Accepted Manuscript Topical timolol maleate for superficial infantile hemangiomas: an observational study Da-Peng Xu, MS, Rong-Yu Cao, MS, Shuang Tong, DDS, Lei Xue, DDS, Ning-Ning Sun, DDS, Xu-Kai Wang, DDS, phD PII:
S0278-2391(14)01850-3
DOI:
10.1016/j.joms.2014.12.026
Reference:
YJOMS 56601
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 19 November 2014 Revised Date:
18 December 2014
Accepted Date: 19 December 2014
Please cite this article as: Xu D-P, Cao R-Y, Tong S, Xue L, Sun N-N, Wang X-K, Topical timolol maleate for superficial infantile hemangiomas: an observational study, Journal of Oral and Maxillofacial Surgery (2015), doi: 10.1016/j.joms.2014.12.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title page Title: Topical timolol maleate for superficial infantile hemangiomas: an observational study Authors:Da-Peng Xu, MS1, Rong-Yu Cao, MS2, Shuang Tong, DDS1, Lei Xue, DDS1, Ning-Ning Sun, DDS1, Xu-Kai Wang, DDS, phD1*
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Affiliations:1Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China 2
Department of Endodontics,School of Stomatology, Shandong University, Jinan, Shandong
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250000, P.R. China Da-Peng Xu, Resident, Department of Oral and Maxillofacial Surgery Rong-Yu Cao, Resident, Department of Endodontics
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Shuang Tong, Attending surgeon, Department of Oral and Maxillofacial Surgery Lei Xue, Attending surgeon, Department of Oral and Maxillofacial Surgery
Ning-Ning Sun, Attending surgeon, Department of Oral and Maxillofacial Surgery Xu-Kai Wang, Professor and dean, Department of Oral and Maxillofacial Surgery *Corresponding author：Dr. Xu-kai Wang: Address to Department of Oral and Maxillofacial
HePing
District,
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Surgery, School of Stomatology, China Medical University, No.117, Nan Jing North Street, Shenyang,Liaoning110002,P.R.China;Tel:+8602422892451
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[email protected]
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E-mail:
ACCEPTED MANUSCRIPT Topical timolol maleate for superficial infantile hemangiomas: an observational study
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Purpose: The objective of this study was to assess the clinical effects and safety of topical timolol
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maleate for the management of superficial infantile hemangiomas(IHs).
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Materials and Methods: Between October 2012 and March 2014, thirty-five infants with
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superficial hemangiomas were treated with the local application of timolol maleate in our
6
department. There were 24 girls and 11 boys included in this study, aged 2 to 10 months with a
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median age of 4.7 months. A total of 35 lesions were treated using topically administrated timolol
8
maleate every 12 hours for a mean duration of 22 weeks (range, 6 to 45 weeks). The follow-up
9
visits were scheduled monthly and changes in the size, texture, and color of the tumor were
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recorded. The treatment response was scored according to a 3-point scale system as follows: good,
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partial, and no response. Adverse effects after medication were evaluated and managed
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accordingly.
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Results: All patients completed treatment. Of the 35 hemangiomas, 18 (51.4%) showed good
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response, 10 (31.4%) demonstrated partial response, and 6 (17.2%) had no response. The total
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response rate was 82.8% (29/35). Clinically, no systemic or local side effects caused by timolol
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maleate were observed in the patients.
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Conclusions: Topical timolol maleate may provide an effective and safe alternative to the
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systemic use of propranolol for the treatment of superficial IHs. Additionally, further prospective
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studies are needed to demonstrate the efficacy and safety of topical timolol maleate for the
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treatment of IHs.
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IHs are the most common benign soft-tissue tumor of infancy and childhood, with an incidence
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of 2-3% in the neonate, 10% in the baby after one year and up to 23% in premature infants. IHs
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usually manifest within the first month of life, exhibit a rapid proliferative phase, and slowly
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involute to near complete resolution.1-3 Although IHs are benign, their growth is quite
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unpredictable due to active endothelial cell proliferation. When IHs involve vital structures, such
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as the eyelid and larynx, they can lead to visual impairment or even threaten life. Facial
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hemangiomas, occurring in approximately 20 to 40% of children, can also result in residual skin
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changes and may be disfiguring after involution.4 Moreover, the parents of affected children often
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worry about the lesions and they seek early treatment to inhibit the growth of the lesion or
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improve the appearance of the hemangioma. The beta-adrenergic receptor antagonist, propranolol, is an effective therapy for IHs, even after
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treatment with corticosteroids or laser have failed.5-7 However, oral propranolol causes systemic
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complications, including vasospasm, hypoglycemia, hypotension, heart blockage, bronchospasm,
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and anaphylactic shock.8 Timolol maleate, a nonselective β-blocker similar to propranolol, is a
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topical solution formulation for the management of glaucoma. Guo et al9 first reported a case with
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eyelid hemangioma treated with topical timolol maleate with good effect and minimal side effects.
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Subseqently Chan et al10 conducted a randomized controlled trial and further confirmed that
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topical timolol maleate was effective treatment of superficial IHs. Here, we describe a series of 35
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patents with superficial IHs treated with topical timolol maleate and to determine the efficacy and
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safety of this drug.
