); Iowa On-
cology Research Association CCOP, Des
Moines, Iowa (Roscoe F. Morton, M.D.); Rapid
City Regional Oncology Group, Rapid City,
South Dakota (Larry P. Ebbert, M.D.); Mayo
Clinic Scottsdale CCOP, Scottsdale, Arizona
(Robert F. Marschke Jr., M.D.); Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada
(Andrew W. Maksymiuk, M.D.); CentraCare
Clinic, St. Cloud, Minnesota (Harold E.
Windschitl, M.D.); Meritcare Hospital CCOP,
Fargo, North Dakota (Ralph Levitt, M.D.); Carle
Cancer Center Community Clinical Oncology
Program, Urbana, Illinois (Alan K. Hatfield,
M.D.); Geisinger Clinical Oncology Program,
q 1997 American Cancer Society
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Danville, Pennsylvania (Suresh Nair, M.D.);
Grand Forks Clinic, Ltd., Grand Forks, North
Dakota (John A. Laurie, M.D.); Siouxland Hematology-Oncology Associates, Sioux City, Iowa
(John C. Michalak, M.D.); and Toledo Community Clinical Oncology Program, Toledo, Ohio
(Paul L. Schaefer, M.D.).
Address for reprints: Charles Loprinzi, M.D.,
Mayo Clinic, 200 First Street, SW, Rochester,
MN 55905.
Received November 1, 1996; revision received
January 23, 1997; accepted January 23, 1997.
2194
CANCER June 1, 1997 / Volume 79 / Number 11
TABLE 1
Mucositis Grading Criteria
Grade
Criteria
0
1
2
3
4
No mucositis
Soreness/erythema
Erythema/ulcers/able to eat solids
Ulcers/required liquid diet only
Alimentation not possible
TABLE 2
Distribution of Baseline Factors
Baseline factors
Denturesa
Yes
No
Smoking historya
None
Yes, currently
Past only
Planned radiation dose
(grays)
30.00–44.99
45.00–50.00
50.01–60.00
ú 60.00
Planned fluoride usea
Yes
No
Amount of oral mucosa in the
radiation fielda
1/3 to 2/3
ú 2/3
Gender
Female
Male
Alcohol use
None
Social
Heavy
Age (yrs)
Median
Mean
a
Antibiotic
lozenge
(n Å 54)
Placebo
preparation
(n Å 58)
27
27
27
31
0.85
13
5
36
15
8
35
0.72
1
4
15
34
0
4
20
34
0.77
33
21
36
22
0.99
P value
FIGURE 1. Mean mucositis score as determined by health care providercompleted questionnaires for patients in (A) the four treatment arms and
(B) the pooled antibiotic lozenge and placebo groups.
43
11
45
13
0.82
17
37
19
39
0.99
28
22
4
25
29
4
0.44
61
59
65
62
0.38
of certain human tumors, particularly squamous cell
carcinomas of the head and neck region.2 – 12
There are no established measures for preventing
radiation-induced mucositis in humans. A recent pilot
trial involving a lozenge containing a combination of
three relatively nonabsorbable antibiotics (tobramycin, polymyxin E, and amphotericin B) in 15 patients undergoing radiation therapy to their oral cavities reported strikingly less mucositis relative to comparable historic controls.13 Additional pilot information
with this approach was also promising.14 This article
describes the results of a trial designed to prospectively evaluate this potential therapy in a placebo-controlled manner.
Stratification factors.
PATIENTS AND METHODS
intake of food and liquids. Severe mucositis may require temporary or permanent cessation of radiation
therapy prior to completion of the planned radiation
treatment program. There is strong clinical and radiobiologic evidence that protraction of overall treatment
time has an adverse influence on the radiocurability
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Patient Eligibility
Adult patients considered for entry onto this clinical
trial must have been scheduled to receive radiation
therapy at a North Central Cancer Treatment Groupapproved radiation oncology facility. At least one-third
of the oral cavity mucosa needed to be included in the
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Antibiotic Lozenge for Radiation-Induced Mucositis/Okuno et al.
2195
FIGURE 3. Mean mucositis scores as determined by patient-completed
FIGURE 2.
Percent of patients with severe or very severe mucositis as
determined by health care provider-completed questionnaires for patients in
(A) the four treatment arms and (B) the pooled antibiotic lozenge and placebo
groups.
