Abstract: Hemangiomas are benign tumors formed by the proliferation of blood vessels and are the most common tumors of childhood. Their evolution is well known. They are tiny or inapparent at birth and increase rapidly in the first months of life (proliferative phase). After a variable time, the lesions stabilize and spontaneous regression occurs, which is complete between 3 and 9 years of life. Large lesions can last through adolescence and leave important scars. About 24% of cases of childhood hemangiomas present complications, and some form of treatment is indicated. The first choice is a systemic corticosteroid, effective in up to 90% of cases, but requiring prolonged treatment at high doses (more than 3 months) and leading to partial response in most patients, with frequent adverse effects. Interferon alpha and vincristine showed effect, albeit slow, in limited series, and can have potential serious side effects. Recently, treatment with propranolol, in usual doses, has shown excellent short- and medium-term response. As it is a drug with a good safety profile, the authors propose that it be the first choice for the treatment of problematic childhood hemangiomas.
Francisco H. C. Felix1
1Pediatric hemato-oncologist, Hospital Infantil Albert Sabin Pediatric Onco-hematology Service, Hospital Infantil Albert Sabin (SOHPHIAS)
Hemangiomas are tumors formed by the proliferation of blood vessels and are the most common tumors of childhood, affecting about 3-10% of caucasian children. They are more frequent in females (1: 1.4-3.0) in white and non-latino individuals. Its causes are unknown, except for rare genetic syndromes in which its frequency is higher. However, preterm infants (<37 gestational weeks), especially extreme premature infants (<32 weeks) and small gestational age infants (SGA) are at a higher risk of developing hemangiomas. Also maternal age over 30 years and a positive family history, as well as placenta previa and preeclampsia, are associated with increased risk. (Haggstrom, 2007). Histologically, hemangiomas form a heterogeneous group (Table 1) (Marler & Mulliken, 2005), although the most common type is known simply as infantile or capillary hemangioma. In relation to its morphology and presentation, the most commonly used classification in Brazil is Curado (table 2) (Curado, 1992).
The evolution of the infantile hemangioma is typical and well known. The lesions are usually minute or inapparent at birth and may increase rapidly in the first months of life (proliferative phase). After a variable time (more commonly until the 3rd month, sometimes until the end of the first year of life), the lesions stabilize. After 1 to 3 years without change, slow spontaneous regression occurs, which is complete between 3 and 9 years of life. Large lesions can last through adolescence and leave important scars. Most cases do not present complications and show spontaneous regression. In 20-40% of the cases residual cicatricial lesions remain. Small hemangiomas (<5 cm in diameter) usually regress completely through age 5 (Adams, 2008).
About 24% of cases of childhood hemangiomas present complications. The most common are ulceration (16%), visual occlusion (5.6%), respiratory obstruction (1.4%), auditory canal obstruction (0.6%), and cardiac involvement (0.4%) (Haggstrom, 2007). Bleeding is uncommon. In general, any complication indicates the need for treatment. In a recently published series, 38% needed treatment. In this series, the majority of the lesions were located on the face (41%) and the most important factor for indication of treatment was the lesion size. Segmental lesions (involving a whole body segment) were much more frequently treated and presented more complications than localized lesions. Despite the treatment, in this series the main delayed complication was the occurrence of disfiguring scars (Haggstrom, 2006).
The most appropriate approach for most lesions is watchful waiting, since they are mostly self-limiting and do not determine important sequels or complications. Problematic lesions of large size, rapid growth or risk of sequelae or life threatening should be addressed (Muler & Mulliken, 2005). Pharmacological treatment has few options. The main choices, although widely used, are still based on limited evidence. The first choice is systemic corticosteroids, most often oral prednisone, at high doses (3 to 5 mg/kg/day of prednisone). This was practically the only treatment for which there was some evidence, albeit limited, until 2008. An observational study determined 93% response in children treated for up to 12 weeks at that dose (Sadan, 1996). The only clinical trial compared oral versus intravenous corticosteroids with a small number of patients and subjective assessment of response and no untreated control (Pope, 2007). This trial showed that 65% of the children needed treatment for more than three months. Eventhough these drugs are known to act quickly and have some efficacy in about 90% of cases, a significant amount of the lesions respond only partially. In addition, treatment needs to be prolonged for six months or more, and a significant amount of side effects occur (Pope, 2007). Significant side effects occur in the short to medium term in most patients treated with this dose (Boon, 1999). No studies have evaluated the possible long-term side effects of prolonged exposure to high doses of corticosteroids. However, studies with children treated for leukemia show that there is a significant increase in the incidence of obesity, hypertension and diabetes, even decades after exposure to corticosteroids.
