Opinion Article
Past, Present, and Future of Propranolol for Hemangiomas of Infancy
Hemangiomas de la infancia: pasado, presente y futuro del tratamiento con propranolol
E. Baselga
Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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Baselga" "autores" => array:1 [ 0 => array:3 [ "nombre" => "E." "apellidos" => "Baselga" "email" => array:1 [ 0 => "dra.baselga@gmail.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hemangiomas de la infancia: pasado, presente y futuro del tratamiento con propranolol" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Hemangiomas of infancy are the most common vascular tumors of childhood, affecting 10% of newborns, especially females. Hemangiomas are biologically unique, and unlike other proliferative lesions, they tend to regress and resolve spontaneously through mechanisms involving intracellular events or signals that are still only partially understood. In many cases, a wait-and-see approach is therefore all that is required. About 10% of hemangiomas are treated, however, because they may compromise vital functions, because ulceration develops, or because they potentially leave the skin disfigured. While it is true that these tumors resolve, treatment can be justified by the fact that they will not necessarily disappear without a trace.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Furthermore, full resolution can take years and the psychological impact the birthmark may have during the early years of a child's socialization is unpredictable. In this issue of <span class="elsevierStyleItalic">Actas Dermo-Sifiliográficas</span>, Bernabeu and coworkers<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> report on a relatively large series of infantile hemangiomas treated with propranolol, one of the most recently introduced therapeutic alternatives. In this article I review what is known about these vascular tumors, reflect on past and present approaches to management, and outline my view of what the future will bring.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Hemangiomas of Infancy: The Past</span><p id="par0010" class="elsevierStylePara elsevierViewall">Perhaps as a result of their high frequency, hemangiomas have generally been understood to be benign. Nevertheless, medicine has still searched persistently for a way to treat them. New treatment modalities have been greeted with enthusiasm, although some were then abandoned in spite of their efficacy because the side effects could not be justified for the treatment of what remains a benign lesion. Others, such as oral corticosteroids, have prevailed over the years as we have waited for better or safer treatments to appear. Some options, such as surgical removal, were taken up once again after periods of disuse, as occurred when radiotherapy, which was popular in the 1950s, was later proscribed after follow-up brought to light complications such as radiodermatitis and skin cancer in the irradiated zone.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">When hemangiomas were reported to respond to systemic corticosteroids at the end of the 1960s,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> this therapy became perhaps the first major advance in the medical management of these tumors and over time we gained a better understanding of the optimal dosage as well as the risks. One of the main disadvantages of systemic corticosteroid treatment is that these drugs only act on the proliferative phase, leaving a very small window of opportunity to initiate therapy with assurance of success given that hemangiomas reach 80% of their size within the first 3 months. Oral corticosteroids halt growth in nearly 80% of patients, but rapid reduction in volume occurs in only a third. Moreover, the use of these drugs to treat hemangiomas requires much higher dosages (nearly 3<span class="elsevierStyleHsp" style=""></span>mg/kg/d) than those used for other indications. High dosages can lead to delayed growth and suppression of the hypothalamic-pituitary-adrenal axis, although the effect is reversed on suspension of treatment. The greatest concern, however, is immunosuppression, which can increase the risk of serious opportunistic infections, such as <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> pneumonia, in children who are in fact being treated for a birthmark that is not life-threatening.