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Patients and methods
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Thirty-five patients who presented with superficial IHs of different body regions were treated
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with topical timolol maleate from October 2012 to March 2014 at the Department of Oral and
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Maxillofacial Surgery, Hospital of Stomatology, China Medical University. There were 24 girls
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and 11 boys. The children ranged in age from 2 to 10 months, with a mean age of 4.7 months.
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None of the treated IHs was located in a life-threatening area. The anatomic locations of the 35
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IHs were as follows: 22 on the head and neck, 8 on the trunk, and 5 on the extremities. The
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diagnosis of hemangioma was made based on the medical history, clinical presentations, and
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Doppler ultrasonography scan. Inclusion criteria for topical timolol maleate treatment of IHs in
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this study included patients younger than 12 months with superficial hemangiomas; No infants
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were administered any treatment before topical timolol maleate, The chest radiograph,
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electrocardiogram, blood glucose, liver function, renal function and blood routine examinations
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were all normal. Infants with cardiovascular disorders, recent outbreaks of wheezing, or family
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history of atomy were excluded from the present study. Informed consent was signed by the
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parents of all children and this clinical study was approved by the China Medical University
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Review Board.
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Treatment was initiated during a short hospitalization of 3 days. Before the start of treatment,
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clinical photographs were obtained. The 0.5% timolol maleate eye drops ( 25 mg/5 mL, Wuhan
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layer using a medical swab. The ophthalmic solution was applied twice daily. All patient parents
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were instructed to continue to perform the procedure and observe for local or systemic adverse
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reactions, such as local itching, inflammation, erosion, ulceration, asthma, after discharge from the
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hospital. The first follow-up visit was performed two weeks after therapy and scheduled monthly
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thereafter. At each clinic visit, the blood pressure, heart rate, and blood glucose were measured
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and clinical photographs were taken. The treatment was continued until the age of 1 year unless
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complete resolution occurred and medication withdrawal was indicated.
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Treatment evaluation consisted of clinical and photographic evaluations of the IHs and
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monitoring of treatment tolerance(safety). The response to the treatment was assessed according to
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the criteria of Garzon et al.11 Our clinical records and the photographs were scored by a panel of 3
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blinded surgeons based on 3 categories: the score based on change in the size of the hemangioma
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ranged from 0 to 2 (0 = proliferation, 1 = cessation, 2 = regression); the score using change in the
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surface tension was 0 or 1 (0 = hard, 1 = soft); the score according to the change in the color was 0
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or 1 (0 = bright red, 1 = lighter or dark). The evaluation consisted of 3 stages after commencing
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treatment: 4 weeks (3-5 weeks), 12 weeks (11-13 weeks), 24 weeks (23-25 weeks). The score of 3
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stages was summed up (range, 0 - 12) for evaluating curative effect. A score higher than 8 was
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considered good response; 3 to 8, partial response; and lower than 3, no response. Cases that other
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therapies were performed because of inefficacy of timolol maleate were scored 0, whereas a
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complete regression within 24 weeks after commencing treatment was scored 12.
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With regard to safety, heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP),
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and blood glucose were close monitored in the course of 3-day hospitalization and recorded one
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hour after each dose. Local side effects such as rash, red spots, erosion, and ulceration were also
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closely observed.
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The ages at treatment initiation, sizes and locations of the treated lesions were divided into 3 or 2
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response groups as follows: 0 to 3 months ( the first rapid proliferating phase ), more than 3 to 6
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months ( the second rapid proliferating phase ) and more than 6 to 10 months ( the early involuting
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phase ); less than 3 cm in diameter and more than 3 cm; facial and nonfacial areas, respectively.
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The Kruskal-Wallis test was used to compare the ages at treatment initiation, sizes and locations of
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the lesions of the response groups. All analyses were performed using the SPSS software version
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18 (SPSS Inc., Chicago). A p value ＜0.05 was considered to be significant.
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Results The clinical features and relevant treatments of the patients are summarized in Table 1. Of the 35
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patients, 18 (51.4%) showed good response (Fig 1, Fig 2, Fig 3 and Fig 4), 11 (31.4%)
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demonstrated partial response, and 6 (17.2%) had no response. The total response rate was 82.8%
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(29/35). The average treatment duration was 22 weeks (range 6 to 45 weeks). During the first 2
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days of treatment, the color of the majority of tumors lightened and the texture became softer,
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particularly in infants younger than 6 months of age. In the 6 no response patients, the
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subcutaneous components of four lesions continued to develop after the initiation of treatment
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with timolol maleate; however, the color or texture of the hemangiomas showed signs of
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regression. Systemic propranolol combined with topical timolol maleate were used to treat the
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nonresponders. No significant differences in the sizes and locations of the lesions were observed
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among the 2 response groups. However, there was a significant difference in the age at treatment
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initiation among the 3 response groups and also suggesting topical timolol maleate is more
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effective against the proliferation phase than the early involution phase of superficial IHs.
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(P＝.016)(Table 2). No infants were withdrawn from the treatment study due to side effects.
