Fulfilling the promise of propranolol
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Dermatologists investigate systemic, topical, and combination therapy for infantile hemangiomas

It’s been only five years since Christine Léauté-Labrèze, MD, and colleagues at two French children’s hospitals made the serendipitous discovery of oral propranolol as an effective treatment against severe infantile hemangiomas (IH). Their findings, first announced in a letter to the editor of the New England Journal of Medicine (2008;358:2469-510), propelled propranolol to first-line treatment for the roughly 12 percent of hemangiomas for which treatment is considered. After publication of the NEJM letter, propranolol “took off like wildfire, because the alternatives were not great,” said Roy G. Geronemus, MD, clinical professor of dermatology at New York University Medical Center. “Particularly with all the issues that took place with the use of systemic corticosteroids in the pediatric population, [treatment] was very problematic.” 

But the rapid ascent of propranolol posed a new set of challenges. What are the contraindications for propranolol? How should patients be monitored? What is the target dosage? How should the dosage be initiated and escalated? Citing “significant uncertainty and divergence of opinion” surrounding these and other treatment issues, a multidisciplinary group of 28 physicians convened in late 2011 to review the available data and develop recommendations. The report that resulted from the conference, published in Pediatrics (2013;131:128-40), included the caveat that “because of the absence of high-quality research data, evidence-based recommendations are not possible at present.” However, the group did issue a “provisional set of best practices” to help guide pediatricians and dermatologists in the selection, treatment, and monitoring of their young patients. 

While some researchers continue to scrutinize the short history of propranolol as a treatment for hemangiomas to define best practice, others have begun looking beyond oral propranolol as monotherapy and exploring the combination of oral propranolol and pulsed dye laser (PDL) therapy and the topical application of both propranolol and timolol. [pagebreak]

Examining the evidence

Complementing the efforts of the consensus conference attendees but addressing a different set of questions, four physicians (including two members of the conference group) undertook a review of 200 published articles about the use of propranolol to treat hemangiomas. “We started using propranolol after that groundbreaking, accidental discovery published in the New England Journal,” said Ann L. Marqueling, MD, clinical assistant professor of dermatology and pediatrics at Stanford University School of Medicine. “It did seem to be effective, but it was hard to counsel patients as to how often it works, how much it has been used, etc. We decided to do a review of the literature, thinking that maybe by pooling the data, we could find out more about exactly how effective it is, what doses are most common, and what kind of side effects exist and how often they occur.” 

After paring down the number of studies to 41 (exclusion criteria included treating fewer than 10 patients), the investigators collected data on a number of factors, including propranolol dose, indications for treatment, treatment duration, response rate, the number of patients with rebound growth after treatment completion, and adverse events. Among their key findings:
  • Propranolol treatment was initiated at a mean age of 6.6 months.
  • Seventy-four percent of the patients were female.
  • The majority of patients were treated with a dose of 2 mg/kg per day.
  • Primary indications for treatment were risk of disfigurement, functional impairment, and ulceration.
  • The mean response rate was 98 percent. Varying methods were used to assess response in the studies; response rate was defined as “as any improvement with propranolol.”
  • The most common adverse events were changes in sleep and acrocyanosis.
  • Less frequent adverse events included hypotension, bradycardia, hypoglycemia, and respiratory events such as infection, wheezing, and bronchoconstriction. [pagebreak]

The high response rate reflected her own experience with propranolol, Dr. Marqueling said, as did the low incidence of severe side effects. Nonetheless, “I think we definitely need to keep an eye on hypotension, bradycardia, hypoglycemia; we should make sure we’re keeping track of those as they’re occurring and figure out what setting they’re occurring in, just because they can be quite severe.” Another area that may draw more scrutiny, Dr. Marqueling suggested, is the effects of propranolol on the brain. “We know that propranolol is a lipophilic drug and can cross the blood-brain barrier. We know that some families report sleep changes and irritability and this may be an area that provokes further investigation.”

PDL plus propranolol 

Pulsed dye lasers have been used to treat infantile hemangiomas since the late 1980s, but only recently have physicians combined PDL with propranolol. As it turns out, the combination is proving highly effective, Dr. Geronemus said. “We tried [combining therapies] on a few patients, and the physicians I was working with and I noticed that the addition of the PDL for those patients on propranolol tended to allow more clearing of the superficial component in a shorter period of time. The results were so dramatic that we felt we had to look and see what we were doing.” 

Dr. Geronemus and his colleagues performed a retrospective study, published in Dermatologic Surgery (2013;39(6):923-33), of 17 infants with facial segmental IH, a group at high risk of complications. Twelve patients were treated with PDL and propranolol concurrently, and five were treated with propranolol for two to eight months, followed by PDL. Two blinded dermatologists rated the degree of IH clearance for each subject using clinical photographs from the medical record. A control group of patients treated with propranolol alone were identified to compare outcomes. [pagebreak]

All 17 infants treated with PDL and propranol achieved complete or near-complete clearance vs. three of eight (38 percent) of those treated with propranolol alone. The concurrent combination therapy group achieved near-complete clearance three months after propranolol was started, while the group receiving PDL after propranolol achieved near-complete clearance after six months. In addition, the authors note, the “cumulative propranolol dose until near-complete clearance was lowest in the concurrent combination group (149 mg/kg), higher in the propranolol-then-PDL group (275.6 mg/kg) and highest in the propranolol-alone group (401.2 mg/kg).”

