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Treatment of Lymphangiomas With OK-432 (Picibanil) Sclerotherapy
A Prospective Multi-institutional Trial
Chantal M. Giguère, MD;
Nancy M. Bauman, MD;
Yutaka Sato, MD;
Diane K. Burke, RN, BSN;
John H. Greinwald, MD;
Seth Pransky, MD;
Peggy Kelley, MD;
Keith Georgeson, MD;
Richard J. H. Smith, MD
Arch Otolaryngol Head Neck Surg. 2002;128:1137-1144.
ABSTRACT
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Objective To describe and to determine the robustness of our study evaluating
the efficacy of OK-432 (Picibanil) as a therapeutic modality for lymphangiomas.
Design and Setting Prospective, randomized trial and parallel-case series at 13 US tertiary
care referral centers.
Subjects Thirty patients diagnosed as having lymphangioma. Ages in 25 ranged
from 6 months to 18 years. Twenty-nine had lesions located in the head-and-neck
area.
Intervention Every patient received a 4-dose injection series of OK-432 scheduled
6 to 8 weeks apart unless a contraindication existed or a complete response
was observed before completion of all injections. A control group was observed
for 6 months.
Outcome Measures Successful outcome of therapy was defined as a complete or a substantial
(>60%) reduction in lymphangioma size as determined by calculated lesion volumes
on computed tomographic or magnetic resonance imaging scans.
Results Overall, 19 (86%) of the 22 patients with predominantly macrocystic
lymphangiomas had a successful outcome.
Conclusions OK-432 should be efficacious in the treatment of lymphangiomas. Our
study design is well structured to clearly define the role of this treatment
agent.
INTRODUCTION
LYMPHANGIOMAS ARE localized malformations in the development of the
lymphatic system that most frequently affect the head and neck.1-4 In
approximately half of these patients, the lesion is present at birth, and
in most, the diagnosis is made before 2 years of age.5-6 Although
spontaneous resolution has been reported to be as high as 41%, this figure
is much lower in most large series. Surgical excision is the recommended treatment
standard,4-5,7 but
the invaginating nature of lymphangiomas, typically consisting of multiple
cysts with a gossamer-thin lining, makes surgery difficult. Complete extirpation
without damage to vital structures is possible in only approximately one third
of cases.6, 8 With incomplete excision,
disease recurrence is extremely high.9
To reduce surgical morbidity and to decrease recurrence rates, a variety
of nonsurgical treatments have been proposed, including radiation, diathermy,
and injection of a variety of agents such as bleomycin sulfate, triamcinolone
acetonide, interferon-alfa, fibrin-fibronectin sealing systems, and alcoholic
solution of zein (corn protein).10-16 Because
these treatment options have met with limited success and cause considerable
local or systemic adverse effects, recent interest has focused on the sclerosant
OK-432 (Picibanil; Chugai Pharmaceutical Co, Ltd, Tokyo, Japan), as an alternative
therapy.17-18
In the past 14 years, a number of reports have described the successful
use of OK-432 for the treatment of lymphangiomas of the head and neck in children.19-25 This
potent immunostimulant is a lyophilized mixture of a low-virulence strain
(Su) of group A Streptococcus pyogenes incubated
with benzylpenicillin.22, 26-28 Many
authors, predominantly from Japan, have recommended its use as primary therapy
in the treatment of lymphangiomas.21, 24 Their
encouraging results and previously published data from our group suggest that
carefully designed clinical studies should be conducted to examine the role
of OK-432 as primary therapy for lymphangiomas.19-20 Three
years ago, we designed and began conducting a multi-institutional, prospective
randomized control study to assess the efficacy of this relatively new treatment.
The purpose of this report is to describe our study design and to evaluate
its robustness by assessing results in 30 patients.
