|Year : 2018 | Volume
| Issue : 2 | Page : 120-123
Therapy for involuting infantile hemangioma: Propranolol effectiveness
Luz Orozco-Covarrubias1, Leticia Lara-Mendoza1, Luis Martín Garrido-García2, Ramón Ruiz-Maldonado1
1 Department of Dermatology, National Institute of Pediatrics, City, Mexico
2 Department of Cardiology, National Institute of Pediatrics, City, Mexico
|Date of Web Publication||26-Mar-2018|
Department of Dermatology, National Institute of Pediatrics, Insurgentes Sur 3700-C, Col. Insurgentes-Cuicuilco, 04530 Mexico, D.F
Source of Support: None, Conflict of Interest: None
Background/Objectives: The efficacy of propranolol as a treatment for infantile hemangiomas (IHs) has been documented. Until now, little has been written about the role of propranolol beyond the proliferation phase of IH. Our aim was to document propranolol efficacy and safety in the treatment of involutive IH. Patients and Methods: Two evaluations were conducted. Investigators evaluated the final clinical results by comparing clinical data at baseline and at the end of the study. Evaluators scored each panel of photographs and were blinded from any clinical information. Both groups used the same scoring system. Patients treated with propranolol in our department between 2009 and 2014 were reviewed. Results: A total of 15 patients with involuting IH treated with propranolol were eligible. Eleven (73%) were females, ranging in age between 16 and 110 months (median 41 months). The types of IH were mixed (n = 13) and superficial (n = 2). The median duration of the propranolol treatment was 20 months (range 6–33 months). The mean size reduction was from 6 cm ± 4.33 before the treatment to 3.98 ± 1.25 at the end of the treatment. The general mean involution according to the investigators' evaluation was 4.1 ± 2.7. The general mean involution according to the evaluators' evaluation was 4.9 ± 1.5. Telangiectasias showed no response. Recurrence was observed in one patient. Transient nightmares were documented in one patient, and nighttime awakenings were documented in another. The therapy was discontinued in neither of these patients. Conclusions: In our experience, propranolol was well tolerated and associated with limited adverse reactions. The use of oral propranolol was effective in the treatment of IH beyond the proliferative phase.
Keywords: Infantile hemangioma, involuting phase, propranolol, tumors
|How to cite this article:|
Orozco-Covarrubias L, Lara-Mendoza L, Garrido-García LM, Ruiz-Maldonado R. Therapy for involuting infantile hemangioma: Propranolol effectiveness. Indian J Paediatr Dermatol 2018;19:120-3
|How to cite this URL:|
Orozco-Covarrubias L, Lara-Mendoza L, Garrido-García LM, Ruiz-Maldonado R. Therapy for involuting infantile hemangioma: Propranolol effectiveness. Indian J Paediatr Dermatol [serial online] 2018 [cited 2018 Aug 15];19:120-3. Available from: http://www.ijpd.in/text.asp?2018/19/2/120/216945
| Introduction|| |
Infantile hemangiomas (IHs) are the most common benign soft-tissue tumors in infancy and have a predictable clinical course: an early rapid growth (proliferative phase) and a gradual involution (involutive phase). It is predicted that all the IH cases have a spontaneous involution of approximately 10% per year.,, The efficacy of propranolol as a treatment for IH has been documented since a report by Léauté-Labrèze et al. in June 2008. In March 2011, Zvulunov et al. reported that propranolol was effective in IH after the proliferative phase. Until now, little has been written about the role of propranolol beyond the proliferative phase of IH. We now present a case series of 15 children with IH where propranolol was used as a treatment to improve IH during the involutive phase. Our aim was to document with other methods propranolol's efficacy and safety in the treatment of involutive IH.
| Patients and Methods|| |
An institutional review board-approved retrospective study of patients older than age 1 with a diagnosis of IH was performed. Patients treated with propranolol in our department between 2009 and 2014 were reviewed. We collected clinical data for each patient (age, sex, lesion location, color, type of lesion, lesion size, number of lesions, distribution, criteria for a syndrome, prior therapies, propranolol treatment parameters, adverse reactions, and response to propranolol) from medical records using standardized data forms. We also collected serial photographs before and after the start of therapy. In each case, a panel of photographs was constructed cropping the IH as much as possible.