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Topical application of 0.5% timolol maleate was well tolerated in all children. The treatment
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procedure (topical timolol maleate) did not influence blood pressure and heart rate monitored in
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all infants. The parents reported no wheezing or anorexia. No local irritation was observed in any
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patient. In one infant, there was a slight relapse 4 weeks after cessation; however, the hemangioma
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regressed upon continuation of the medication. The majority of the patient parents were satisfied
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with the cosmetic and functional results after the end of treatment.
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Discussion
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Infantile hemangiomas are the most common benign tumors of endothelial cells in children,
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approximately 60% of which occur in the head and neck region.12 Although the majority of IHs
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eventually involute, approximately 10% continue to grow with various complications. Facial
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disfigurement is not rare and may lead to psychosocial distress in children and their parents.13
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Therefore, the treatment strategy for hemangiomas should depend on the age of the child, location
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and extent of the hemangioma, and growth phase of the lesions. The objective of any therapeutic
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intervention for IHs is halting the further growth of the hemangioma, accelerating regression,
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minimizing the psychosocial distress caused by the lesions, and minimizing any morbidity
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associated with the treatment of the lesions.14 Le′aute′-Labre`ze et al.5 in 2008, first reported their serendipitous finding of the remarkable
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effect of propranolol on IHs. Since then, many clinical studies have been performed and
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confirmed the usefulness of systemic propranolol for treating IHs. Currently, propranolol has
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replaced corticosteroids as the preferred first-line therapy for the management of IHs. However,
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oral propranolol causes systemic complications, including anaphylactic shock, vasospasm,
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hypoglycemia, hypotension, heart blockage, and bronchospasm. Moreover, the treatment response
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of oral propranolol for deep-seated hemangiomas was better than for superficial hemangiomas,8,15
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and topical therapy has been attempted for the treatment of superficial hemangiomas. Timolol
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maleate is a topical nonselective beta-adrenergic antagonist, which has been widely used in
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ophthalmology. Guo et al.9 first reported the successful treatment of a four-month-old infant with a
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superficial hemangioma of the eyelid using topical timolol maleate. Pope et al.16 described a series
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of 6 patients with head and neck superficial hemangiomas who responded well to timolol maleate.
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Khunger et al.17 described a case of a large hemifacial infantile hemangioma associated with
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PHACE syndrome treated with topical timolol lotion that showed a dramatic response. No side
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effects occurred in the above studies. In our study, all patients completed treatment. Early
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intervention during the proliferative phase induced regression or stabilized growth of the
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hemangiomas. Of the 35 hemangiomas, 18 (51.4%) showed good response, 11 (31.4%)
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demonstrated partial response, and 6 (17.2%) had no response The total response rate was 82.8%
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(29/35). Regression (within the age of 12 months) of the hemangiomas treated with timolol
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maleate occurred earlier than spontaneous involution, which is generally observed after the age of
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12 months. Moreover, in 21 patients younger than 6 months, 14 demonstrated a good response and
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4 showed a partial response. The efficacy of topical timolol maleate reached 85.7%, suggesting
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that topical timolol maleate is more effective against the proliferation phase than the early
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involution phase of superficial IHs.
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The efficacy of percutaneously applied timolol maleate may be attributed to several factors.
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The barrier function of infantile skin does not appear to be fully developed until the age of one
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year.18 The lipophilic nature of timolol maleate can enhance transcutaneous penetration. In
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The mechanism of action of timolol maleate in IHs remains unknown, but is presumably the same
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as for propranolol.20 Vasoconstriction, down-regulation expression of vascular endothelial growth
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factor (VEGF) and basic fibroblast growth factor (bFGF) and induced apoptosis of capillary
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endothelial cells may be responsible for the regression of hemangiomas.5,21
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Compared to systemic propranolol, the advantages of topical timolol maleate for superficial
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IHs include the ease of administration, high compliance, high local concentration of timolol
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maleate at the capillaries of the hemangioma without high systemic concentration, and a minimal
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risk of drug-related adverse events, particularly when applied to the face, and in particular, the
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periorbital area. In our study, topical application of 0.5% timolol maleate was well tolerated in all
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children. The treatment did not influence blood pressure and heart rate in the infants. The parents
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reported no wheezing or anorexia. No local irritation was observed in any patient. Therefore,
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topical application of timolol maleate is relatively safe for the management of superficial IHs.
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Although our study has several limitations, including the small sample size, lack of control
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group with spontaneous involution, and retrospective design, it does demonstrate that topical
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timolol maleate applied twice daily has a beneficial effect and better safety for the treatment of
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superficial IHs. Additional prospective randomized studies are necessary to demonstrate the
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efficacy and safety of topical therapy.