PATIENTS AND METHODS
Patients with the clinical diagnosis of a lymphangioma underwent evaluation
to determine their eligibility for this prospective study. Pretreatment assessment
included a complete history and physical examination, extensive laboratory
analysis, medical photography, and computed tomography or magnetic resonance
imaging. Lymphangiomas were required to be purely macrocystic (defined as
cystic spaces  2 cm3) or mixed (macrocystic component 50%
of the total disease). Lesions located in the neck were staged according to
the clinical staging system for lymphangiomas proposed by de Serres et al.29 Based on disease extent and location, the system
classifies the disease as follows: stage I, unilateral infrahyoid disease;
stage II, unilateral suprahyoid disease; stage III, unilateral infrahyoid
and suprahyoid disease; stage IV, bilateral suprahyoid disease; and stage
V, bilateral infrahyoid and suprahyoid disease. Patients with a penicillin
allergy were excluded.
Children and adolescents, aged 6 months to 18 years with lymphangiomas
of the head and neck, were eligible to participate in the randomized arm of
the study. Two thirds of the participants were randomized to an immediate-treatment
group (ITG) in which they received OK-432 therapy shortly after enrollment,
and one third were randomized to a delayed-treatment group (DTG) in which
they underwent an initial 6-month observation, thereby serving as control
subjects for the study. If regression of their lymphangiomas was not observed
after 6 months, this group began OK-432 therapy.
Persons with life-threatening lymphangiomas were placed in a third,
nonrandomized emergency-treatment group. Finally, persons who were younger
than 6 months or older than 18 years, or who had lymphangiomas in sites other
than the head and neck region were enrolled in a fourth nonrandomized open-label
group.
A standard OK-432 protocol was followed for all patient groups. In general,
treatments were administered with the patient under general anesthesia, although
local anesthesia can be used in older patients. As described in our previous
series, a solution of OK-432 was prepared by dissolving 0.1 mg of OK-432 in
10 mL of isotonic sodium chloride solution. Under sterile conditions, a 20-gauge
angiocatheter needle was introduced into the cyst. After withdrawing the needle,
cyst contents were aspirated through the angiocatheter. Cyst localization
was aided by the use of fluoroscopy, ultrasonography, transillumination, or
palpation.
After aspirating most of the cyst fluid and taking care not to dislodge
the angiocatheter, OK-432 was injected. A maximum volume of 20 mL was used
per treatment session to inject 1 or several cysts, depending on the characteristics
of the lymphangioma. After the injection, patients were monitored in the postanesthesia
care unit for several hours before discharge and by means of regular telephone
calls during the first 2 weeks thereafter. A diary was used to record temperature,
adverse effects, and antipyretic use. Injections were spaced at 6 to 8 weeks,
with a total of 4 treatments, unless a contraindication existed or a complete
response was observed before completion of therapy.
The complete pretreatment history and physical examination with radiography
was repeated at 6 months and 1 and 2 years after completion of therapy. Outcome
was determined by calculating lesion volume, defined as the product of orthogonal
dimensions on computed tomography or magnetic resonance imaging findings,
before and after therapy by a single radiologist (Y.S.) masked to the clinical
status, date of the radiographic study, and study site. Reduction of lymphangioma
size was recorded in 10% decrements as complete (90%), substantial (60%-80%),
intermediate (20%-50%), or none (<20%). Clinical success was defined as
complete or substantial responses to therapy.
Tests of toxicity and sterility were performed on each new lot number
of OK-432. Informed consent was obtained from patients or parents before each
treatment. The study has been approved by the institutional review boards
in each of the 13 participating sites. Contingency tables were analyzed using
the Fisher exact test.
RESULTS
To assess study design, we evaluated data from 30 persons (18 male patients)
who completed OK-432 therapy (Table 1).
These patients constituted the intent-to-treat group. The on-protocol group
excluded from the intent-to-treat group 4 patients with microcystic disease,
1 patient who did not have a lymphangioma, and 1 patient who withdrew from
the study.
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Table 1. Results of OK-432 Sclerotherapy*
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Our results show that patients with macrocystic lymphangiomas have a
significantly better treatment outcome compared with patients with mixed or
microcystic lesions (Table 2).
