7 Medical Management of Hemangiomas
Early referral is essential to prevent unwanted morbidity and enable timely evaluation. To define more clearly the extent of concern and to work in concert to begin therapy, specialists must promptly evaluate patients with vision- or airway-threatening hemangiomas. Initiating therapy may abrogate more complicated future interventions or surgery. Details regarding laser and surgical interventions are discussed in Chapter 8.
Medical therapy for hemangiomas of infancy has been administered topically, intralesionally, or systemically. From the 1960s until 2008, corticosteroids (systemic, topical, or intralesional) were the first-line therapy for proliferating hemangiomas requiring medical treatment, despite potential side effects with systemic use (cushingoid appearance, irritability, immune suppression, hypertension, cardiomyopathy, adrenal and immune suppression, pseudotumor cerebri, Pneumocystis carinii pneumonia). 1 , 2 , 3 , 4 , 5 Reports of side effects specific to intralesional corticosteroids for periorbital hemangiomas have included iris depigmentation, cellulitis, and retinal artery occlusion. 6 , 7 , 8 Ultrapotent topical steroids showed a stabilizing effect and some improvement. 9 , 10 , 11
Other therapies have also been used. Subcutaneous interferon-α injections initially showed promise as an antiangiogenic agent for hemangiomas of infancy 12 ; however, an unexpected neurotoxicity (spastic diplegia) observed in some patients precluded its use. 13 Intravenous vincristine was effective for recalcitrant hemangiomas, but the necessity for a central intravenous access and potential toxicities limited its use. 14 , 15 Response to topical imiquimod cream for superficial hemangiomas has been variable, with some patients experiencing severe ulceration and crusting in the area where the medication was applied. 16 , 17 , 18
A profound shift in medical management of hemangiomas occurred after a publication in 2008 documenting the serendipitous observation that propranolol, a nonselective β-blocker, inhibited growth and stimulated involution of hemangiomas ( Fig. 7.1 ). 19
Subsequently, more than 450 articles have been published according to PubMed (August 2014), most reporting successful clinical outcomes for hemangiomas of different types in a variety of locations, including cutaneous, periocular, subglottic, ulcerated, and hepatic hemangiomas. 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 Use of propranolol has also been shown to be safe and effective in patients with PHACE (posterior fossae anomalies, hemangioma, arterial anomalies, cardiac and cerebrovascular anomalies, eye anomalies) syndrome, although the authors advise caution in dosing. 33
One study demonstrated stable brain perfusion via serial single-photon emission computed tomography studies in a cohort of infants with PHACE arteriopathy treated with propranolol. 34 A phase III double-blind, randomized international multicenter study comparing oral β-blocker treatment for proliferating hemangiomas at two different doses versus placebo for infants aged 1 to 5 months showed promising clinical improvement, with no major toxicities; see www.firstwordpharma.com/node/1023912#axzz2eOZOKW47. Propranolol, in a pediatric-friendly preparation without harmful excipients, was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2014 and is marketed as Hemangeol in the United States and Hemangiol in Europe.
A multicenter retrospective chart review study compared patients treated with oral corticosteroids and those treated with propranolol. Patients treated with β-blockers experienced fewer side effects, superior clinical outcome, and fewer surgical referrals. The authors also concluded that oral β-blocker therapy was more cost-effective than oral corticosteroids. 35 A randomized, double-blind, placebo-controlled controlled clinical trial for infants younger than 4 months with proliferative hemangiomas (mean age at the beginning treatment, ~12 ± 2.2 weeks; placebo group, 12.4 +/-2.6; treatment group, 12.5 ± 2.1). Ultrasound measurement of the thickness of hemangiomas after 4 weeks of treatment demonstrated a statistically significant decrease in the propranolol-treated group, supporting the early institution of therapy to prevent proliferation and potential associated morbidities. 36
No uniform protocol for drug-related pretreatment evaluation has been established. Some practitioners observe patients for several hours or days in a clinic or hospital setting during initiation of therapy, whereas others do not. Most prescribers obtain some form of cardiac clearance before the initiation of oral β-blockers; however, the degree of evaluation is not consistent (electrocardiogram, echocardiogram, Holter monitor, full cardiac consultation), and some investigators do not routinely perform pretreatment cardiac evaluation. 37 Furthermore, initiation of therapy is greatly variable, ranging from overnight hospital admission, day hospital observation for several hours, or no hospital- or office-based monitoring. 23 , 30 , 38 , 39 , 40 Initiation of dosing is generally gradual, up to the maintenance dose (2 mg/kg daily divided every 8 hours in most reports); however, the protocols are also variable. A recently published consensus statement provides guidelines established through evidence-based discussions by a multidisciplinary expert panel. 41
Potential adverse effects of propranolol include cool extremities, gastrointestinal symptoms, hypotension, nocturnal restlessness, reactive airway, and bradycardia, with rare but significant reports of hypoglycemia. 25 , 42 , 43 , 44 The medication should be held during intercurrent illnesses associated with diminished oral intake or respiratory symptoms, as in association with any procedures done with the patient under anesthesia for which the child will be fasting. 45 Risk of rebound after discontinuing therapy has been reported and may be minimized by gradual tapering of the medication (unpublished, personal experience). One study found a higher rate of rebound in segmental hemangiomas or those with a subcutaneous component. 46
Alternative nonselective β-blockers (nadolol, atenolol) may obviate concerns related to immediate and long-term side effects; however, further studies are required to assess this more fully. 47 , 48 Topical β-blocker therapy (timolol maleate 0.5% gel-forming solution, Alcon Laboratories, Fort Worth, TX) is an attractive alternative for local therapy and seems to be well tolerated, although it should be used for superficial discrete hemangiomas, not on the lips, and cautiously on ulcerated hemangiomas ( Fig. 7.2 ). 49 , 50 , 51 , 52 , 53 , 54 , 55
A study comparing topical imiquimod with timolol showed comparable clinical response. 56 Most current registered clinical trials for hemangiomas of infancy are studying oral or topical β-blocker therapy (www.clinicaltrials.gov). I do not have a hard and fast rule regarding the duration of therapy, as in my experience, there appears to be great variability in response to medical treatment of hemangiomas, which may reflect patient variability in drug pharmacokinetics, type of hemangioma, age at initiation (proliferative phase versus later), and other factors. I generally weight-adjust the dosage during the proliferative phase, then gradually taper to twice daily dosing (i.e., two thirds of the total daily dose) once the child is sleeping through the night, unless clinically prohibited (e.g., with airway hemangioma or aggressive periocular hemangioma). Ideally, to prevent rebound growth, the dosage is tapered gradually. I find that some patients require very low doses for a prolonged period to prevent rebound growth.