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References
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1. Mulliken JB, Glowacki J: Hemangiomas and vascular malformations in infants and children: a
171 172 173 174 175 176 177 178
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classification based on endothelial characteristics. Plast Reconstr Surg 69:412, 1982 2. Zheng JW, Zhou Q, Yang XJ, et al:Treatment guideline for hemangiomas and vascular malfor-
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mations of the head and neck. Head Neck 32:1088, 2010
3. Cohen-Barak E, Rozenman D, Shani Adir A: Infantile haemangiomas and quality of life. Arch Dis Child 98:676, 2013
4. Garzon MC, Luky AW, Hawrot A, et al: Ultrapotent topical corticosteroid treatment of Hemangiomas of infancy. J Am Acad Dermatol 52:281, 2005 5. Le′aute′-Labre`ze C, Dumas de laRoque E, Hubiche T, et al: Propranolol for Severe Hemangiomas of Infancy. N Engl J Med 358:2649, 2008 6. Yuan WL, Jin ZL, Wei JJ, et al: Propranolol given orally for proliferating infantile haemangio-
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mas: analysis of efficacy and serological changes in vascular endothelial growth factor and
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endothelial nitricoxide synthase in 35 patients. Br J Oral Maxillofac Surg 51:656, 2013
187 188 189 190 191 192 193 194 195 196 197 198 199 200
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Solution. Arch Ophthalmol 128:255, 2010
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9. Guo S, Ni N: Topical treatment for capillary hemangioma of the eyelid using beta-blocker
10. Chan H, Mckay C, Adam S, et al: RCT of timolol maleate gel for superficial infantile hemangiomas in 5-to 24-week-olds. Pediatrics 131:e1739, 2013
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Eengl J Med 359:2846, 2008
11. Garzon MC, Lucky AW, Hawrot A, et al: Ultrapotent topical corticosteroid treatment of hemangiomas of infancy. J Am Acad Dermatol 52:281, 2005
12. Puttgen KB: Diagnosis and management of infantile hemangiomas. Pediatr Clin North Am 61:383, 2014
13. Zweegers J, van der Vleuten CJ: The psychosocial impact of an infantile haemengioma on
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8. Siegfried EC,Keenan WJ,AI-Jureidini S:More on propranolol for hemangiomas of infancy. N
children and their parents. Arch Dis Child 97:922, 2012
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:review of literature. Int J Pediatr Otorhinolaryngol 74:338, 2010
14. Xu G, Lv R, Zhao Z, et al: Topical propranolol for treatment of superficial infantile hemangioma. J Am Acad Dermatol 67:1210, 2012
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7. Zimmermann AP, Wiegand S, Werner JA, et al:Propranolol therapy for infantile haemangiomas
15. Qin ZP, Liu XJ, Li KL, et al: Treatment of infantile hemangiomas with low-dose propranolol
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: evaluation of short-term efficacy and safety. Zhonghua Yi Xue Za Zhi 89:3130, 2009
16. Pope E, Chakkittakandiyil A: Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol 146:564, 2010
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17. Khunger N, Pahwa M: Dramatic response to topical timolol lotion of a large hemifacial
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infantile haemangioma associated with PHACE syndrome. Br J Dermatol 164:886, 2011
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18. Stamatas GN, Nikolovski J, Mack MC, et al: Infant skin physiology and development during the first years of life: a review of recent findings based on in vivo studies. Int J Cosmet Sci
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33:17, 2011 19. Ye XX, Jin YB, Lin XX, et al: Topical timolol in the treatment of periocular superficial
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infantile hemangiomas: a prospective study. Zhonghua Zheng Xing Wai Ke Za Zhi
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28:161, 2012
209 210
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20. Storch CH, Hoeger PH: Propranolol for infantile hemangiomas: insights into molecular mechanisms of action. Br J Dermatol 163:269, 2010
21. Le′aute′-Labre`ze C, Taieb A: Efficacy of beta-blockers in infantile hemangiomas: the
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physiopathological significance and therapeutic consequences. Ann Dermatol Venerol
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135:860, 2008
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Characteristics
n (%)
Gender Male Female Mean age Range Mean treatment duration Range Age at treatment initiation
11(31.4) 24(68.6) 4.7 mos 2 to 10 mos 22 wks 6 to 45 wks 21(60.0)
＜6 mos
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＞6 mos Tumor size in diameter
25(71.4)
＜3 cm
10(28.6)
＞3 cm
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Location Head and neck Trunk Extremities Previous treatment Ulceration PHACES
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22(62.9) 8(22.8) 5(14.3) 0(0) 0(0) 0(0)
Table 2. DIFFERENCES IN AGE UPON INITIATION OF TREATMENT, SIZE AND LOCATION OF LESIONS AMONG 3 OR 2 RESPONSE GROUPS
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Table 1. CHARACTERISTICS AND RELEVANT TREATMENT OF THE PATIENTS
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Table
Age, mos
Size, cm
χ2
9
2
1
8.332
.016
9
5
2
2
14
4
7
3
35
18
11
6
25
13
8
4
0.033
.857
0-3
12
Total ＜3
test No
N
＞6-10
Kruskal-wallis
Partial
Group
＞3-6
Treatment response Good
P
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5
3
2
Total
35
18
11
6
Facial
22
13
6
3
Nonfacial
13
5
5
3
Total
35
18
11
6
＞3
Location
243 244
.245
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1.352
Figure legends
Figure1. 3.5-month old boy with a focal superficial hemangioma in the left periorbital area.
246
A:Before treatment, B.12 weeks after topical timolol maleate treatment, the color of tumor has
247
faded.
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Figure2. 3-month old girl with a large superficial hemangioma in the left abdomen. A: Before
249
treatment; B: 32 weeks after timolol maleate treatment, the color of tumor has lightened.
250
Figure3. 2.5-month old girl with a large superficial hemangioma in the left forechest. A:Before
251
treatment; B: 10 weeks after topical timolol maleate treatment, the color of tumor become lighter.