TABLE 3
Measures of Mucositis Evaluated by Health Care Provider
Efficacy variable
Maximum mucositis
Mild
Moderate
Severe
Very severe
Overall mean weekly
mucositis scorea
Mean number of weeks of
severe and very severe
mucositis
Antibiotic
lozenge
(n Å 54)
Placebo
preparation
(n Å 58)
(n Å 49)
7
21
17
4
(n Å 54)
6
16
27
5
(n Å 49)
1.48
(n Å 54)
1.56
0.85
(n Å 49)
1.04
(n Å 54)
1.31
0.18
a
P value
0.16
Mean weekly mucositis score was the sum of all weekly mucositis scores divided by the total number
of weeks reported.
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questionnaires for patients in (A) the four treatment arms and (B) the
pooled antibiotic lozenge and placebo groups.
radiation therapy fields, and the planned dose must
have been ¢ the following values: 1) 45 grays (Gy)
using 1.20 – 2.20 Gy per fraction, or 2) 30 Gy using ¢3.0
Gy per fraction. Patients were required to be entered
onto the study before the fourth fraction of radiation
therapy. Patients were ineligible for this study if they
had open mouth sores at study entry, had received
prior radiation therapy to the oral mucosa, were receiving concomitant chemotherapy, or were using
other prophylactic drugs or mouthwashes (with the
exception of alkaline saline solutions).
Study Design
Patients were stratified before randomization by the
following: 1) whether they wore dentures; 2) smoking
history; 3) planned total radiation therapy dose; 4)
planned use of fluoride (more than using a fluoride
toothpaste); and 5) the amount of the oral mucosa in
the radiation field (° vs. ú two-thirds). In addition,
information was collected regarding the use of alcohol,
although this was not used as a stratification factor.
Patients were subsequently randomized to 3 treatment arms: 1) a chlorhexidine mouthwash, 15 mL, 4
times daily (used as a 30-second mouth rinse, then
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CANCER June 1, 1997 / Volume 79 / Number 11
TABLE 4
Measures of Mucositis Evaluated by Patients
Efficacy variable
Maximum mucositis
None
Mild
Moderate
Severe
Very severe
Overall mean weekly mucositis scorea
Mean number of weeks of severe and
very severe mucositis
Antibiotic
lozenge
(n Å 54)
Placebo
preparation
(n Å 58)
(n Å 52)
2
5
6
35
4
(n Å 52)
1.61
(n Å 56)
4
3
2
39
8
(n Å 56)
1.95
0.02
(n Å 52)
2.71
(n Å 56)
3.70
0.04
P value
0.21
a
Mean weekly mucositis score was the sum of all weekly mucositis scores divided by the total number
of weeks reported.
FIGURE 4. Percent of patients with severe or very severe mucositis as
determined by patient-completed questionnaires for patients in (A) the
four treatment arms and (B) the pooled antibiotic lozenge and placebo
groups.
expectorated without swallowing) throughout the period of radiation therapy and for 2 weeks thereafter;
2) a placebo mouthwash, which appeared identical to
the chlorhexidine mouthwash and was used in the
same schedule; or 3) an oral nonabsorbable antibiotic
lozenge comprised of 10 mg of amphotericin B, 1.8
mg of tobramycin, and 20 mg of polymyxin E. Patients
were instructed not to eat or drink for 30 minutes after
each lozenge or mouthwash. If the treatment assignment was to either of the mouthwash arms, only a
coded bottle number was communicated to the treatment center. A planned interim analysis performed
after 75 patients (50% of planned accrual) had been
entered discovered that the chlorhexidine arm appeared detrimental. This portion of the study subsequently was closed and reported.15
The protocol was then modified to delete the
mouthwash arms but to assess the lozenge in a double-blinded manner because results for the nonblinded antibiotic lozenge arm appeared promising
(compared with the placebo mouthwash). An identical-appearing placebo lozenge was developed, and
subsequent patients were randomized to receive anti-
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biotic versus placebo lozenges in a traditional doubleblinded, two-arm design.
Lozenges were to be sucked until they completely
dissolved and were to be administered four times daily
throughout radiation therapy and for two subsequent
weeks. Nothing was to be taken orally for 30 minutes after
each dose.
