Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 2  |  Page : 429-434

Evaluating the efficacy of different treatment modalities in cases of infantile hemangioma


1 Department of Dermatology, Andrology and STDs, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Dermatology, Benha Children Hospital, Qaliubiya, Egypt

Date of Submission22-Mar-2021
Date of Decision17-May-2021
Date of Acceptance23-May-2021
Date of Web Publication27-Jul-2022

Correspondence Address:
Aya A A. Ahmed
Quweisna, Menoufia
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_70_21

Rights and Permissions
  Abstract 


Objective
This study aimed to evaluate different treatment modalities of infantile hemangiomas with their benefits and side effects within 3 months of treatment.
Background
The most common vascular tumors in infants are infantile hemangiomas, usually present as a premonitory mark with rapid postnatal growth, followed by slow involution. For those requiring systemic medications, early treatment is critical.
Patients and methods
A randomized-controlled trial was conducted on 120 patients with hemangioma distributed into four treatment groups. The first group was treated by placebo, the second group was treated by topical timolol only, the third group was treated by topical timolol + oral propranolol and the fourth group was treated by topical timolo + intralesional steroid.
Results
Significant response was found in 90.9% of the patients in the topical timolol + oral propranolol group, 78.1% of the patients in the topical timolol-only group and 72.7% of the patients in the topical timolol + intralesional steroid group. In terms of the side effects, the topical timolol + intralesional steroid had the most side effects (54.5%), followed by the topical timolol + propranolol group (45.5%) and the topical timolol-only group (18.8%). There was a statistically significant difference in lesion size, the visual analog scale, side effects, and response.
Conclusion
The combination of topical timolol with oral propranolol is a very rapid, effective, simple, and safe treatment for compound hemangiomas, achieving more remarkable clinical results and fewer side effects than other methods of treatment. Therefore, we can use this combination as the first line of treatment.

Keywords: hemangioma, intralesional, propranolol, steroid, timolol


How to cite this article:
Al Shami HN, Ahmed AA, Hassan RA. Evaluating the efficacy of different treatment modalities in cases of infantile hemangioma. Menoufia Med J 2022;35:429-34

How to cite this URL:
Al Shami HN, Ahmed AA, Hassan RA. Evaluating the efficacy of different treatment modalities in cases of infantile hemangioma. Menoufia Med J [serial online] 2022 [cited 2024 Mar 29];35:429-34. Available from: http://www.mmj.eg.net/text.asp?2022/35/2/429/352209




  Introduction Top


The most common vascular tumors in infants are infantile hemangiomas (IH)[1]. They may occur due to angiogenesis and vasculogenesis disorders[2]. Rapid proliferation, followed by involution is the characteristic growth pattern of IH; thus, conservative therapy strategies based on observation without early interference were prevalent[3]. The first choice for proliferating hemangiomas is early and active intervention[4]. The mainstay for hemangioma treatment is corticosteroids[5]. Oral corticosteroids can be effective in preventing further hemangioma growth, but special attention should be focused on tapering the dose and we should be aware of its numerous potential systemic side effects[6]. For all cutaneous hemangiomas, the most common modality of treatment is intralesional steroid therapy as it is safe and effective[7]. For controlling the proliferation of capillary hemangioma, propranolol has been reported to be effective at a dose of 2 mg/kg/day[8]. Recently, propranolol has been used as the main first-line systemic medical therapy for the treatment of hemangiomas[9]. Topical timolol started to be applied for hemangiomas, especially for superficial lesions, to decrease the side effects caused by other drugs[10].

The aim of this work was to evaluate different treatment modalities of IH, with their benefits and side effects, within three months of treatment.


  Patients and methods Top


This was a prospective study that was approved by the Ethical Committee of the Faculty of Medicine Menoufia University with number 28419REM35, and informed consent was obtained from patients' parents. This study included 120 children with hemangioma ranging in age from 2 to 18 months, with a median age of 7 months, attending the dermatology outpatient clinic during the period from February 2019 to February 2020. The patients were randomly divided into four equal groups. Thirty patients received the placebo, 30 patients received topical timolol only, 30 patients received topical timolol + oral propranolol and 30 patients received topical timolol + intralesional steroid.

The children were excluded from the study if they were on previous medications, had contraindications to β-blockers and other IH lesions including ulcerated, mucosal and mixed. A complete assessment of the history was performed for all patients, in addition to local and general examinations. The placebo group was administered saline solution drops three times a day on the hemangioma surface for 3 months.

For oral propranolol treatment, one tablet of Inderal 10 mg (Propranolol Hydrochloride; AstraZeneca Corporation, Cambridge, United Kingdom) was dissolving in 10 cm of water and then the dose was loaded into an oral syringe according to weight at a dosage of 2.0 mg/kg/day, divided into two doses and taken within half an hour after meals for 3 months.