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Figure4. 4-month old boy with a focal superficial hemangioma in the nose. A: Before treatment;
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B: 28 weeks after topical timolol maleate treatment, the tumor has completely disappeared.
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S0278-2391(14)01850-3
DOI:
10.1016/j.joms.2014.12.026
Reference:
YJOMS 56601
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 19 November 2014 Revised Date:
18 December 2014
Accepted Date: 19 December 2014
Please cite this article as: Xu D-P, Cao R-Y, Tong S, Xue L, Sun N-N, Wang X-K, Topical timolol maleate for superficial infantile hemangiomas: an observational study, Journal of Oral and Maxillofacial Surgery (2015), doi: 10.1016/j.joms.2014.12.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title page Title: Topical timolol maleate for superficial infantile hemangiomas: an observational study Authors:Da-Peng Xu, MS1, Rong-Yu Cao, MS2, Shuang Tong, DDS1, Lei Xue, DDS1, Ning-Ning Sun, DDS1, Xu-Kai Wang, DDS, phD1*
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Affiliations:1Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China 2
Department of Endodontics,School of Stomatology, Shandong University, Jinan, Shandong
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250000, P.R. China Da-Peng Xu, Resident, Department of Oral and Maxillofacial Surgery Rong-Yu Cao, Resident, Department of Endodontics
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Shuang Tong, Attending surgeon, Department of Oral and Maxillofacial Surgery Lei Xue, Attending surgeon, Department of Oral and Maxillofacial Surgery
Ning-Ning Sun, Attending surgeon, Department of Oral and Maxillofacial Surgery Xu-Kai Wang, Professor and dean, Department of Oral and Maxillofacial Surgery *Corresponding author：Dr. Xu-kai Wang: Address to Department of Oral and Maxillofacial
HePing
District,
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Surgery, School of Stomatology, China Medical University, No.117, Nan Jing North Street, Shenyang,Liaoning110002,P.R.China;Tel:+8602422892451
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[email protected]
；
E-mail:
ACCEPTED MANUSCRIPT Topical timolol maleate for superficial infantile hemangiomas: an observational study
2
Purpose: The objective of this study was to assess the clinical effects and safety of topical timolol
3
maleate for the management of superficial infantile hemangiomas(IHs).
4
Materials and Methods: Between October 2012 and March 2014, thirty-five infants with
5
superficial hemangiomas were treated with the local application of timolol maleate in our
6
department. There were 24 girls and 11 boys included in this study, aged 2 to 10 months with a
7
median age of 4.7 months. A total of 35 lesions were treated using topically administrated timolol
8
maleate every 12 hours for a mean duration of 22 weeks (range, 6 to 45 weeks). The follow-up
9
visits were scheduled monthly and changes in the size, texture, and color of the tumor were
10
recorded. The treatment response was scored according to a 3-point scale system as follows: good,
11
partial, and no response. Adverse effects after medication were evaluated and managed
12
accordingly.
13
Results: All patients completed treatment. Of the 35 hemangiomas, 18 (51.4%) showed good
14
response, 10 (31.4%) demonstrated partial response, and 6 (17.2%) had no response. The total
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response rate was 82.8% (29/35). Clinically, no systemic or local side effects caused by timolol
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maleate were observed in the patients.
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Conclusions: Topical timolol maleate may provide an effective and safe alternative to the
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systemic use of propranolol for the treatment of superficial IHs. Additionally, further prospective
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studies are needed to demonstrate the efficacy and safety of topical timolol maleate for the
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treatment of IHs.
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IHs are the most common benign soft-tissue tumor of infancy and childhood, with an incidence
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of 2-3% in the neonate, 10% in the baby after one year and up to 23% in premature infants. IHs
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usually manifest within the first month of life, exhibit a rapid proliferative phase, and slowly
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involute to near complete resolution.1-3 Although IHs are benign, their growth is quite
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unpredictable due to active endothelial cell proliferation. When IHs involve vital structures, such
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as the eyelid and larynx, they can lead to visual impairment or even threaten life. Facial
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hemangiomas, occurring in approximately 20 to 40% of children, can also result in residual skin
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changes and may be disfiguring after involution.4 Moreover, the parents of affected children often
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worry about the lesions and they seek early treatment to inhibit the growth of the lesion or
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improve the appearance of the hemangioma. The beta-adrenergic receptor antagonist, propranolol, is an effective therapy for IHs, even after
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treatment with corticosteroids or laser have failed.5-7 However, oral propranolol causes systemic
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complications, including vasospasm, hypoglycemia, hypotension, heart blockage, bronchospasm,
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and anaphylactic shock.8 Timolol maleate, a nonselective β-blocker similar to propranolol, is a
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topical solution formulation for the management of glaucoma. Guo et al9 first reported a case with
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eyelid hemangioma treated with topical timolol maleate with good effect and minimal side effects.
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Subseqently Chan et al10 conducted a randomized controlled trial and further confirmed that
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topical timolol maleate was effective treatment of superficial IHs. Here, we describe a series of 35
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patents with superficial IHs treated with topical timolol maleate and to determine the efficacy and
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safety of this drug.