Each patient was given oral and written instructions at study entry regarding standard mouth care
procedures during the course of radiation therapy.
These included instructions to drink 6 to 8 glasses of
water per day, to brush the teeth after each meal with
a soft toothbrush and a noncommercial toothpaste, to
rinse and cleanse the oral cavity every 2 hours
throughout the day with either the study mouthwash
(for 4 doses per day for those assigned to receive a
mouthwash) or a solution containing one-half teaspoon salt and one-half teaspoon baking soda mixed
in a large glass of warm water, and to avoid such products as commercial mouthwashes, tobacco, alcoholic
beverages, very hot, cold, or spicy foods, acidic foods,
fruit drinks, and hard or coarse foods. It was recommended that patients be evaluated by a dentist prior
to beginning radiation therapy.
Patients were to be examined by a radiation oncologist or radiation oncology nurse at least weekly to
grade their oral mucositis according to World Health
Organization criteria (Table 1).16 In addition, patients
were requested to fill out questionnaires (by which
they scored their own mucositis) on a weekly basis
throughout the course of radiation therapy and for 4
weeks thereafter. The patient’s weight, use of analgesic
agents, antibiotics, antifungal agents, mouthwashes
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Antibiotic Lozenge for Radiation-Induced Mucositis/Okuno et al.
other than the study mouthwash, and tube feedings,
as well as treatment interruptions and length of interruptions, were documented.
The original accrual goal was to enter 50 assessable patients into each of the study arms so that a onesided 0.02-level Wilcoxon test comparing the study
agent against a placebo would have 90% power to detect reductions in mucositis severity considered clinically meaningful. Specifically, a clinically significant
effect was defined as obtaining results such that half
the study agent mucositis grades were identical to the
placebo grades and the other half were one class less
severe, e.g., mild rather than moderate. The distributions of baseline factors were compared between the
two treatment arms using Fisher’s exact test for categoric variables and Wilcoxon tests for ordinal level
data.
Between May 1991 and April 1993, 29 patients
were randomized to receive the unblinded antibiotic
lozenge, 25 patients were randomized to receive the
chlorhexidine mouthwash, and 31 patients were randomized to receive a placebo mouthwash. Between
October 1993 and July 1994, another 26 patients were
randomized to receive the blinded antibiotic lozenge,
whereas 27 patients were assigned to receive the
blinded placebo lozenge. One patient on the unblinded antibiotic lozenge arm was determined to be
ineligible. Hence a total of 112 eligible patients were
randomized to receive antibiotic lozenges (54 patients)
versus a placebo preparation (58 patients).
Toxicity and efficacy measures were compared between the blinded placebo lozenge (n Å 27) and
blinded antibiotic lozenge (n Å 26) groups. Subsequent comparisons were made between the blinded
and unblinded antibiotic lozenge to determine
whether blinding had any impact on efficacy or toxicity. Cross-validation of placebo results were performed
by comparing the placebo lozenge and placebo
mouthwash groups. Finally, pooling of both of the placebo groups (mouthwash and lozenge) and both of
the antibiotic lozenge groups (blinded and unblinded)
was performed because no significant differences were
found in the previous two procedures. This allowed for
an omnibus verification of placebo versus antibiotic
lozenge with increased sample size and power.
Toxicity was measured by the incidence of patient-reported or health care provider-observed side
effects and by measures derived from the patient questionnaires. These were comprised of 1) the maximum
grade of burning, discomfort, or pain caused by the
study medication; 2) the maximum grade of taste alteration; 3) the maximum grade of teeth staining; and 4)
an incidence measure as to whether the patient be-
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2197
lieved that the study medication was producing any
side effects.
Treatment efficacy was compared in terms of the
maximum severity and duration of mucositis and the
average daily level of mucositis. The percentage of
time with severe or very severe mucositis and area
under the curve (AUC) of reported mucositis over the
course of the study were also used as measures of
treatment effectiveness. The distributions of these effect variables were compared among the treatment
arms by log rank testing for the duration of mucositis,
Fisher’s exact test for categoric variables, and Wilcoxon tests for the ordinal level data.
