Treatment of infantile hemangioma with propranolol: A review of 25 cases

Treatment of infantile hemangioma with propranolol: A review of 25 cases

Mohamed Ramadan (a), MD; KaramAAllam(b), MD; Mostafa Hariedy(b), MSc; Ahmed  Elsherbiny(b), MD

{a) Pediatric Surgery Unit, Sohag Craniofacial Unit, Sohag University Hospital. (b) Plastic Surgery Department, Sohag Craniofacial Unit, Sohag University

Hospital.

Introduction: Hemangioma is considered the most common tumor of infancy  Rapid growth of hemangioma during its proliferative phase can lead to disfigurement and is sometimes associated with complications. Propranolol has been used recentlyin the treatment forinfantile hemangiomas and has shown promising results. We are reporting our initial experience with the use of propranolol in treatment of hemangiomas  during infancy

Patients  and  methods:  This study is a retrospective analysis  of data of 25 patients  with cutaneous  infantile  hemangiomas  treated  with  oral  propranolol  in  the  hamangioma  and vascular malformation clinic, Sohag Craniofacial Unit, Sohag University Hospital.

Results:  Favorable response to propranolol  was observed in all patients in terms of arrest of growth, reduction of size and/or fading of color of the lesion. No significant side effects were observed necessitating stopping of treatment.

Conclusion: Propranolol is an effective  treatment  for infantile  hemangioma  and  should be considered as a first line therapy. Also it was safely used in infancy with no significant complications reported in our series.

Key words: Hemangioma, propranolol, medical treatment, systemic treatment, treatment outcome.

Introduction:

Hemangiomas      are      considered      the most   common   tumors    of   infancy   with an  occurrence  rate  of  approximately   1  in

10  children.l   Hemangiomas   represent   an

aesthetic deformity for the patients and sometimes    functional    problems.    Specific for  haemangiomas,   it starts  with  the  phase of   proliferation,   then   a   stationary   phase and finally the  involution  phase  which partially regresses over several years. The proliferative growth may be complicated by ulceration, bleeding, or infection with some lesions manifested by potentially dangerous symptoms.!

Current treatment approaches for infantile hemangiomas  include  topical,  intralesional,

and systemic  therapies. 2  Laser  and surgical

modalities   are  sometimes   used   depending on the  clinical  scenario.  Risks and  benefits of  medical  or  surgical  versus  observation alone  treatment  must  be  carefully  weighed in tailoring  management  to the  specific clinical situation at hand.2 There are many treatment lines described for hemangiomas which include Intralesional and systemic corticosteroids,3 chemotherapy  (vincristine and interferon alpha)4, liquid nitrogen cryotherapy,5 laser ablation6 and surgical excision.7   Timing  of treatment  and method of administration depend on the clinical situations. Other factors that affect therapeutic choices include; age of the patient, location, and  size  of  the  hemangioma  and  the anticipated complications.2

Propranolol,  a non-selective  beta-blocker

Am-Shams] Surg 2014; 7(19):1-10

with membrane stabilizing activity, causing accelerated  involution  of hemangioma,  was first reported in 2008 by Leiautei-Labreize following an incidental finding.8 This finding has been supported by later additional reports.9-12 This  retrospective  study  reports our initial experience with the use of proplanolol in the treatment of hemagiomas. The objective of this study is to describe and analyze our protocol of using propranolol as a first-line treatment and a single therapy in the management of infantile hemangioma.

Patients and methods:

A retrospective  review of 25 patients having cutaneous infantile hemangioma were treated with oral propranolol.  The study was performed in the hemangioma and vascular malformation  clinic  of  Sohag  Craniofacial Unit   at   Sohag   University   Hospital   from October 2009 to February 2012.

Reviewed  data  included  sex, location  of the lesion, photography, age at diagnosis, age at start of treatment, indication of starting treatment,   pre-treatment   assessment,   dose and duration of treatment, favorable response to treatment and any side effects.