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Patients and methods
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Thirty-five patients who presented with superficial IHs of different body regions were treated
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with topical timolol maleate from October 2012 to March 2014 at the Department of Oral and
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Maxillofacial Surgery, Hospital of Stomatology, China Medical University. There were 24 girls
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and 11 boys. The children ranged in age from 2 to 10 months, with a mean age of 4.7 months.
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None of the treated IHs was located in a life-threatening area. The anatomic locations of the 35
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IHs were as follows: 22 on the head and neck, 8 on the trunk, and 5 on the extremities. The
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diagnosis of hemangioma was made based on the medical history, clinical presentations, and
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Doppler ultrasonography scan. Inclusion criteria for topical timolol maleate treatment of IHs in
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this study included patients younger than 12 months with superficial hemangiomas; No infants
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were administered any treatment before topical timolol maleate, The chest radiograph,
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electrocardiogram, blood glucose, liver function, renal function and blood routine examinations
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were all normal. Infants with cardiovascular disorders, recent outbreaks of wheezing, or family
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history of atomy were excluded from the present study. Informed consent was signed by the
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parents of all children and this clinical study was approved by the China Medical University
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Review Board.
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Treatment was initiated during a short hospitalization of 3 days. Before the start of treatment,
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clinical photographs were obtained. The 0.5% timolol maleate eye drops ( 25 mg/5 mL, Wuhan
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layer using a medical swab. The ophthalmic solution was applied twice daily. All patient parents
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were instructed to continue to perform the procedure and observe for local or systemic adverse
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reactions, such as local itching, inflammation, erosion, ulceration, asthma, after discharge from the
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hospital. The first follow-up visit was performed two weeks after therapy and scheduled monthly
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thereafter. At each clinic visit, the blood pressure, heart rate, and blood glucose were measured
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and clinical photographs were taken. The treatment was continued until the age of 1 year unless
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complete resolution occurred and medication withdrawal was indicated.
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Treatment evaluation consisted of clinical and photographic evaluations of the IHs and
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monitoring of treatment tolerance(safety). The response to the treatment was assessed according to
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the criteria of Garzon et al.11 Our clinical records and the photographs were scored by a panel of 3
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blinded surgeons based on 3 categories: the score based on change in the size of the hemangioma
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ranged from 0 to 2 (0 = proliferation, 1 = cessation, 2 = regression); the score using change in the
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surface tension was 0 or 1 (0 = hard, 1 = soft); the score according to the change in the color was 0
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or 1 (0 = bright red, 1 = lighter or dark). The evaluation consisted of 3 stages after commencing
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treatment: 4 weeks (3-5 weeks), 12 weeks (11-13 weeks), 24 weeks (23-25 weeks). The score of 3
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stages was summed up (range, 0 - 12) for evaluating curative effect. A score higher than 8 was
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considered good response; 3 to 8, partial response; and lower than 3, no response. Cases that other
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therapies were performed because of inefficacy of timolol maleate were scored 0, whereas a
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complete regression within 24 weeks after commencing treatment was scored 12.
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With regard to safety, heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP),
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and blood glucose were close monitored in the course of 3-day hospitalization and recorded one
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hour after each dose. Local side effects such as rash, red spots, erosion, and ulceration were also
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closely observed.
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The ages at treatment initiation, sizes and locations of the treated lesions were divided into 3 or 2
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response groups as follows: 0 to 3 months ( the first rapid proliferating phase ), more than 3 to 6
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months ( the second rapid proliferating phase ) and more than 6 to 10 months ( the early involuting
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phase ); less than 3 cm in diameter and more than 3 cm; facial and nonfacial areas, respectively.
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The Kruskal-Wallis test was used to compare the ages at treatment initiation, sizes and locations of
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the lesions of the response groups. All analyses were performed using the SPSS software version
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18 (SPSS Inc., Chicago). A p value ＜0.05 was considered to be significant.
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Results The clinical features and relevant treatments of the patients are summarized in Table 1. Of the 35
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patients, 18 (51.4%) showed good response (Fig 1, Fig 2, Fig 3 and Fig 4), 11 (31.4%)
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demonstrated partial response, and 6 (17.2%) had no response. The total response rate was 82.8%
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(29/35). The average treatment duration was 22 weeks (range 6 to 45 weeks). During the first 2
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days of treatment, the color of the majority of tumors lightened and the texture became softer,
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particularly in infants younger than 6 months of age. In the 6 no response patients, the
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subcutaneous components of four lesions continued to develop after the initiation of treatment
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with timolol maleate; however, the color or texture of the hemangiomas showed signs of
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regression. Systemic propranolol combined with topical timolol maleate were used to treat the
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nonresponders. No significant differences in the sizes and locations of the lesions were observed
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among the 2 response groups. However, there was a significant difference in the age at treatment
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initiation among the 3 response groups and also suggesting topical timolol maleate is more
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effective against the proliferation phase than the early involution phase of superficial IHs.
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(P＝.016)(Table 2). No infants were withdrawn from the treatment study due to side effects.
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Topical application of 0.5% timolol maleate was well tolerated in all children. The treatment
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procedure (topical timolol maleate) did not influence blood pressure and heart rate monitored in
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all infants. The parents reported no wheezing or anorexia. No local irritation was observed in any
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patient. In one infant, there was a slight relapse 4 weeks after cessation; however, the hemangioma
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regressed upon continuation of the medication. The majority of the patient parents were satisfied
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with the cosmetic and functional results after the end of treatment.