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Another unresolved problem is interference with the child's vaccination schedule: at present we do not know if it is appropriate to vaccinate patients under such treatment or if vaccination should be delayed until after treatment or repeated once treatment is complete.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In the 1990s, a group led by Folkman, who pioneered research on the mechanisms of angiogenesis, described the efficacy of interferon in hemangiomas of infancy even in cases that were unresponsive to corticosteroids.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> However, the description of spastic diplegia in up to 10% of treated patients relegated this approach to use only in tumors that were resistant and life-threatening.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In the search for safer antiangiogenic drugs for cases refractory to oral corticosteroids, Enjorlas and coworkers<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> tested vincristine. This drug, while slow to act, proved highly effective and had few adverse effects. The only route of administration, however, is a central venous line, which presents evident problems when treating an infant for a nonmalignant growth.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Hemangiomas of Infancy: The Current Situation</span><p id="par0030" class="elsevierStylePara elsevierViewall">The discovery that propranolol was effective in this setting was a casual observation by alert French dermatologists,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> whose report once again changed our therapeutic approach to these tumors radically. Response to propranolol is so good and rapid that nearly 100 articles have been published on this use since the first study appeared in 2008. This drug is not new: it has been on the market since 1964, and its pharmacokinetics and side effects are well known. Propranolol has been shown to be effective on hemangiomas of all types and locations, including lesions affecting the throat and liver and those that have become ulcerated. Moreover, this drug acts well beyond the proliferative phase, even benefiting patients as old as 2.5 years.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Response is so rapid that color changes can be seen within 24<span class="elsevierStyleHsp" style=""></span>hours. Maximum response is usually evident at 10 weeks and a plateau occurs at around 20 weeks.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The dosage in most studies has been 2<span class="elsevierStyleHsp" style=""></span>mg/kg/d, divided into 2 or 3 doses. Assessment by a cardiologist is recommended prior to treatment, and blood pressure, heart rate, and blood sugar levels should be monitored, especially after the first few doses and after any increase in dosage.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Hemangiomas of Infancy: The Future</span><p id="par0035" class="elsevierStylePara elsevierViewall">Given the excellent results seen with propranolol, it is my opinion that this drug will replace systemic corticosteroids as the first-line therapy for hemangiomas of infancy.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Many questions remain, however.