Two evaluations were conducted. Two investigators evaluated the final clinical results of the treatment individually (investigators) by comparing clinical data at baseline and at the end of the study. Four dermatologists and two pediatricians evaluated the final photographic results individually (evaluators). The evaluators scored each panel of photographs and were blinded from any clinical information. The dermatologists were from departments of dermatology of different hospitals. The pediatricians were from our hospital and were unaware of our patients. Both groups (two investigators and six evaluators) used the same scoring system, which ranged from 0 (representing maintenance of volume and color) to 10 (representing total flattening and clearance). A mean score for each patient was calculated, which was followed by a general mean involution score for each group and a global mean involution. The mean initial size of the IH was compared with its mean final size. Based on the mean score for each patient, spontaneous involution was calculated and then a general mean calculated spontaneous involution.
| Results|| |
A total of 15 patients with involuting IH treated with propranolol were eligible for this study. Eleven (73%) were females, ranging in age between 16 and 110 months (median 41 months). The median age at IH-growth cessation was 14 months (range 5–30 months). The IH locations are presented in [Table 1]. Localized hemangiomas had almost complete involution in 5/8 versus 5/7 segmental hemangiomas. The types of IH were mixed (n = 13) [Figure 1] and superficial (n = 2). Of these, two fit the diagnostic criteria for PHACE syndrome, and one had multifocal lesions with visceral involvement. A cardiovascular examination found an atrial septal defect in one patient.
|Figure 1: Superficial and deep (mixed) infantile hemangioma of the nose (a) before propranolol at the age of 34 months and (b) after propranolol at the age of 53 months|
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Eighty-seven percent (13/15) had received treatment during the proliferative phase, and 92% (12/13) were treated with oral corticosteroids. Other previous treatments included plus propranolol (two cases), plus timolol (one case), and interferon (one case).
The treatment was initiated in outpatient settings. The treatment parameters are presented in [Table 2]. The median duration of propranolol treatment was 20 months (range 6–33 months).
By comparing clinical data at baseline and at the end of the study, the response to propranolol treatment was found to be mainly changes in IH color from a deep red to gray-purple in 5 versus 12 patients (33% vs. 80%). Telangiectasias showed no response [Figure 2]. The mean size reduced from 6 cm ± 4.33 before the treatment to 3.98 ± 1.25 at the end of treatment. The general mean involution by the investigators' evaluation was 4.1 ± 2.7.
|Figure 2: Superficial telangiectasia in a segmental infantile hemangioma (a) before propranolol at the age of 36 months and (b) after propranolol at the age of 49 months|
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The general mean involution by the evaluators' evaluation was 4.9 ± 1.5.
The global mean involution (investigators and evaluators) of IH in our cases was 4.95 ± 1.59; the general mean calculated of spontaneous involution of IH in our cases was 1.05 ± 0.51 (P = 0.0001).
At the time of clinical assessment, the therapy was discontinued in five patients when the residual lesion ceased to respond to the therapy. One of these patients showed evidence of a relapse of his/her hemangioma.
Adverse reactions were presented in two cases: one patient with transient nightmares and one child with sleep walking. The therapy was discontinued in neither of these patients.
| Discussion|| |
Our experience treating 15 patients with involuting IH supported other reports , indicating that propranolol was an effective drug for treating this condition. Propranolol treatment showed important benefits in our series with relatively “old” patients. The indications for intervention in involuting IH were mostly disfigurement particularly of segmental lesions with a higher frequency of complications and developmental abnormalities. Most of our patients were treated during the proliferative phase; the response observed may have indicated that, even so, propranolol therapy at an older age led to clinical improvement.
There was no difference in response to propranolol with regards to the hemangiomas' location. The response was similar in segmental versus localized hemangiomas.
Our study was a single-center study, which allowed for clinical and photographic evaluations. Using varied methods by Zvulunov et al. to assess the response to propranolol treatment on involuting IH, we documented the efficacy of propranolol in treating IH beyond the proliferative phase.
Our study statistically confirmed that propranolol significantly accelerated the involution rate of involuting IH. As Zvulunov et al. indicated, none of our patients' IH completely involuted with propranolol, but this therapy improved its esthetic appearance. In addition, our patients and their parents accepted this outcome very well.
The parents did not want to stop the medication due to the good results, even when we considered that the response to therapy had ceased. Currently, there is evidence that it is better to manage IH in the postproliferative phase with oral propranolol than wait until they regress spontaneously. The implementation of surgical procedures can occur earlier, as we did in one of our cases.
The mechanism of action of propranolol in proliferative and involutive phases of IH is not completely understood. Propranolol has an inhibitory effect of angiogenesis by antagonizing the vascular endothelial growth factor (VEGF). The VEGF and basic fibroblastic growth factor are elevated in infants with proliferative IH and reduced in infants with involuting IH., Propranolol induces apoptosis of endothelial cells, and it is suggested that apoptosis of endothelial cells is the mechanism involved in the natural involution of IH.