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Discussion
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Infantile hemangiomas are the most common benign tumors of endothelial cells in children,
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approximately 60% of which occur in the head and neck region.12 Although the majority of IHs
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eventually involute, approximately 10% continue to grow with various complications. Facial
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disfigurement is not rare and may lead to psychosocial distress in children and their parents.13
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Therefore, the treatment strategy for hemangiomas should depend on the age of the child, location
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and extent of the hemangioma, and growth phase of the lesions. The objective of any therapeutic
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intervention for IHs is halting the further growth of the hemangioma, accelerating regression,
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minimizing the psychosocial distress caused by the lesions, and minimizing any morbidity
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associated with the treatment of the lesions.14 Le′aute′-Labre`ze et al.5 in 2008, first reported their serendipitous finding of the remarkable
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effect of propranolol on IHs. Since then, many clinical studies have been performed and
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confirmed the usefulness of systemic propranolol for treating IHs. Currently, propranolol has
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replaced corticosteroids as the preferred first-line therapy for the management of IHs. However,
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oral propranolol causes systemic complications, including anaphylactic shock, vasospasm,
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hypoglycemia, hypotension, heart blockage, and bronchospasm. Moreover, the treatment response
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of oral propranolol for deep-seated hemangiomas was better than for superficial hemangiomas,8,15
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and topical therapy has been attempted for the treatment of superficial hemangiomas. Timolol
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maleate is a topical nonselective beta-adrenergic antagonist, which has been widely used in
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ophthalmology. Guo et al.9 first reported the successful treatment of a four-month-old infant with a
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superficial hemangioma of the eyelid using topical timolol maleate. Pope et al.16 described a series
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of 6 patients with head and neck superficial hemangiomas who responded well to timolol maleate.
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Khunger et al.17 described a case of a large hemifacial infantile hemangioma associated with
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PHACE syndrome treated with topical timolol lotion that showed a dramatic response. No side
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effects occurred in the above studies. In our study, all patients completed treatment. Early
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intervention during the proliferative phase induced regression or stabilized growth of the
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hemangiomas. Of the 35 hemangiomas, 18 (51.4%) showed good response, 11 (31.4%)
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demonstrated partial response, and 6 (17.2%) had no response The total response rate was 82.8%
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(29/35). Regression (within the age of 12 months) of the hemangiomas treated with timolol
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maleate occurred earlier than spontaneous involution, which is generally observed after the age of
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12 months. Moreover, in 21 patients younger than 6 months, 14 demonstrated a good response and
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4 showed a partial response. The efficacy of topical timolol maleate reached 85.7%, suggesting
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that topical timolol maleate is more effective against the proliferation phase than the early
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involution phase of superficial IHs.
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The efficacy of percutaneously applied timolol maleate may be attributed to several factors.
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The barrier function of infantile skin does not appear to be fully developed until the age of one
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year.18 The lipophilic nature of timolol maleate can enhance transcutaneous penetration. In
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The mechanism of action of timolol maleate in IHs remains unknown, but is presumably the same
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as for propranolol.20 Vasoconstriction, down-regulation expression of vascular endothelial growth
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factor (VEGF) and basic fibroblast growth factor (bFGF) and induced apoptosis of capillary
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endothelial cells may be responsible for the regression of hemangiomas.5,21
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Compared to systemic propranolol, the advantages of topical timolol maleate for superficial
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IHs include the ease of administration, high compliance, high local concentration of timolol
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maleate at the capillaries of the hemangioma without high systemic concentration, and a minimal
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risk of drug-related adverse events, particularly when applied to the face, and in particular, the
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periorbital area. In our study, topical application of 0.5% timolol maleate was well tolerated in all
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children. The treatment did not influence blood pressure and heart rate in the infants. The parents
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reported no wheezing or anorexia. No local irritation was observed in any patient. Therefore,
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topical application of timolol maleate is relatively safe for the management of superficial IHs.
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Although our study has several limitations, including the small sample size, lack of control
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group with spontaneous involution, and retrospective design, it does demonstrate that topical
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timolol maleate applied twice daily has a beneficial effect and better safety for the treatment of
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superficial IHs. Additional prospective randomized studies are necessary to demonstrate the
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efficacy and safety of topical therapy.