Various combinations of local and systemic therapies for ulcerated hemangiomas are described in single case reports and small series and are summarized in comprehensive reviews. 57 , 58 Nonadherent dressings (petrolatum-based, nonstick gauze, hydrocolloid), emollients, and topical antibiotics can provide barrier protection. Oral or topical β-blockers can be used judiciously in conjunction with the preceding ( Fig. 7.3 ). Systemic antibiotics may be necessary for superinfected ulcerated hemangiomas. Additionally, analgesics, topical hemostatic agents for bleeding, or pulsed dye laser treatments may be required. Recombinant platelet-derived growth factor (becaplermin gel) is efficacious for ulcerated hemangiomas 59 , 60 ; however, a “black box” warning restricts its use as a result of reports of increased incidence of malignancy when used for diabetic ulcers (www.fda.gov/Safety/MedWatch/S). Scarring from severely ulcerated hemangiomas may require later surgical intervention. Aggressively ulcerating hemangiomas may benefit from early surgical excision.
The precise mechanism of action is unclear; however, in vitro studies support a variety of effects of propranolol on hemangioma endothelial cells studied in vitro. It has been shown to be antiproliferative, apoptotic, to induce adipogenesis (which is seen with involution), to affect endothelial β-adrenergic receptors and other cellular pathways, as condensed in Table 7.1 . 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76
Proposed mechanism of action
Early: vasoconstriction (decreased nitrous oxide release)
Intermediate: angiogenesis inhibition (interference with VEGF- and bFGF-induced endothelial cell proliferation, matrix metalloproteinases)
Long-term: hemangioma endothelial cell apoptosis
Storch and Hoeger, 2010
G/G phase cell-cycle arrest, inhibition of VEGF-induced tyrosine phosphorylation of VEGF-R-2
Lamy et al, 2012
Inhibition of endothelial progenitor cell homing
Zou et al, 2013
Hastens adipogenesis in hemangioma stem cells
Triggers apoptosis of hemangioma endothelial cells
Wong et al, 2012
Endothelial cell type-independent
Blockade of endothelial cell proliferation, migration, and multiple functions
Stiles et al, 2013
Inhibition of inhibit hemangioma endothelial cell proliferation and induction of apoptosis, dose-dependent VEGF expression downregulation
Ji et al, 2012
Inhibition of AT-converting enzyme and ATII receptor 2, resulting in decreased ATII and VEGF
Itinteang et al, 2011
Inhibition of hemangioma β2-adrenoceptor
Hadaschik et al, 2012; Ji et al, 2013
Inhibition of hemangioma endothelial nitric oxide synthase
Dai et al, 2012
HIF-1α-related inhibition of VEGF-A
Chim et al, 2012
Targeting hemangioma endothelial cell pericytes
Boscolo et al, 2013
Decreases serum VEGF level in propranolol-treated hemangioma patients within first month of treatment
Chen et al 2013
ERK signaling down-regulation, interference with hemangioma endothelial proliferation
Ji et al, 2013
Hemangioma-derived endothelial cell apoptosis, decreased VEGF expression
Ji et al, 2013
Inhibition of endothelial progenitor cell homing
Apoptosis induction via activation of the intrinsic and extrinsic apoptotic pathways
Tu et al, 2013
Growth inhibition, not apoptosis of hemangioma cells
Kum and Khan, 2013
Abbreviations: AT, angiotensin; HIF, Hypoxia inducible factor; VEGF, vascular endothelial growth factor; ERK, extracellular signal-regulated kinases.
Although guidelines and published studies and case series are available, the decision of whether to, how to, and when to begin treatment for patients with hemangiomas is provider dependent and may differ based on the training, area of expertise, and clinical focus of the physician. Parents must also be comfortable with the decisions; and other specialists (e.g., ophthalmologists), if necessary, should be involved with serial follow-up to provide input, which will contribute to dosing decisions.
What has become evident is that early treatment of hemangiomas can effectively prevent morbidity, functional impairment, and anatomical distortion, in many cases avoiding the need for surgical intervention.