We did not observe severe adverse reactions. However, we emphasize that therapy should include thorough education regarding the proper administration of propranolol, warning signs to watch for, and what parents should do if any side effects are noticed.
Two of our patients with segmental IH without meeting the full diagnostic criteria for PHACE syndrome were treated in our group; they did not have cerebral vascular abnormalities. Caution must be taken when using propranolol with patients with PHACE syndrome.
Relapse of involuting IH in patients treated with propranolol has been documented. One year 10 months after stopping propranolol, one of our patients had a visible recurrence of IH (patient with IH on his/her trunk) [Table 1] at 3 years 9 months of age. While we were unable to explain the cause, incomplete apoptosis during treatment was proposed.
Finally, we did not find that treatments during the proliferative phase had any influence on the response to propranolol during the involuting phase. Corticosteroids were not a therapeutic option for involuting IH, but one of our patients was simultaneously treated with prednisone (0.5 mg/kg/day, four months) before we noticed because of the patient's mother's decision. This patient did not respond better.
Propranolol was well tolerated and associated with limited adverse reactions. We agreed with Vivas-Colmenares et al. that the use of oral propranolol was effective in the treatment of IH beyond the proliferative phase. We did not observe complete responses in any of our patients. Complete responses (total clearance and flattening or only residual telangiectasia) were reported in 72.2% of the patients, and partial responses were reported in 27.8%. We found almost total clearance and flattening with or without telangiectasia in 66.7% of the patients and partial volume reduction or clearance in 26.7%. Our evaluation was likely more rigorous. None of the reported patients by Zvulunov et al. had completely involuted IH.
The retrospective nature of our study and the limited number of cases were important limitations. It was difficult to determine differences between those who had treatment during the proliferative phase versus those who did not. It was also difficult to determine when the benefits of propranolol tapered off according to the type and location of the hemangiomas. Further, prospective studies are needed.
| Conclusions|| |
The use of oral propranolol is effective in the treatment of IH beyond the proliferative phase. In our experience, propranolol was well tolerated and associated with limited adverse reactions.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Luu M, Frieden IJ. Haemangioma: Clinical course, complications and management. Br J Dermatol 2013;169:20-30.
Bauland CG, Lüning TH, Smit JM, Zeebregts CJ, Spauwen PH. Untreated hemangiomas: Growth pattern and residual lesions. Plast Reconstr Surg 2011;127:1643-8.
Couto RA, Maclellan RA, Zurakowski D, Greene AK. Infantile hemangioma: Clinical assessment of the involuting phase and implications for management. Plast Reconstr Surg 2012;130:619-24.
Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N
Engl J Med 2008;358:2649-51.
Zvulunov A, McCuaig C, Frieden IJ, Mancini AJ, Puttgen KB, Dohil M, et al.
Oral propranolol therapy for infantile hemangiomas beyond the proliferation phase: A multicenter retrospective study. Pediatr Dermatol 2011;28:94-8.
Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, Mazereeuw-Hautier J, et al.
Propranolol for severe infantile hemangiomas: Follow-up report. Pediatrics 2009;124:e423-31.
Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: Clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol 2002;138:1567-76.
Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: Insights into the molecular mechanisms of action. Br J Dermatol 2010;163:269-74.
Przewratil P, Sitkiewicz A, Andrzejewska E. Local serum levels of vascular endothelial growth factor in infantile hemangioma: Intriguing mechanism of endothelial growth. Cytokine 2010;49:141-7.
Sommers Smith SK, Smith DM. Beta blockade induces apoptosis in cultured capillary endothelial cells. In Vitro
Cell Dev Biol Anim 2002;38:298-304.
Martin K, Bleib F, Chamlin S, AQ2 Chiu YE, Frieden IJ, Frommelt PC, et al
. Propranolol treatment of infantile hemangiomas: Anticipatory guidance for parents and care takers. Pediatr Dermatol 2013;30:155-9.
Metry D, Frieden IJ, Hess C, Siegel D, Maheshwari M, Baselga E, et al.
Propranolol use in PHACE syndrome with cervical and intracranial arterial anomalies: Collective experience in 32 infants. Pediatr Dermatol 2013;30:71-89.
Bagazgoitia L, Hernández-Martín A, Torrelo A. Recurrence of infantile hemangiomas treated with propranolol. Pediatr Dermatol 2011;28:658-62.
Vivas-Colmenares GV, Bernabeu-Wittel J, Alonso-Arroyo V, Matute de Cardenas JA, Fernandez-Pineda I. Effectiveness of propranolol in the treatment of infantile hemangioma beyond the proliferation phase. Pediatr Dermatol 2015;32:348-52.
[Figure 1], [Figure 2]
[Table 1], [Table 2]