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References
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1. Mulliken JB, Glowacki J: Hemangiomas and vascular malformations in infants and children: a
171 172 173 174 175 176 177 178
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classification based on endothelial characteristics. Plast Reconstr Surg 69:412, 1982 2. Zheng JW, Zhou Q, Yang XJ, et al:Treatment guideline for hemangiomas and vascular malfor-
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mations of the head and neck. Head Neck 32:1088, 2010
3. Cohen-Barak E, Rozenman D, Shani Adir A: Infantile haemangiomas and quality of life. Arch Dis Child 98:676, 2013
4. Garzon MC, Luky AW, Hawrot A, et al: Ultrapotent topical corticosteroid treatment of Hemangiomas of infancy. J Am Acad Dermatol 52:281, 2005 5. Le′aute′-Labre`ze C, Dumas de laRoque E, Hubiche T, et al: Propranolol for Severe Hemangiomas of Infancy. N Engl J Med 358:2649, 2008 6. Yuan WL, Jin ZL, Wei JJ, et al: Propranolol given orally for proliferating infantile haemangio-
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mas: analysis of efficacy and serological changes in vascular endothelial growth factor and
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endothelial nitricoxide synthase in 35 patients. Br J Oral Maxillofac Surg 51:656, 2013
187 188 189 190 191 192 193 194 195 196 197 198 199 200
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Solution. Arch Ophthalmol 128:255, 2010
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9. Guo S, Ni N: Topical treatment for capillary hemangioma of the eyelid using beta-blocker
10. Chan H, Mckay C, Adam S, et al: RCT of timolol maleate gel for superficial infantile hemangiomas in 5-to 24-week-olds. Pediatrics 131:e1739, 2013
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Eengl J Med 359:2846, 2008
11. Garzon MC, Lucky AW, Hawrot A, et al: Ultrapotent topical corticosteroid treatment of hemangiomas of infancy. J Am Acad Dermatol 52:281, 2005
12. Puttgen KB: Diagnosis and management of infantile hemangiomas. Pediatr Clin North Am 61:383, 2014
13. Zweegers J, van der Vleuten CJ: The psychosocial impact of an infantile haemengioma on
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8. Siegfried EC,Keenan WJ,AI-Jureidini S:More on propranolol for hemangiomas of infancy. N
children and their parents. Arch Dis Child 97:922, 2012
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:review of literature. Int J Pediatr Otorhinolaryngol 74:338, 2010
14. Xu G, Lv R, Zhao Z, et al: Topical propranolol for treatment of superficial infantile hemangioma. J Am Acad Dermatol 67:1210, 2012
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7. Zimmermann AP, Wiegand S, Werner JA, et al:Propranolol therapy for infantile haemangiomas
15. Qin ZP, Liu XJ, Li KL, et al: Treatment of infantile hemangiomas with low-dose propranolol
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: evaluation of short-term efficacy and safety. Zhonghua Yi Xue Za Zhi 89:3130, 2009
16. Pope E, Chakkittakandiyil A: Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol 146:564, 2010
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17. Khunger N, Pahwa M: Dramatic response to topical timolol lotion of a large hemifacial
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infantile haemangioma associated with PHACE syndrome. Br J Dermatol 164:886, 2011
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18. Stamatas GN, Nikolovski J, Mack MC, et al: Infant skin physiology and development during the first years of life: a review of recent findings based on in vivo studies. Int J Cosmet Sci
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33:17, 2011 19. Ye XX, Jin YB, Lin XX, et al: Topical timolol in the treatment of periocular superficial
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infantile hemangiomas: a prospective study. Zhonghua Zheng Xing Wai Ke Za Zhi
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28:161, 2012
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20. Storch CH, Hoeger PH: Propranolol for infantile hemangiomas: insights into molecular mechanisms of action. Br J Dermatol 163:269, 2010
21. Le′aute′-Labre`ze C, Taieb A: Efficacy of beta-blockers in infantile hemangiomas: the
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physiopathological significance and therapeutic consequences. Ann Dermatol Venerol
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135:860, 2008
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Characteristics
n (%)
Gender Male Female Mean age Range Mean treatment duration Range Age at treatment initiation
11(31.4) 24(68.6) 4.7 mos 2 to 10 mos 22 wks 6 to 45 wks 21(60.0)
＜6 mos
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25(71.4)
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10(28.6)
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Location Head and neck Trunk Extremities Previous treatment Ulceration PHACES
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22(62.9) 8(22.8) 5(14.3) 0(0) 0(0) 0(0)
Table 2. DIFFERENCES IN AGE UPON INITIATION OF TREATMENT, SIZE AND LOCATION OF LESIONS AMONG 3 OR 2 RESPONSE GROUPS
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Table
Age, mos
Size, cm
χ2
9
2
1
8.332
.016
9
5
2
2
14
4
7
3
35
18
11
6
25
13
8
4
0.033
.857
0-3
12
Total ＜3
test No
N
＞6-10
Kruskal-wallis
Partial
Group
＞3-6
Treatment response Good
P
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5
3
2
Total
35
18
11
6
Facial
22
13
6
3
Nonfacial
13
5
5
3
Total
35
18
11
6
＞3
Location
243 244
.245
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1.352
Figure legends
Figure1. 3.5-month old boy with a focal superficial hemangioma in the left periorbital area.
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A:Before treatment, B.12 weeks after topical timolol maleate treatment, the color of tumor has
247
faded.
248
Figure2. 3-month old girl with a large superficial hemangioma in the left abdomen. A: Before
249
treatment; B: 32 weeks after timolol maleate treatment, the color of tumor has lightened.
250
Figure3. 2.5-month old girl with a large superficial hemangioma in the left forechest. A:Before
251
treatment; B: 10 weeks after topical timolol maleate treatment, the color of tumor become lighter.
252
Figure4. 4-month old boy with a focal superficial hemangioma in the nose. A: Before treatment;
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B: 28 weeks after topical timolol maleate treatment, the tumor has completely disappeared.
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