Because multiple variables were used to assess efficacy, the authors applied the O’Brien Global Test17
to provide a single P value simultaneously comparing
the two pooled arms with respect to maximum mucositis severity reported by the patient and the health
care provider, the average weekly mucositis grade reported by the patient and the health care provider,
the percentage of days with severe/very severe pain
reported by the patient and the health care provider,
the area under the patient-reported mucositis curve,
and the number of breaks in radiation therapy.
RESULTS
Because the initial study goal was to have 50 patients
per study arm, the major planned analysis was a comparison between the patients who were randomized
to receive the antibiotic lozenge arm (n Å 54) versus
those randomized to receive the placebo (n Å 58). That
is, the unblinded lozenge data from the first study
would be combined with the blinded lozenge data
from the second study and the placebo mouthwash
data from the first study would be combined with the
placebo lozenge data from the second study unless
there was convincing evidence of their noncomparability.
Table 2 summarizes the baseline patient characteristics of the two pooled treatment groups. No substantial differences in any of these characteristics were
found. Moreover, equivalent proportions (64%) of the
patients in the two groups completed the planned
study therapy.
Mucositis severity data reported by the health care
providers are illustrated in Figures 1 and 2 and summarized in Table 3. These show that there were no
substantial differences or substantive trends in mucositis scores as measured by health care providers either
among the four treatment arms or between the two
pooled treatment groups. Furthermore, there were no
differences in the number or duration of radiation
therapy interruptions.
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CANCER June 1, 1997 / Volume 79 / Number 11
Patient-reported mucositis scores are illustrated
in Figures 3 and 4 and summarized in Table 4. Although the mucositis scores in the unblinded lozenge
arm were generally lower that those in the other arms,
they were not quite significantly different from those
in the blinded lozenge arm (AUC P Å 0.06). Because
there was no significant difference in the mucositis
scores in the 2 placebo arms (AUC P Å 0.14), the
planned pooled analysis was performed. The mean
weekly mucositis score of the patients in the pooled
lozenge group was 1.6 versus 2.0 for the pooled placebo group (P Å 0.02). In addition, the antibiotic lozenge patients scored themselves as having a shorter
duration of Grade 3 – 4 mucositis (median 2.7 weeks
vs. 3.7 weeks; P Å 0.04).
The O’Brien Global Test17 combining the results
of all the efficacy measures into a single comparison
between the pooled antibiotic lozenge and pooled placebo groups indicated a statistically superior efficacy
for the pooled antibiotic lozenge group (P Å 0.02).
Toxicities were assessed primarily by open-ended
questions on the weekly questionnaires. The few nausea/upset stomach reports were observed in equivalent numbers in both pooled groups. There were no
reports of diarrhea on any of the treatment arms.
Currently, there is no established prophylactic
method to decrease radiation-induced oral mucositis.
Furthermore, despite preliminary data suggesting that
chlorhexidine could decrease radiation-induced mucositis,18,19 the authors’ recently reported doubleblind, placebo-controlled, randomized trial failed to
determine any benefit for the chlorhexidine mouthwash.15
Pilot data from two sources suggested that nonabsorbable antibiotic lozenges, similar to those utilized
in this trial, could reduce radiation-induced mucositis.13,14 In the current trial, the authors did not observe
any significant trend in the mucositis scores judged
by the health care providers, and the antibiotic lozenges did not alter the incidence or duration of radiation therapy interruptions. However, significantly
lower mucositis scores were reported by the patients
in the pooled lozenge group. The magnitude of patient-reported benefit for the antibiotic lozenge was
modest, reducing the patient-reported mucositis score
by one ordinal level (e.g., from moderate to mild) and
shortening the duration of severe mucositis by 1 week.
Similar results were observed by Symonds et al.20 In
their study using antibiotic lozenges versus placebo in
275 patients undergoing radiation therapy, they found
improved patient-reported maximum mucositis; a decrease in the severity of dysphagia, distribution, and
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area of mucositis; and less weight loss in the antibiotic
lozenge arm.
In summary, although the magnitude of benefit
appears modest at best, there is some evidence suggesting that the use of nonabsorbable antibiotic lozenges may alleviate patient-reported mucositis associated with radiation therapy. However, it is not clear
whether these antibiotic lozenges should be established as part of standard clinical practice, given the
modest patient-reported benefit, the lack of health
care provider-reported benefit, and the unblinded
study design for the first half of this trial.
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