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The dose-response curve has not yet been established, for example. Although most studies have prescribed 2<span class="elsevierStyleHsp" style=""></span>mg/kg/d, many have used lower or higher dosages with good results. That there is a dose-effect relationship is known, as a better outcome has been observed at higher doses. However, we do not know if using higher doses will allow us to prescribe shorter regimens or if, on the other hand, lower doses taken over a longer period might give the same results with less risk. The optimal duration of treatment has also not yet been established. Although there is a notion that the hemangioma is likely to grow back if treatment is interrupted before the age of 6 to 9 months, no clinical trials have yet compared treatment regimens with different durations. In fact, we have sometimes seen hemangiomas grow back after interrupting treatment at 18 months of age, well past the tumor's proliferative phase. We have also yet to see trials comparing propranolol to oral corticosteroids, or trials assessing combination therapy.The mechanism that might explain propranolol's effect on hemangiomas of infancy is also poorly understood at this time, although it has been suggested that it may be related to control of hypoxia, the induction of apoptosis, the reduction of vascular endothelial growth factor or fibroblast growth factor, or even attenuation of renin-angiotensin system activity in the endothelium of the hemangioma itself.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13–15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">When large facial hemangiomas are treated with propranolol, we still know little of the possible risks or the best way to monitor for the main adverse events (principally hypotension, bradycardia, bronchospasm, hypoglycemia, and hyperkalemia). For this reason, individual hospitals have established their own protocols in keeping with available resources; practices range from hospital admission for the first days of treatment to observation in a day hospital, outpatient monitoring by health care staff, or parent monitoring of blood pressure at home.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The risk of treating large facial hemangiomas accompanied by agenesis, hypoplasia, and tortuosity of large cerebral vessels (PHACE syndrome) is another area where knowledge is lacking.</p><p id="par0050" class="elsevierStylePara elsevierViewall">It is very important to remember that propranolol has not been approved for use in treating infantile hemangioma. Its prescription therefore necessarily falls into the category of compassionate use. This should be of particular concern to us, as these tumors are not usually life-threatening and as most patients are in the age range when the incidence of sudden infant death is highest. Written informed consent must therefore be obtained before treatment can start. Even when parents have consented, however, the prescribing physician's burden of responsibility is great, particularly since it not usually difficult to obtain permission from parents who trust their doctor. The answer to our questions about the use of this drug in hemangiomas of infancy, and the approval of this indication, will depend on the completion of randomized clinical trials. Unfortunately, trials of drugs that have been on the market for so long are always difficult and costly because the pharmaceutical industry usually lacks interest in funding them.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Analysis of the 36 hemangiomas in the series reported by Bernabeu and coworkers,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> in spite of the limitations of its retrospective study design, supports the view of this drug's prospects as I have explained them: its clinical efficacy is more than promising and its safety profile is good, as shown by the adoption of this therapeutic alternative by important centers in Spain and its inclusion in international guidelines.