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Clinical Update: Pediatrics
Old Drug Offers New Approach to Infantile Hemangiomas
A chance discovery by a French pediatric dermatologist has paved a new path for treating periocular infantile hemangiomas.1 The new treatment is actually a half-century-old warhorse of a drug: the beta-blocker propranolol. Christine Léauté-Labrèze, MD, who practices at Children’s Hospital in Bordeaux, had given the drug to a four-month-old infant and almost immediately observed a diminishment of the color and volume of the baby’s hemangioma.
“It’s caught on like wildfire,” said David A. Plager, MD, director of pediatric ophthalmology at Indiana University in Indianapolis. “I can’t recall a medicine that was so rapidly accepted as an improvement over what we already had.” The old standards, intralesional or systemic steroids, as well as alpha interferon and the chemotherapeutic agent vincristine, are associated with significant side effects.
In the two years since the original French report, Dr. Plager has treated about 30 children with propranolol. “We haven’t used oral steroids in a hemangioma patient since we started using propranolol,” he said. “We love not using systemic steroids because patients don’t have to deal with their side effects. Those include effects on the immune system, endocrine system, diet, appetite . . . the list goes on and on.” He noted that in the case of intralesional injections, it can even include blindness from embolization of the medicine.
The culprit under pursuit. Hemangiomas are a common tumor of childhood that can occur anywhere on the body and can have both aesthetic and functional consequences. They appear during the first few months of life and typically stop growing by one year. Ophthalmologists get involved when lesions form around the eye, potentially impairing eyelid movement or visual acuity and putting a child at risk for amblyopia.
A large enough hemangioma can even cause the heart to pump harder to feed the blood vessels, said Tamara R. Fountain, MD, professor of ophthalmology at Rush University Medical Center in Chicago. “So it’s just thrilling to see a therapeutic effect from this drug, sometimes within 24 hours.” Dr. Fountain, an oculoplastic specialist, explained that surgery is sometimes not a satisfactory option. “It’s almost impossible to remove hemangiomas because the tangle of vessels has no distinct boundaries. The best surgical goal is to clear the visual axis and minimize induced mechanical astigmatism.”
A word of caution. Elaine C. Siegfried, MD, professor of pediatrics and dermatology at St. Louis University noted that the enthusiasm for propranolol resembles the optimism that greeted earlier hemangioma treatments and that was eventually dampened. “There was a lot of excitement about alpha interferon, for example, until reports of spastic diplegia appeared,” she said. Yet she is herself hopeful for propranolol, noting that a subset of hemangiomas is severe and life-threatening, justifying new treatments even if they carry risks. She said that, since the French discovery, 51 references have appeared in the literature and five clinical trials have begun recruiting patients. In fact, she is an investigator for one of the propranolol trials.
While Dr. Plager is cognizant of the side effects of propranolol—most notably hypoglycemia, bradycardia, bronchospasm and hypotension—he argued that they are rare and can be managed or avoided. He added that propranolol has a long history of safe use for conditions such as tachydysrhythmias and congestive heart failure.
The French connection. In fact, it was exactly cardiac complications resulting from steroid treatment for a hemangioma of the nasal pyramid that prompted Dr. Léauté-Labrèze to put her four-month-old patient on propranolol. Soon after, she observed a change in the color of the hemangioma and saw that it started to subside. She first thought the improvement was a coincidence. But three months later, she noticed a similar effect after administering propranolol to a child who developed tachycardia after treatment with corticotherapy. The hemangioma softened when palpated and a week later the mass was greatly diminished. Dr. Léauté-Labrèze then started using propranolol to treat other children with significant hemangiomas.
How Propranolol Might Work
Despite reports of dramatic shrinking of the hemangioma within a day or two of taking the medication, the response has not been uniform across patients. In a recent study, for which Dr. Plager was a coinvestigator, 17 babies between 3 weeks and 12 months of age were carefully ramped up on oral propranolol to 2 mg/kg/day for one to two weeks. Ten babies experienced excellent results, defined as greater than 50 percent reduction in size, and six had good results, meaning the hemangiomas decreased, though less than 50 percent. In the seventeenth baby, no further growth of the hemangioma occurred, and none of the 17 babies showed adverse effects.2 All of the babies’ families were satisfied with the outcomes.
“We don’t know why some respond better than others,” Dr. Plager said. For that matter, he said, the fundamental mechanism of action is not really known.
Dr. Léauté-Labrèze theorized that propranolol’s action as a vasoconstrictor may explain why the hemangioma softens following administration. She also thinks that by blocking beta-adrenergic receptors propranolol reduces the expression of VEGF and bFGF (basic fibroblast growth factor) and, in turn, the angiogenesis prompted by those factors.
Two Protocols So Far
“There are a couple of ways to put kids on propranolol,” Dr. Siegfried said. “We know you can’t start on a high dose.” Dr. Plager agreed. His research team developed a protocol for outpatient treatment with propranolol, while acknowledging that the pretreatment evaluation, the ideal therapeutic dose, the ideal treatment duration and knowing how to discontinue the drug all still need to be verified in large-scale studies.
Alert! Before starting any infant on propranolol, Dr. Plager warns clinicians to first establish that the infant doesn’t have PHACES, a hemangioma syndrome that is significantly more complicated than a localized lesion. PHACES is an acronym representing these criteria:
Posterior fossa (brain malformations usually present at birth);
Hemangioma usually covering a large area of the head or neck;
Arterial lesions (abnormalities of vessels in the neck or head);
Cardiac abnormalities/aortic coarctation;
Children’s Hospital of Wisconsin maintains one of the most comprehensive sources of information on the management of PHACES.3
Protocol #1. PHACES complexity aside, Dr. Plager said, the protocol below is probably reflective of what many ophthalmologists are doing now:
Because propranolol predisposes the patient to hypoglycemia, Dr. Plager advised holding off treatment in the first week of life until the infant’s feeding habits are established, or any time when the infant’s oral intake is insufficient.
Protocol #2. Dr. Siegfried suggested a somewhat different protocol.4
Dr. Léauté-Labrèze specifed that propranolol is effective for infantile (capillary) hemangiomas, rather than venous malformations, cavernous hemangiomas or port-wine stains of Sturge-Weber syndrome.