For topical treatment, Timolol Maleate 0.5% drops (Egyptian International Pharmaceutical Industries Co., Asher Ramadan, Sharqia Governorate, Egypt) were administered three times a day for 3 months. A gentle thin layer was rubbed on the hemangioma. Before beginning the treatment, we sent all patients to the pediatric cardiologist for examination. Patients were included in the group if this evaluation was normal.

Intralesional steroid was used at a dose of 40 mg/ml triamcinolone acetonide (KENACORT-A Wilmington, DE 19897 United States; Glaxo SmithKline Company, London, England); it was injected every month intralesionally. A volume of 0.2 ml was injected per cm of lesion diameter with a maximum of 1 ml. The treatment was continued for 3 months.

The visual analog scale (VAS) was used to evaluate the therapeutic efficacy. Three independent physicians who were blinded to the treatment pattern checked clinical photographs of the hemangiomas before and after treatment. Changes in the cosmetic appearance affected the VAS score. We graded the therapeutic responses as follows: Excellent 90: 100, Good 51: 90, Fair 1: 50, and Poor -100: 0.

Statistical analysis

The analyses were carried using SPSS software (Statistical Package for the Social Sciences, version 24; SPSS Inc., Chicago, Illinois, USA). Frequency tables with percentages were used for categorical variables, and descriptive statistics (median and range) were used for numerical variables. The Kruskal–Wallis test was used to compare quantitative variables, while the χ2 test or McNemar–Bowker tests were used to analyze categorical variables. A P value less than 0.05 was considered statistically significant.


  Results Top


The median age of the patients was 7 (2–18) months. The male to female ratio was 1: 3.1. The median weight was 9 (4–13) kg. The most frequent site for hemangiomas was in the head (57.5%). The median size of the lesion was 3 (1–8) cm2. Most children (89.2%) were of gestational age greater than 37 weeks. Progesterone was used during pregnancy in 20.0% of the patients. The median VAS score was 66.0 (−55.0 to 100.0). The response to the different treatment modalities was excellent in 25.0%, fair in 15.8%, good in 40.8% and poor in 18.3% of the study participants. The side effects of the treatment modalities were identified in 32.5% of the cases. The reported side effects were pruritis, ulceration, hypoglycemia, hyperpigmentation, erosions, edema, and atrophy [Table 1].
Table 1: Baseline characteristics of the study participants

Click here to view


The median VAS score was −31.6 (−55.0 to −7.6) in the placebo group, 66.6 (35.0–97.6) in the timolol group, 90.6 (37–100) in the timolol + propranolol group and 68.3 (38.0–97.3) in the timolol + steroid group. A statistically significant difference existed between the different treatment options considering the size of the lesion and the VAS score [Table 2].
Table 2: Baseline characteristics in terms of treatment modalities

Click here to view


Excellent response to the treatment was reported in 18.8% of the patients in the timolol-only group, 36.4% of the patients in the timolol + propranolol group and 36.4% of the patients in the timolol + steroid group. Poor response to the treatment was reported in 100.0% of the patients in the placebo group. In the timolol-only group, pruritis was reported in 18.8% of the patients. In the timolol + propranolol group, erosion was reported in 18.2% and hypoglycemia was reported in 18.2% of the patients. In the timolol + steroid group, atrophy was reported, in 9.1% of the patients, edema was reported in 18.2%, hyperpigmentation was reported in 9.1% and ulceration was reported in 18.2% of the patients. There was a highly statistically significant difference between different treatment modalities in terms of the side effects and response. In terms of the side effects, timolol + steroid led to the most frequent side effects (54.5%) compared with the other groups [Table 3].
Table 3: Response and side effects of treatment modalities

Click here to view


A statistically significant clinical response was found in 78.1% of the patients in the timolol group [Figure 1], 90.9% of the patients in the timolol + propranolol group [Figure 2] and 72.7% of the patients in the timolol + steroid group [Figure 3].
Figure 1: A 9-month-old female with hemangioma on the trunk treated with topical timolol only. (a) Before treatment. (b) After 3 months of therapy.

Click here to view
Figure 2: A 2-month-old female with hemangioma on the back treated with topical timolol and oral propranolol. (a) Before treatment. (b) After 3 months of therapy.

Click here to view
Figure 3: A 13-month-old male with hemangioma on the trunk treated with topical timolol and intralesional steroid. (a) Before treatment. (b) After 3 months of therapy.

Click here to view



  Discussion Top


Infantile hemangioma often occurs in infants with an incidence rate of 5–10%[11]. The use of topical timolol has shown promise in the treatment of cutaneous hemangiomas. It was found that there was a reduction in the redness and thickness of superficial lesions within the first 2 weeks, with some eventually showing almost complete resolution[12]. However, the response of thick hemangiomas is less than that of superficial lesions[13].