25  patients  (10  males  and  15  females)

with their ages at presentation ranged from 2 to14 months with an average 5.5 months. The lesions were located in the head/face/neck (18 hemangiomas; 62%), trunk (6 hemangiomas;

21%) and upper/lower extremity (5 hemangiomas; 17%). The lesions were found in  multiple  locations  in  four  cases  (16%). There was associated invasion of the trachea (confirmed  by a bronchoscope)  in two cases with cheek and neck hemangioma Table (1).

Before starting treatment with propranolol,

all patients were assessed by a pediatrician for baseline evaluation which included medical history, clinical chest and cardiac assessment and ECG. Treatment with propranolol was initiated at presentation for all patients after informing  the  parents  about  the  drug  and its possible side effects and getting signed informed   consents.   Oral   propranolol   was

given to all patients in a dose of 3 mg/kg/day

doubled  in the second week to reach 3 mg/ kg/day in the third week.  Follow up during treatment was weekly in the first 3 weeks then twice weekly for evaluation of compliance to treatment and dosing, assessing response to treatment and observing any side effects.

All   of  the  following   were   considered

favorable response to treatment with propranolol:  arrest  of  growth  of  the  lesion over the period of treatment  during the early active  proliferation  phase,  reduction  of size of the lesion, healing  of any ulcers over the lesion, lightening  of the color of the  lesion from red to grey/white, or flattening of the surface ofthe lesion.

Because of the retrospective nature of the

study,  no  volumetric  measurement   of  the lesion before or after treatment was available.

Inclusion  criteria  comprised  the  rapidly

growing   haemangioma,   lesion   with functional  or significant cosmetic deformity, lesion likely to affect physiological functions or cause significant cosmetic deformity, even in smaller lesions with high cosmetic concern and parents' wishes.

Results:

The duration of treatment ranged from 1.5 to 4.5 months with an average of2.6 months. The duration of follow up ranged from 3.5 to

9.5 months  with  an average  of 6.5 months.

A favorable  response  to treatment  was seen in all patients in terms of arrest of growth of the lesion, decrease in size and fading of the color ofthe lesion. Two cases were presented with ulcers which were healed with treatment. One case with cheek and neck hemangioma associated invasion ofthe trachea (confirmed by  a  bronchoscope)   was  complaining   of stridor which improved after 4.5 months of treatment.

No  side   effects   were  reported   by  the

family or observed  by the authors during or after treatment. The authors did not report re­ growth during the period of follow up. Case examples are shown in Figures (1,2,3).

Discussion:

divided  in 3 doses. The dose was gradually increased starting by 1 mg/kg/day for a week,

Until    recent considered     the

time,    corticosteroid    was first-line    treatment          for

Figure (1): Hemangioma of the right cheek at the age of3 months (A) and at the age of7 months after 4 months of treatment with propranolol {B).

Figure {2): Hemangioma affecting  the whole nose and right periorbital region at the age of

12 months (A) and at the age of 15 months after 3.5 months of treatment with propranolol (B).

Figure (3): Hemangioma  of the left forearm at the age of 3 months (A) and at the age of 7 months after 4 months of treatment with propranolol {B).

Table 1: The presentation of the patients.

infantile   hemangioma   in  the   proliferative phase included systemic or intralesional administration.8 In tum, localized or residual infantile hemangioma in the involutive phase were treated with surgical excision or laser therapy. 13,l4

Steroids  have a long  record  of targeting the   proliferative     phase                of   hemangiomas causing     their shrinkage;       however,          they can            cause    significant          side       effects        and rebound  growth  can  occur  upon  cessation of  treatment.l5  Likewise,  chemotherapeutic options, such as vincristine or interferon, can have significant side effects, and also require port   placement. 15  A   meta-analysis    study conducted by Izadpanah et ai16 revealed that propranolol achieves a greater response rate in  the  treatment  of  infantile  hemangiomas in   comparison   with          corticosteroids    with response rate approaching 100% compared to less than 90% for corticosteroids.l6

Propranolol is a non-selective  -blocker developed in the 1950s by Sir James Blackl7 and the first found to be useful in clinical medicine.l7 Propranolol use for infantile hemangiomas was accidentally discovered in 2008 by a group of physicians from Bordeaux Children's  Hospital in France in several patients with extensive infantile hemangiomas who received treatment with propranolol for cardiac problems.8 Promising results with regression of hemangioma followed the initiation  of propranolol  without  recurrence of hemangioma growth were reported.48