Current guidelines regarding the use of propranolol do not address the concomitant use of laser therapy, “so this is something that adds more depth to that discussion,” Dr. Geronemus said. “The other thing we found that we didn’t report in the study is that there appears to be less rebounding, which is one of the problems you see sometimes when propranolol is removed or tapered.” He said he plans to continue to study the propranolol-PDL combination with larger groups of patients, adding that “all this is evolving very quickly. It’s really been quite remarkable how the standard of care has changed, right before our eyes, for a very common problem. I think a combination of the right medical approach and the right laser approaches can be synergistic and extremely helpful to the patient.”

A German physician who has published studies of PDL treatment of hemangiomas since 2000 also noted an apparent synergistic effect when PDL and propranolol are use together. Margitta Poetke, MD, of the Elisabeth Klinik in Berlin, presented results of her recent study at the 2011 Excellence in Paediatrics meeting in London. According to a report in the online Hospitalist News (“Propranolol/Laser Therapy Offers New Option for Infantile Hemangioma,” Jan. 4, 2011), the study included 23 infants with facial hemangiomas that were “causing severe functional impairment, such as occlusion of the eye or destruction of the lip.” Nine were treated with propranolol alone and 14 were treated with propranolol and laser therapy. [pagebreak]

“Propranolol plus laser therapy appeared to be more effective, with only one rebound hemangioma occurring in a child with a cutaneous/subcutaneous hemangioma out of 14 children treated with the combination,” said the report. Dr. Poetke’s assessment was that “laser treatment in combination with propranolol seems to have an additive, positive effect…and the risk of a rebound growth seems to be much lower.”

Megha M. Tollefson, MD, a pediatric dermatologist at the Mayo Clinic, said that while “many of us will use propranolol as monotherapy in the majority of patients needing systemic treatment, I also use PDL on infants that are on propranolol but have an ulcerated hemangioma, where the area of ulceration is slow to heal and we need a little bit extra to treat that area of ulceration. I also often use it around age four or five, to clean up whatever of the hemangioma is left over, like telangiectasia, but by then they’re usually done with propranolol or other treatments.”

Treatment with topicals

In addition to its growing prominence as an oral agent for IH treatment, propranolol administered topically in a 1 percent ointment is proving effective against superficial hemangiomas. Karin Kunzi-Rapp, MD, PhD, dermatologist and head of the Laser Therapy Center at the University of Ulm, Germany, published a study of 45 infants with 65 superficial hemangiomas in Pediatric Dermatology (2012;29(2):154-59). Parents were instructed to apply the ointment in a thin layer twice daily. In two ulcerated hemangiomas, the topical propranolol was applied only in areas of the hemangioma surrounding the ulceration, and two sessions of PDL treatment were added. In a group of 39 children aged six months or younger, with 57 hemangiomas, initiation of regression was observed in 23 patients (59 percent), cessation of growth in 10 (26 percent) and no response or proliferation of newly developed subcutaneous components in six (15 percent). In a second group of six children older than seven months, signs of improvement were seen after two or three months in all 10 hemangiomas. The topical application was well tolerated in all children; in seven preterm infants, therapy began in the neonatal intensive care unit. [pagebreak]

“All cases of initial cutaneous hemangiomas, flat cutaneous hemangiomas in the growing phase, and residuals from large hemangiomas after oral propranolol are good candidates for topical therapy,” Dr. Kunzi-Rapp said. Oral propranolol is indicated for “large facial IH with endangering localization and large segmental IH on the trunk and extremities.” The topical preparation may have an edge in terms of delivering the drug where it is most needed, she noted, because “only a small amount of [topically applied] propranolol permeates through the skin into the blood system; most of the drug accumulates in the hemangioma after repeated applications.” Dr. Kunzi-Rapp did advise caution in using topical propranolol near the mouth or on the hands because “oral uptake by licking is likely.”

A case report by a group of Chinese physicians, published in the Journal of the American Academy of Dermatology (2012;67(6):1210-13) also evaluated the safety and efficacy of a 1 percent propranolol ointment in the treatment of superficial IH. They report that among 28 hemangiomas in 25 children, 90 percent showed either good or partial responses, and suggest that topical propranolol may be a good adjuvant treatment “during the wait-and-see period.”

Dr. Tollefson noted that while response to topical therapy is not as “dramatic” as it is to oral propranolol, “a really good application of topical is in the smaller, mostly superficial hemangiomas, where you don’t necessarily need to treat with systemic medication. The one thing we don’t know quite as much about yet is if it’s safe to use around the eye, or on ulcerated hemangiomas. Those that are ulcerated have a little bit more risk of having systemic absorption of the medication.”

For patients at Lucile Packard Children’s Hospital, Dr. Marqueling uses topical timolol, a nonselective beta blocker similar to propranolol that has been used for decades to treat glaucoma. “It comes as a solution for the eyes, so it’s a very easy medication to apply. I tend to use it for hemangiomas that have a bright red, superficial component. It absorbs deeply enough to decrease the redness, but not enough to make a difference for the deep component that’s a little more bluish. We limit the dose to about one or two drops a day, to make sure a very minimal amount absorbs.” In an attempt to decrease the growth of ulcerated hemangiomas, “we use it around the ulceration and then treat the ulcer itself with generic wound care. That tends to help substantially in some cases.”

 

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