Propranolol has been used for the treatment of arrhythmia and hypertension for nearly 50 years, and in 2008, Storch and Hoeger accidentally found that propranolol can inhibit the growth of hemangiomas[14].

Mazzola[15] first reported the use of an intralesional corticosteroid injection for the treatment of hemangiomas to overcome the steroidal systemic effects. In the review of the literature, it was found that intralesional steroid is safe and effective, with minimal and temporary side effects[7].

Our results are in agreement with Wu et al.[16], who found that hemangioma was more common in females, and the most frequent site for hemangiomas was in the head. This could be explained by the considerable social and psychological consequences that females and their parents face because of hemangioma. The median age was 7 months and this was different from Ge et al.[17], who reported a median age of 3 months. The mean size of the lesion before treatment was 3.27 cm2 and this was in agreement with Wu et al.[16], who reported a mean size of the lesion before treatment of 4.42 cm2. We reported that 10.8% of children were born prematurely and this was different from Wu et al.[16], who reported that 20.9% were born prematurely. Progesterone was used during pregnancy in 20.0% of the patients, and this was different from Wu et al.[16], who reported progesterone use in 11.5%. The female to male ratio was 3.1:1 and this was different from Wu et al.[16], who reported a female to male ratio of 2.79:1, but similar to Prasetyono and Djoenaedi[18], who reported a female to male ratio of 3.2: 1. A statistically significant difference existed between the treatment options in terms of size and VAS, and this was not in agreement with Wu et al.[16] There was no statistically significant difference in terms of age and between males and females in SE, and this was different from Wu et al.[16] There was no statistically significant difference between males and females in responses, and this agreed with Wu et al.[16] The therapeutic efficacy was evaluated using VAS and this was similar to Wu et al.[16], but different from Xue et al.[19], who used a Doppler ultrasonography scan.

In the topical timolol + oral propranolol group, our result showed that the mean age was 6.77 months and this was in agreement with Ge et al.[17], who reported a mean age of 4.96 ± 4.15 months. The female to male ratio was 4.5: 1, while Ge et al.[17] reported a female to male ratio of 1.5: 1. We reported that 18.2% of the patients were born prematurely, and this was in line with Ge et al.[17], who reported that 11.2% of the patients were born prematurely. The response was 100%, and this was similar to Ge et al.[17].

Our clinical responses were different from those of Xue et al.[19], who found an excellent response in 76%, good response in 18% and moderate response in 6% of the patients. Our protocol for providing treatment was different from that of Xue et al.[19], who used propranolol at a dose of 1–1.5 mg/kg/day in a single dose, along with topical administration of timolol eye drops twice per day. Children were admitted to monitor the pulse rate and blood pressure every half an hour for the first 4 hours, and this was similar to Kader, Fawzy[20].

In the topical timolol-only group, the mean age was 7.95 months and this was different from Pope et al.[21], who reported a mean age of 11.7 months. The female to male ratio was 4.3: 1 and this was different from Wu et al.[16], who reported a female to male ratio of 2.7: 1. We reported that 6.2% of the patients were born prematurely, and this was different from Wu et al.[16], who reported that 21.5% of the patients were born prematurely. Progesterone during pregnancy was used in 18.8% of the patients and this was parallel to Wu et al.[16], who reported progesterone use during pregnancy in 12.4% of the patients. The median VAS score was 66.6, and this was parallel to Wu et al.[16], who reported a median VAS score of 77.2. We reported that 18.8% of the patients had local side effects and this was parallel to Wu et al.[16], who reported that 3.3% of the patients had local side effects.

In the topical timolol and intralesional steroid injection group, the mean age was 9.31 months and this was different from Xu et al.[22], who reported a mean age of 3.98 months. The mean size was 4.68 cm2, and this was similar to Xu et al.[22], who reported a mean size of 3.87 ± 0.29 cm2. Intralesional steroid injection was used at a dose of 40 mg/ml triamcinolone acetonide and this was different from Xu et al.[22], who injected diprospan. A volume of 0.2 ml was injected per cm of lesion diameter with a maximum of 1 ml. Timolol 0.5% drops were administered by the parents per guardians 1 day after the injection, and this was in line with Xu et al.[22] No systemic complications were observed and this was in agreement with Xu et al.[22] We believed that the higher percentage of local side effects in our study than that of Xu's study could be explained by the difference in the steroid material used as we used triamcinolone acetonide in our study, while Xu used diprospan.

Limitations

The relatively low number of patients is a limitation of this study.