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Various randomized placebo-controlled trials are underway to compare different doses of the drug over different periods, and there are also trials comparing propranolol to oral corticosteroids and other β-blockers such as nadolol. A list of such studies can be consulted at <a href="http://clinicaltrials.gov/">http://clinicaltrials.gov/</a>. At this time I would like to encourage pediatric and other dermatologists who treat infants with hemangiomas to explain this option to families. If the infant's lesion might be treatable with propranolol, the physician can propose enrollment in a worldwide multicenter study in which Spain is participating. The inclusion criteria can be read at <a href="http://clinicaltrials.gov/ct2/show/study/NCT01056341">http://clinicaltrials.gov/ct2/show/study/NCT01056341</a>. Participating hospitals include Hospital de la Santa Creu i Sant Pau in Barcelona and Hospital San Juan de Dios in Barcelona; Hospital La Paz and Hospital del Niño Jesús in Madrid; Hospital Virgen del Rocío in Seville; Hospital Universitario de La Coruña in La Coruña; and Hospital Universitario de Valencia in Valencia.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In conclusion, hemangiomas of infancy constitute a fast-moving field in which treatment options are constantly being reconsidered, as reflected in the changes that have taken place over the past 4 decades. The recent addition of propranolol to the therapeutic arsenal for hemangioma has improved the clinical response we can expect. As we learn more about this drug's mechanisms of action in this clinical setting, we can also expect to extend our understanding of the pathogenesis of these benign endothelial tumors.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of Interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">Dr Baselga is a principal investigator and coordinator of the HEMANGIOL study in Spain.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Hemangiomas of Infancy: The Past" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Hemangiomas of Infancy: The Current Situation" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Hemangiomas of Infancy: The Future" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflict of Interest" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Baselga A, Hemangiomas de la infancia: pasado, presente y future del tratamiento con propranolol. Actas Dermosifiliogr.2011;102:484-86.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prospective Study of Infantile Hemangiomas: Clinical Characteristics Predicting Complications and Treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.N. Haggstrom" 1 => "B.A. Drolet" 2 => "E. Baselga" 3 => "S.L. Chamlin" 4 => "M.C. Garzon" 5 => "K.A. Horii" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1542/peds.2006-0413" "Revista" => array:6 [ "tituloSerie" => "Pediatrics" "fecha" => "2006" "volumen" => "118" "paginaInicial" => "882" "paginaFinal" => "887" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16950977" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tratamiento con propanolol oral para hemangiomas infantiles graves: series de 28 pacientes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J. Bernabeu- Wittel" 1 => "J.J. Pereyra-Rodríguez" 2 => "M.E. Mantrana-Bermejo" 3 => "I. Fernández-Pineda" 4 => "J.C. de Agustin" 5 => "J. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 5 | 11 | 16 |
| 2024 Octubre | 89 | 46 | 135 |
| 2024 Septiembre | 98 | 31 | 129 |
| 2024 Agosto | 130 | 45 | 175 |
| 2024 Julio | 73 | 42 | 115 |
| 2024 Junio | 90 | 37 | 127 |
| 2024 Mayo | 88 | 31 | 119 |
| 2024 Abril | 74 | 29 | 103 |
| 2024 Marzo | 82 | 27 | 109 |
| 2024 Febrero | 61 | 32 | 93 |
| 2024 Enero | 57 | 38 | 95 |
| 2023 Diciembre | 57 | 20 | 77 |
| 2023 Noviembre | 60 | 23 | 83 |
| 2023 Octubre | 67 | 33 | 100 |
| 2023 Septiembre | 50 | 28 | 78 |
| 2023 Agosto | 61 | 15 | 76 |
