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The treatment algorithm for infantile hemangiomas has changed dramatically over the last 3½ years, with the introduction of propranolol as a novel therapeutic agent for the subset of hemangiomas that require intervention. The publication of a letter to the editor by Léauté-Labrèze and colleagues in 2008 was widely read and cited in the dermatology literature, resulting in the widespread use of this nonselective, lipophilic beta-blocker for the treatment of problematic infantile hemangiomas.
The excitement generated by this serendipitous discovery has led to concerns over potential overuse and undermonitoring of the medication, perhaps inadvertently fostered by the fact that this initial publication offered little instruction on drug initiation or monitoring. Currently—although without the use of comparative, randomized, controlled trials—propranolol is rapidly gaining first-line status in the treatment armamentarium for infantile hemangiomas among many experts in the field of vascular anomalies. Some respected clinicians still favor a slower, more cautious approach to propranolol use, however, and prefer corticosteroids as first-line therapy, given their >40 years of use and good tolerability in most patients.
Since comparative, head-to-head trials are yet to be published (although, it should be noted, they are under way), clinicians treating children with symptomatic infantile hemangiomas must cull the literature carefully to determine the best treatment option for their patients. Since the initial report by Léauté-Labrèze,1 there have been >110 English - language publications about propranolol and hemangiomas. Not too far back in many experienced clinicians' minds is the story of interferon, which was initially heralded as an exciting treatment alternative to corticosteroids but was later shown to be associated with up to a 20% risk for spastic diplegia, with the highest risk reported in infants <12 months of age.2
When prednisolone is used to treat infantile hemangiomas, the agent must be administered at high doses, with most clinicians recommending 2 to 3 mg/kg/day.3 In the study by Greene and Couto (reviewed in this issue), the investigators use 3-mg/kg/day dosing, with their choice based on a meta-analysis that showed a significantly greater response at this higher dose.4 The authors admit that most patients have residual hemangioma at the end of prednisolone therapy, which is an important difference from infants described in most propranolol treatment reports.
Although the mention of treatment until "complete involution" in the paper by Sans and coworkers (reviewed in this newsletter) is likely an overstatement of effect, in my clinical experience, it is true that the degree of involution observed during propranolol therapy is often greater than that noted with corticosteroid use. What remains unclear, however, is whether this greater degree of change in hemangioma size is due to a truly differing drug effect or whether it may be related, in part, to the fact that most clinicians attempt to taper prednisolone as early as possible, given their concern over potential side effects. Propranolol, on the other hand, is considered by many to be the more innocuous of the two agents, is often continued for longer periods of time, and, as such, perhaps overlaps with some natural involution.
In addition, it is very important to recognize that many infants are now being treated with propranolol who, in the past, would likely have been managed expectantly (ie, medical intervention is now offered to many patients with disfiguring or cosmetically sensitive, but not truly function- or life-threatening lesions, so we may not be comparing the same with the same). What does appear to be no longer debatable, however, is that propranolol has the ability to induce involution in hemangiomas that are beyond the early proliferative phase of growth. The Sans and Hogeling papers, both reviewed in this issue, report on such patients. In comparison, prednisolone is generally accepted to be effective primarily in the early proliferative phase of hemangioma growth, which occurs in the first 3 to 5 months of life.5
In the study by Greene and Couto, the strongest assertion is the authors' observation that corticosteroids have a long track record of safe use, and although their potential side effects are well known and numerous, the majority of steroid-treated infants with hemangiomas do very well and experience transient, if any, adverse effects.
Medication is administered on an outpatient basis in all cases, and no expensive monitoring or testing is required. In contrast, propranolol, although associated with few side effects in most patients treated over the last 3 years, does have the potential for such rare, but truly life-threatening, adverse effects as hypoglycemia (including hypoglycemic seizure), hypotension, bradycardia, and bronchospasm.
Many clinicians advocate, as I do, inpatient admission for initial propranolol dosing for certain patients, including the very young and those at high risk for potential complications (eg, those with PHACE [an acronym that describes a neurocutaneous syndrome encompassing the following features: posterior fossa brain malformations, large facial hemangiomas, arterial anomalies, cardiac anomalies and aortic coarctation, and eye abnormalities6] syndrome or with heart failure), which adds a considerable expense.
Currently, the greatest need exists for large head-to-head studies that compare the traditional treatment standard, corticosteroids, with the new alternative, propranolol. The other great limitation that affects all studies of infantile hemangiomas, especially those discussed in this newsletter, is the lack of a validated outcome measure.
Hemispheric measurements with tape measures fail to document fully the extent of most lesions and are poorly reproducible by different providers. With ultrasound, it is difficult to compare the same lesion over time, and even excellent medical photography systems fail to fully appreciate the clinical extent of many hemangiomas, especially when normal growth of the infant is taken into account. There is much fertile ground for continued research.
Just as it is difficult to believe that the patients in the study by Greene and Couto experienced no side effects, it is equally difficult to believe the 100% efficacy reported by Sans and collaborators. The truth about both therapies likely lies somewhere in the great between, and it is, as always, the task of the clinician to navigate those often murky waters.
Commentary References
| 1. |
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(24):2649-2651. |
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| 2. |
Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope 2004;114(7):1231-1236. |
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| 3. |
Frieden IJ, Haggstrom AN, Drolet BA, et al. Infantile hemangiomas: current knowledge, future directions. Proceedings of a research workshop on infantile hemangiomas, April 7-9, 2005, Bethesda, Maryland, USA Pediatr Dermatol. 2005;22(5):383-406. |
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| 4. |
Bennett ML, Fleischer AB Jr, Chamlin SL, Frieden IJ. Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation. Arch Dermatol2001;137(9):1208-1213. |
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| 5. |
Chang LC, Haggstrom AN, Drolet BA, et al; Hemangioma Investigator Group. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics. 2008;122(2):360-367. |
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| 6. |
Metry DW, Dowd CF, Barkovich AJ, Frieden IJ. The many faces of PHACE syndrome. J Pediatr. 2001;139(1):117-123. |
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