  Conclusion Top


The combination of topical timolol with oral propranolol is very effective and safe, and gave the fastest response for the treatment of compound hemangiomas when compared with other treatment modalities in the study.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Léauté-Labrèze C, Harper JI, Hoeger PH. Infantile haemangioma. Lancet 2017; 390:85–94.  Back to cited text no. 1
    
2.
Laken PA. Infantile hemangiomas: pathogenesis and review of propranolol use. Adv Neonatal Care 2016; 16:135–142.  Back to cited text no. 2
    
3.
Sidbury R. Update on vascular tumors of infancy. Curr Opin Pediatr 2010; 22:432–437.  Back to cited text no. 3
    
4.
Hohenleutner U, Landthaler M, Hamm H, Sebastian G. Hemangiomas of infancy and childhood. J Dtsch Dermatol Ges 2007; 5:334–338.  Back to cited text no. 4
    
5.
Greenberger S, Boscolo E, Adini I, Mulliken JB, Bischoff J. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med 2010; 362:1005–1013.  Back to cited text no. 5
    
6.
Ranchod TM, Frieden IJ, Fredrick DR. Corticosteroid treatment of periorbital haemangioma of infancy: a review of the evidence. Br J Ophthalmol 2005; 89:1134–1138.  Back to cited text no. 6
    
7.
Wasserman BN, Medow NB, Homa-Palladino M, Hoehn ME. Treatment of periocular capillary hemangiomas. J AAPOS 2004; 8:175–181.  Back to cited text no. 7
    
8.
Manunza F, Syed S, Laguda B, Linward J, Kennedy H, Gholam K, et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants. Br J Dermatol 2010; 162:466–468.  Back to cited text no. 8
    
9.
Darrow DH, Greene AK, Mancini AJ, Nopper AJ. Diagnosis and management of infantile hemangioma. Pediatrics 2015; 136:e1060–e1104.  Back to cited text no. 9
    
10.
Danarti R, Ariwibowo L, Radiono S, Budiyanto A. Topical timolol maleate 0.5% for infantile hemangioma: its effectiveness compared to ultrapotent topical corticosteroids–a single-center experience of 278 cases. Dermatology 2016; 232:566–571.  Back to cited text no. 10
    
11.
Fu Y, Yang ZG, Zhao LY. Angiogenesis characteristics of infantile hemangioma and feasibility observation of transplantation model of human hemangioma on mice. Eur Rev Med Pharmacol Sci 2017; 21:1276–1280.  Back to cited text no. 11
    
12.
Lee KC, Bercovitch L. Update on infantile hemangiomas. Semin Perinatol 2013; 37:49–58.  Back to cited text no. 12
    
13.
Oranje AP, Janmohamed SR, Madern GC, de Laat PC. Treatment of small superficial haemangioma with timolol 0.5% ophthalmic solution: a series of 20 cases. Dermatology 2011; 223:330–334.  Back to cited text no. 13
    
14.
Lou H, Xu G, Huo R. Curative effect and safety of propranolol combined with prednisone in the treatment of infantile hemangiomas. Exp Ther Med 2018; 15:4677–4682.  Back to cited text no. 14
    
15.
Mazzola RF. Treatment of haemangiomas in children by intralesional injections of steroids. Chirurgia Plast 1977; 4:161–171.  Back to cited text no. 15
    
16.
Wu HW, Wang X, Zhang L, Zheng JW, Liu C, Wang YA. Topical timolol vs. oral propranolol for the treatment of superficial infantile hemangiomas. Front Oncol 2018; 8:605.  Back to cited text no. 16
    
17.
Ge J, Zheng J, Zhang L, Yuan W, Zhao H. Oral propranolol combined with topical timolol for compound infantile hemangiomas: a retrospective study. Sci Rep 2016; 6:19765.  Back to cited text no. 17
    
18.
Prasetyono TO, Djoenaedi I. Efficacy of intralesional steroid injection in head and neck hemangioma: a systematic review. Ann Plast Surg 2011; 66:98–106.  Back to cited text no. 18
    
19.
Xue L, Tong S, Liu Z, Du Y, Wang X. Topical timolol maleate combined with oral propranolol in treatment for nasus externus infantile hemangiomas: a retrospective study of 17 cases. Int J Clin Exp Med 2016; 9:6511–6517.  Back to cited text no. 19
    
20.
Kader MA, Fawzy AM. β-Blocker versus triamacinolone acetate in the treatment of infantile periocular hemangioma. Egypt J Cataract Refract Surg 2016; 22:42–49.  Back to cited text no. 20
    
21.
Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol 2010; 146:564–565.  Back to cited text no. 21
    
22.
Xu P, Yu Q, Huang H, Zhang W, Li W. A self-controlled study of intralesional injection of diprospan combined with topical timolol cream for treatment of thick superficial infantile hemangiomas. Dermatol Ther 2018; 31:e12595.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Patients and methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1006    
    Printed26    
    Emailed0    
    PDF Downloaded97    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]