| 2023 Julio | 65 | 38 | 103 |
| 2023 Junio | 61 | 24 | 85 |
| 2023 Mayo | 50 | 29 | 79 |
| 2023 Abril | 40 | 34 | 74 |
| 2023 Marzo | 49 | 15 | 64 |
| 2023 Febrero | 70 | 29 | 99 |
| 2023 Enero | 40 | 47 | 87 |
| 2022 Diciembre | 73 | 65 | 138 |
| 2022 Noviembre | 32 | 34 | 66 |
| 2022 Octubre | 36 | 20 | 56 |
| 2022 Septiembre | 39 | 47 | 86 |
| 2022 Agosto | 38 | 44 | 82 |
| 2022 Julio | 33 | 46 | 79 |
| 2022 Junio | 42 | 35 | 77 |
| 2022 Mayo | 88 | 41 | 129 |
| 2022 Abril | 42 | 39 | 81 |
| 2022 Marzo | 59 | 59 | 118 |
| 2022 Febrero | 35 | 24 | 59 |
| 2022 Enero | 34 | 42 | 76 |
| 2021 Diciembre | 40 | 51 | 91 |
| 2021 Noviembre | 22 | 43 | 65 |
| 2021 Octubre | 34 | 55 | 89 |
| 2021 Septiembre | 29 | 58 | 87 |
| 2021 Agosto | 27 | 52 | 79 |
| 2021 Julio | 32 | 38 | 70 |
| 2021 Junio | 18 | 40 | 58 |
| 2021 Mayo | 31 | 47 | 78 |
| 2021 Abril | 47 | 58 | 105 |
| 2021 Marzo | 39 | 20 | 59 |
| 2021 Febrero | 38 | 26 | 64 |
| 2021 Enero | 38 | 27 | 65 |
| 2020 Diciembre | 19 | 11 | 30 |
| 2020 Noviembre | 20 | 20 | 40 |
| 2020 Octubre | 34 | 14 | 48 |
| 2020 Septiembre | 19 | 14 | 33 |
| 2020 Agosto | 28 | 18 | 46 |
| 2020 Julio | 19 | 8 | 27 |
| 2020 Junio | 29 | 29 | 58 |
| 2020 Mayo | 14 | 21 | 35 |
| 2020 Abril | 29 | 19 | 48 |
| 2020 Marzo | 28 | 13 | 41 |
| 2020 Febrero | 6 | 7 | 13 |
| 2020 Enero | 0 | 2 | 2 |
| 2019 Diciembre | 4 | 2 | 6 |
| 2019 Noviembre | 0 | 2 | 2 |
| 2019 Octubre | 0 | 3 | 3 |
| 2019 Septiembre | 4 | 9 | 13 |
| 2019 Agosto | 0 | 6 | 6 |
| 2019 Julio | 0 | 6 | 6 |
| 2019 Junio | 2 | 17 | 19 |
| 2019 Mayo | 0 | 46 | 46 |
| 2019 Abril | 2 | 21 | 23 |
| 2019 Marzo | 2 | 11 | 13 |
| 2019 Febrero | 0 | 7 | 7 |
| 2019 Enero | 2 | 2 | 4 |
| 2018 Diciembre | 1 | 0 | 1 |
| 2018 Noviembre | 1 | 0 | 1 |
| 2018 Octubre | 3 | 0 | 3 |
| 2018 Septiembre | 2 | 0 | 2 |
| 2018 Mayo | 0 | 4 | 4 |
| 2018 Marzo | 0 | 1 | 1 |
| 2018 Febrero | 27 | 8 | 35 |
| 2018 Enero | 40 | 6 | 46 |
| 2017 Diciembre | 36 | 5 | 41 |
| 2017 Noviembre | 21 | 8 | 29 |
| 2017 Octubre | 28 | 4 | 32 |
| 2017 Septiembre | 31 | 4 | 35 |
| 2017 Agosto | 35 | 8 | 43 |
| 2017 Julio | 41 | 2 | 43 |
| 2017 Junio | 36 | 15 | 51 |
| 2017 Mayo | 39 | 16 | 55 |
| 2017 Abril | 31 | 24 | 55 |
| 2017 Marzo | 26 | 26 | 52 |
| 2017 Febrero | 28 | 7 | 35 |
| 2017 Enero | 31 | 11 | 42 |
| 2016 Diciembre | 41 | 13 | 54 |
| 2016 Noviembre | 41 | 17 | 58 |
| 2016 Octubre | 39 | 24 | 63 |
| 2016 Septiembre | 38 | 11 | 49 |
| 2016 Agosto | 34 | 6 | 40 |
| 2016 Julio | 34 | 3 | 37 |
| 2016 Junio | 8 | 11 | 19 |
| 2016 Mayo | 11 | 13 | 24 |
| 2016 Abril | 4 | 0 | 4 |
| 2016 Marzo | 5 | 0 | 5 |
| 2016 Febrero | 8 | 1 | 9 |
| 2016 Enero | 8 | 2 | 10 |
| 2015 Diciembre | 6 | 1 | 7 |
| 2015 Noviembre | 5 | 4 | 9 |
| 2015 Octubre | 13 | 5 | 18 |
| 2015 Septiembre | 1 | 1 | 2 |
| 2015 Agosto | 10 | 3 | 13 |
| 2015 Julio | 38 | 12 | 50 |
| 2015 Junio | 33 | 2 | 35 |
| 2015 Mayo | 101 | 10 | 111 |
| 2015 Abril | 41 | 11 | 52 |
| 2015 Marzo | 40 | 9 | 49 |
| 2015 Febrero | 27 | 6 | 33 |
| 2015 Enero | 34 | 10 | 44 |
| 2014 Diciembre | 41 | 10 | 51 |
| 2014 Noviembre | 29 | 11 | 40 |
| 2014 Octubre | 49 | 19 | 68 |
| 2014 Septiembre | 38 | 11 | 49 |
| 2014 Agosto | 29 | 15 | 44 |
| 2014 Julio | 56 | 21 | 77 |
| 2014 Junio | 70 | 10 | 80 |
| 2014 Mayo | 77 | 13 | 90 |
| 2014 Abril | 57 | 14 | 71 |
| 2014 Marzo | 80 | 18 | 98 |
| 2014 Febrero | 54 | 16 | 70 |
| 2014 Enero | 55 | 18 | 73 |
| 2013 Diciembre | 68 | 13 | 81 |
| 2013 Noviembre | 48 | 19 | 67 |
| 2013 Octubre | 52 | 19 | 71 |
| 2013 Septiembre | 40 | 20 | 60 |
| 2013 Agosto | 6 | 11 | 17 |
| 2013 Julio | 7 | 21 | 28 |
| 2013 Junio | 8 | 14 | 22 |
| 2013 Mayo | 7 | 16 | 23 |
| 2013 Abril | 16 | 15 | 31 |
| 2013 Marzo | 31 | 8 | 39 |
| 2013 Febrero | 130 | 5 | 135 |
| 2013 Enero | 38 | 6 | 44 |
| 2012 Diciembre | 14 | 3 | 17 |
| 2012 Noviembre | 0 | 1 | 1 |
| 2012 Septiembre | 1 | 0 | 1 |
| 2012 Agosto | 2 | 0 | 2 |
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