Paradigm shift in treatment of hemangiomas

James Bergman, MD, FRCP(c) (biography and disclosures)

What I did before
Hemangiomas of infancy are soft tissue tumours that general practitioners and pediatricians commonly see in their practices. These growths occur in up to 2% of newborns.  They are benign vascular proliferations that typically undergo a growth phase (until approximately 6-12 months), followed by a plateau phase, and then enter a slow gradual involution phase. The general rule of thumb is that 50% are gone by 5 years, 70% by 7 years, and 90% by 9 years. It is important for the practitioner to discuss with the patient’s family that “gone” does not always mean that the area will later be completely normal.  After involution there can be variable amounts of residual hemangioma.  At times after involution, especially with large exophytic hemangiomas, there can be excess fibrofatty tissue that may require surgical revision.  Families can be reassured that hemangiomas are benign and often observation alone is all that is warranted.  In a patient with an uncomplicated hemangioma the physician can continue with normal routine health care. The family should be advised that if the lesion is not following the normal course or if there are concerns then earlier reassessment is warranted.  If there are complicating factors (e.g. associated bleeding or ulceration) and or special locations (e.g. Periocular, large facial, perineal) then active intervention and close follow up may be necessary…
The associated risk of each patient’s hemangioma needs to be weighed in order to decide if intervention is necessary.  If the clinician determines that the hemangioma places the patient in a life or function threatening situation * then treatment is necessary. A variety of treatments have been used for hemangiomas, but historically hemangiomas that put patients at serious risk have been treated with high dose oral corticosteroids (2- 5 mg/kg/day of prednisone), often for months.  This gold standard treatment has been effective for these serious hemangiomas, but it also placed our patients at risk of serious steroid side effects, such as suppression of growth, the immune system and the adrenal axis.
* Examples of life or function threatening hemangiomas include:  Periocular – visual complication; Beard distribution – airway involvement;  Perineal/perianal –ulceration/infection;  Sacral/large perineal – urogenital abnormalities/ imperforate anus;  Midline lumbrosacral – spinal dysraphism; Large segmental  hemangiomas-  may be associated congenital abnormalities in the segment; Large plaque type facial hemangiomas- PHACES syndrome = Posterior fossa abnormalities, Hemangioma, Arterial abnormalities, Cardiac, Eye abnormalities,  Sternal  cleft;  Multiple hemangiomas- Systemic hemangiomatosis, i.e. internal hemangiomas primarily liver.

What changed my practice
In 2008, oral Propanolol, a non-selective Beta blocker, was serendipitously noted to shrink hemangiomas present in cardiac patients 1.  This experience has been repeated by other groups and many pediatric dermatologists now use Propanolol instead of oral corticosteroids as first line therapy for serious hemangiomas. The use of Propanolol for hemangiomas is not without risks and its use has been reported to be associated with hypotension, bradycardia, bronchospasm, hypoglycemia and hypothermia 2, 3.  Different Pediatric centres have created a variety of treatment protocols that primarily differ in their monitoring, and rates of dosage increase and tapering.  In general, the dose usually starts at approximately 0.5 mg/kg/day and is slowly titrated up to 2 mg/kg/day.   In the future with ongoing research and clinical experience we will gain more knowledge on the rates of side effects, preferred dose and duration of treatment.  At that point firm recommendations regarding monitoring requirements and the setting in which the treatment can be best provided.  However, at this time, due to the above listed issues the use of oral propanol for hemangiomas should only be undertaken by those familiar with the treatment in association with close observation of the patient for potential side effects.
Additionally, there are some reports on the use of topical Timolol o.5% gel; a non-selective topical beta blocker commonly used for glaucoma, for the treatment of less worrisome hemangiomas 4, 5. The reports to date have demonstrated safety and efficacy.

What I do now
At present, for hemangiomas patients who I feel need systemic therapy I personally use oral Propanolol instead of systemic steroids, as I believe that the benefit risk analysis presently favours Propanolol.  If I think that a patient could potentially have a problem in the near future, I will often start a trial of topical Timolol with close observation for any progression of the lesion. A good example of this scenario would be a small periocular hemangioma that has no evidence of ocular effects based on pediatric ophthalmologic exam.  This early topical therapy may offset the need for systemic therapy in the future.
Timolol 0.5% has been used in the literature, but this concentration was chosen due to the fact that it is the commercially available concentration. While a small body of literature supports the use of Timolol 0.5% it is not clear whether this is the optimal concentration.  I initially used 0.5% but due to a partial response I subsequently increased the dose to Timolol 2% compounded into a gel.  The patients I have treated with Timolol 2% have demonstrated clinical benefit without parental reports of clinical side effects.  However, there is no present data on comparison of the efficacy of different Timolol concentrations.  Due to the issues of potential increase of cutaneous medication absorption in infants and the lack of data on the level of absorption through hemangiomas, when I first started using 2% Timolol I initially performed Timolol levels on my patients Reassuringly I was not able to demonstrate any measurable serum drug levels (to be published in future). In the future, as we gain more comfort with the safety and efficacy of topical Timolol we may be able to offer the option of treatment to patients/families that are experiencing significant psychosocial stress due to hemangiomas that are not threatening function. It may also become a useful agent for hemangiomas that are potentially at risk of future sequelae.  Theoretically if used early enough the growth of the at risk lesion may be controlled, thus potentially offsetting the need for systemic therapy.  Topical and oral Beta blockers are exciting new treatment options that have caused a paradigm shift in the treatment of hemangiomas away from steroid.

References (Note: Article requests require a login ID with CPSBC or UBC)
1)      Leaute-Labreze C  et al: Propanolol for severe hemangiomas of infancy.   N Engl J Med  2008; 358(24):2649-2651. (full text)
2)      Starkey E. Propanolol for infantile hemangiomas: A review.  Arch  Dis Child. 2011 Sep:96(9):890-3. (full text)
3)      Siegfried EC et al:More on propanolol for hemangiomas of infancy.   N Engl J Med  2008; 359(26):2846-2847. (full text)
4)      Pope E et al. Topical Timolol gel for infantile hemangiomas: a pilot study. Arch of Dermatol. 2010 May; 146(5):564-5. (full text)
5)      Ni N, Topical Timolol for periocular hemangiomas: a report of further study. Arch Ophthalmol 2011 Mar: 129(3):377-9. (View article with CPSBC or UBC)
6)      Ni N. Current concepts in the management of periocular hemangioma. Curr Opin Ophthalmol 2011 Sep; 22(5):419-25. (View article with CPSBC or UBC)
7)      Spiteri Cornish K. The use of Propanolol in the management of periocular haemangioma- a systematic review, Eye (Lond). 2011 ju 8:1-7. (View article with CPSBC or UBC)
8)      Zaher, H. Oral Propanolol: an effective, safe treatment for infantile hemangiomas. Eur J Dermatol 2011 Jul-Aug; 21(4):558-63. (View article with CPSBC)

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Paradigm shift in treatment of hemangiomas

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