The mechanism  of action of propranolol on  hemangioma  is  still  unclear.  It is hypothesized that as a -adrenergic antagonist it  induces  vasoconstriction,  resulting  in colour change and palpable softening  of the hemangiomas,   or   that   propranolol   might cause downregulation of growth factors,  such as vascular endothelial growth factor, and up­ regulation of cellular  apoptosis.8,17

Hemangioma-derived stem cells (HemSCs) are  considered the  cellular  precursors of infantile   hemangioma.18  These   cells   have been used to develop a murine hemangioma model.     It  was    found    that    propranolol inhibited   angiogenesis  via  down-regulating the expression of vascular endothelial growth factor in hemangioma derived stem cells.18,19

Also  propranolol was  shown  to  have  effect on primary  infantile  hemangioma endothelial cells (IHECs) by causing significant apoptosis through  the extrinsic and intrinsic  pathways. There was marked  increase  in the expression of  caspase-8,   cytochrome  c,  apoptosis­ inducing factor, caspase-3 and poly (ADP­ ribose) polymerase 1, as well as a concomitant reduction in lamin Bl  expression in a dose dependant manner.20

There  was  a  concern  about  which  stage of   hemangioma  could   propranolol  to   be given  for  better  response. In  a  study  with two groups of patients, 37 out of 38 patients showed  response  to propranolol who  started treatment  before   reaching   the   age   of  one year  (97%),  whereas  the  proportion was  23 out of 31 patients  who started treatment after reaching one year of age (74%).21 Our patient population was all in the proliferative stage or near its end. The previous study could suggest that propranolol could  be a valuable medical treatment for  cases  presented late  after  the end ofthe proliferative stage.

Studies     showed     marked     success     m using propranolol for treating infantile hemangiomas with  a response rate  reaching

100%  in  most  studies  with  the  range  from fair to excellent  results.9-12,22-26 Our study showed   response  in  all  cases  ranged  from arrest of growth of the lesion, decrease  in size, fading of the  color of the lesion  and healing of ulcers.  No considerable side  effects  were reported   by the  family   or  observed by  the authors during  or after treatment.

Although propranolol is considered a safe drug, its adverse  effects are in the form  of bradycardia,    hypotension,    hypoglycemia, and  bronchospasm.27,28  Electrocardiograms and   echocardiograms  were   recommended by some authors for all patients before the initiating     propranolol   treatment   to    rule out    contraindications   to     -blockade.27,28

Slowly    increasing  the   dose   of   the   drug and close monitoring of heart rate, blood pressure,  and serum  glucose  levels have also been recommended in the initial phase of treatment.27,28

Albuquerque et ai21 reported  their  results with  69  patients  with  hemangiomas treated with propranolol. They reported  no cases needed  to discontinue propranolol due to serious or intolerable side effects. They found that 16 patients reported mild side effects in the form  of transitory dyspnea,  cold  extremities, precordial pain  or slow  weight  gain.  Taking into consideration that the patient  population in the previous  study was up to 19 years  old and they used doses up to 4 mg/Kg.21

Georgountzou et ai26 admitted their patients for 24 hours for heart rate and blood pressure monitoring every hour for 6 h following each dose  (twice  daily)  and blood  glucose  testing lh after  each  dose.  They  also  recorded  the heart  rate and blood  pressure  after  one week then monthly.  No hypoglycemia reported  but slight hemodynamic changes  occurred  in 4 patients  without  hindrance of initiating  or stopping the treatment.26

Propranolol is a cheap,  effective  and safe treatment of  hemangioma during  infancy.  It should  be considered the  first line treatment of  hemangioma due  to  the  better  response rate  and  fewer  side  effects  reported than corticosteroids. Additional study  on  a larger scale  of  patients   with  the  use  of  objective volume  assessments (e.g  3D camera)  is advised.  Also longer  follow  up is needed  to assess the relapse rate.

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