Of note, total lesion volume was not predictive of a successful response (Table 3). Patients with stage I, II, or
III disease had a significantly better clinical response to therapy than did
those with stage IV or V disease (Table
4, Figure 1, and Figure 2). The ITG patients also had a significantly
greater response rate than the DTG patients (10:12 vs 0:3). In total, 19 (86%)
of the 22 on-protocol patients with macrocystic or mixed lymphangiomas were
treated successfully with OK-432 (Table
5 and Table 6).
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Table 2. Predictors of Success in the Intent-to-Treat Group*
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Table 3. Patient Characteristics Grouped by OK-432 Therapy Outcome
in the Intent-to-Treat Group
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Table 4. Response to OK-432 Therapy by Stage of Disease*
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Figure 1. Patient 3 with a stage I lymphangioma
of the left side of the neck. Photographs taken before (A) and after (B) a
single injection demonstrate a complete response to OK-432 treatment.
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Figure 2. Patient 3. A, Cystogram demonstrating
a large unilateral infrahyoid cystic lesion. B, Computed tomographic scan
of the same lesion before injection with OK-432.
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Table 5. Overall Success of OK-432 Therapy*
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Table 6. Response to OK-432*
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Minor adverse effects, including erythema, swelling, discomfort at the
site of the injection, and pyrexia, were noted by most patients, but these
resolved within 5 to 6 days of treatment. Three major adverse effects also
occurred. The first involved a patient (patient 19) in whom left-sided proptosis
developed secondary to a spontaneous intracystic hemorrhage 4 weeks after
OK-432 injection of a lymphangioma adjacent to the left orbit. An orbital
decompression was required in this patient. The second major adverse effect
was a case of cervical cellulitis (patient 7) 4 to 5 weeks after the first
injection, and a short course of intravenous antibiotics was required. The
third major adverse effect was the development of stridor and impending airway
obstruction in a patient (patient 5) with a massive lymphangioma of the left
side of the neck that extended intrathoracically. An urgent tracheostomy was
performed in this patient (Figure 3 and Figure 4).
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Figure 3. Patient 5. A, Photograph of patient
with a massive left-sided neck lymphangioma extending into the mediastinum.
B, Three-dimensional reconstruction of computed tomographic scan demonstrates
marked deviation of the trachea (long arrow points to the endotracheal tube)
and a vessel overlying the lymphangioma (short arrow). R indicates right side.
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Figure 4. Patient 5. Computed tomographic
scan demonstrates a large neck and thoracic lymphangioma (A) that responded
completely to 2 injections of OK-432 (B). Patient 5 underwent decannulation
after successful therapy with OK-432 (C and D). R indicates right side.
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COMMENT
To assess study design before completing enrollment, we report data
on 30 patients who have been enrolled in a prospective multi-institutional
trial to evaluate the safety and efficacy of OK-432 in the treatment of lymphangiomas.
To date, a smaller number of patients than expected have been randomized to
the DTG. Malenrollment was determined to be the cause; physicians had included
patients in our database who did not participate in the study. From the randomized
arm of the study, it appears that OK-432 treatment for head and neck lymphangiomas
in children will be significantly more effective than observation alone, although
the small number of patients in the DTG and the incomplete data collection
preclude an accurate estimate of the rate of spontaneous regression of lymphangiomas.
In 1 patient in the ITG, spontaneous regression occurred before initiation
of therapy, resulting in a minimum observed regression rate in the randomized
arm of 1 (5%) of 22 patients.
Our overall success rate, defined as the complete and substantial response
rates, was 19 (66%) of 29 patients in the intent-to-treat group, which is
in keeping with results of retrospective studies on the efficacy of OK-43218 (Table 5).
However, if we exclude patients with microcystic disease, 86% of patients
in the on-protocol group had a successful response to therapy. Macrocystic
lesions respond significantly better than mixed (P =
.02) and microcystic (P<.001) lesions, to such
a degree that among the 19 patients treated successfully, 18 (95%) had macrocystic
disease. The 5 patients with microcystic lesions failed to demonstrate any
response to the OK-432 treatment (Figure 5).
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Figure 5. Patient 4. Magnetic resonance
imaging scan of a mixed lymphangioma involving the right suprahyoid region
before (A) and after (B) 4 injection treatments demonstrates no change in
the microcystic portion of the lesion.
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Only 1 subject enrolled in our clinical trial had a lesion involving
a site other than the head and neck (Figure
6). Although we cannot draw conclusions based on this case alone,
it appears that complete response to therapy may have been due to the macrocystic
nature of the lesion.
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Figure 6. Patient 29. Magnetic resonance
imaging scan of a macrocystic lesion involving the right elbow before (A)
and after (B) 2 OK-432 injections demonstrates a complete response to the
treatment.
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In 1995, a clinical staging system for lymphangiomas was proposed by
de Serres et al29 to predict prognosis and
outcome of surgical intervention. Like de Serres et al, we found that patients
with stages I, II, and III disease had significantly greater response rates
to OK-432 than did patients with stages IV and V disease (P = .02). If we define successful outcome to therapy as complete responses
only, our results compare favorably with the surgical results they reported.
Current numbers are not sufficiently large in any of the stages for disease
in the neck to permit a meaningful comparison of the 2 treatment options.
Patient 2 had a retropharyngeal lymphangioma that would have been extremely
difficult to resect. With a pretreatment tracheotomy placed for airway protection,
the patient's lesion regressed completely after 2 injections of OK-432 (Figure 7).
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Figure 7. Patient 2. A, Magnetic resonance
imaging scan of a large retropharyngeal lymphangioma causing upper airway
obstruction. B, Complete resolution of the lesion after 2 injection treatments
of OK-432 is seen.
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In general, adverse effects were minor, short-lived, and self-limited.
Of the major adverse effects, the development of proptosis 4 weeks after injection
of a periorbital lymphangioma is worrisome. Based on its time of occurrence
and the magnetic resonance imaging findings of fluid-fluid levels suggestive
of intracystic hemorrhage, we believe that this complication is unlikely to
be related to the OK-432 treatment. Other authors also have reported the successful
use of OK-432 to manage orbital lymphangioma.30 Nevertheless,
we advise caution in treating lymphangiomas located in this site. With massive
cervical lymphangiomas, the potential for airway compromise after therapy
also exists, and preventive measures such as pretreatment tracheotomy or close
postinjection observation should be considered.
With additional patient accrual, we will be able to address the effect
that confounding variables such as previous surgery have on the outcome of
OK-432 treatment of lymphangiomas. Increased enrollment also will provide
us with a more accurate determination of the rate of spontaneous regression.
To evaluate whether responses to therapy are sustained, longer follow-up will
be required. These limitations notwithstanding, based on the data we present,
we believe that OK-432 will be efficacious in the treatment of lymphangiomas
and that the design of this clinical study is sufficiently robust to clearly
define its role.
AUTHOR INFORMATION
Accepted for publication January 10, 2002.
This study was supported in part by grant FD-R-001774 from the US Food
and Drug Administration, Rockville, Md (Dr Smith).
Corresponding author and reprints: Richard J. H. Smith, MD, Department
of Otolaryngology, The University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242
(e-mail: richard-smith{at}uiowa.edu).
From the Departments of Otolaryngology (Drs Giguère, Bauman,
and Smith and Ms Burke) and Radiology (Dr Sato), The University of Iowa, Iowa
City; the Departments of Otolaryngology, Children's Hospital, Cincinnati,
Ohio (Dr Greinwald), Children's Association Medical Group, San Diego, Calif
(Dr Pransky), and The Children's Hospital, Denver, Colo (Dr Kelley); and the
Department of Pediatric Surgery, Children's Hospital of Alabama, Birmingham
(Dr Georgeson).
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