Used in about 12% of patients, topical or intralesional corticosteroids, or other types of intralesional treatment have no evidence of efficacy. Surgical resection is only performed in a minority of patients (around 5%) and, since most of the lesions undergo spontaneous regression, it is usually contraindicated. In cases of ulceration, local infection is common and most patients will require local care with topical antibiotics and dressings, although some patients may require systemic antibiotics and hospital admission. Flat hemangiomas are not treated with drugs or surgery, but can be properly conducted with pulsed dye laser, with good aesthetic results. Limited series of patients with large refractory lesions were treated with interferon alpha 2a (Ezekowitz, 1994) or vincristine (Perez, 2002). Although these drugs have shown an effect in the described cases, this effect is slow and partial. In addition, the use of interferon has recently been associated with severe neurological complications (Barlow, 1998).
In 2008, a communication published in the New England Journal of Medicine reported for the first time the use of propranolol to treat childhood hemangiomas (Léauté-Labrèze, 2008). The first patient was a 4-month-old child with a nasal capillary hemangioma who received high-dose corticosteroids with stabilization of the lesion, but developed hypertrophic cardiomyopathy, possibly due to corticoids. Propranolol at the usual pediatric dose was initiated and an immediate change occurred in the first 24 hours, with change in coloration and “softening” of the lesion. Ten months later, the lesion was completely flat, regressed. Another 10 patients were treated by the group between 2006 and 2007, with similar results. After this first publication, other reports of cases successfully treated with propranolol were described, and the initial article was already cited about 140 times (a survey conducted in Google Scholar in January 2011).
The subsequent report (Sans, 2009) of the same group that made the discovery showed that propranolol treatment was effective in 100% of the patients they treated, with a rapid, immediate-onset effect that is radiologically evident as early as two months after its inception. They also demonstrated the rapid reversal of complications such as ocular obstruction and ulceration. Due to some cases of recurrence after early termination of treatment, the authors propose that it be done throughout the proliferative phase of the development of hemangiomas, until at least 1 year of age. Another group made similar observations, reporting 87% efficacy in the regression of infantile hemangiomas treated in the proliferative phase (Holmes, 2011). They observed a possible dose-dependent effect and proposed propranolol as the first choice to treat complicated childhood hemangiomas. A large number of case reports followed the first observational study of 2008, showing effect of propranolol in isolated cases of childhood hemangioma in several topographies. The treatment of pediatric patients with problematic hemangiomas began more than seven years ago when the first patients with an indication of second-choice treatment were referred to receive interferon alpha in the Albert Sabin Infant Oncology Service (SOHP-HIAS). Since January 2009, we have treated patients with hemangiomas with oral propranolol. A research project coordinated by this author was approved by the Institutional Review Board of HIAS in 2009, and is in progress, in data collection phase. It should be added that the use of propranolol for the treatment of infantile hemangiomas is not approved by ANVISA (brazillian regulatory agency) and therefore constitutes an off-label use of this substance. Here at SOHP-HIAS, we report to the Pharmacy and Therapeutics Commission for the non-standard use of propranolol in pediatric patients with hemangiomas. Parents or guardians of children receive detailed explanation of the treatment and it is initiated after informed consent.
At present, we indicate treatment with propranolol concomitant with conventional treatment or in children with contraindication to the conventional treatment for infantile hemangiomas. We also treat patients with large residual lesions after conventional therapy or refractory to this therapy. However, we use a reduced dose of corticosteroid (1-2 mg/kg/day) for a short time (1-2 months) in patients who achieve good results in the initial phase of treatment. The dose of propranolol we use is 0.5 to 2.0 mg/kg/day, divided in 1-3 times daily in a stepup fashion. The dose starts at 0.5-1.0 mg/kg/day and we further increase it 50% per week, the target dose reaching 2.0 mg/kg/day in 2-3 weeks. In patients with a slow response or primary refractoriness to propranolol at this dose, we increased the dose (if tolerated) to a maximum of 4.0 mg/kg/day. Treatment with propranolol is maintained up to one year of age or for at least one year in order to avoid relapse.
Our results are still under evaluation, but apparently we can reproduce the good results already published (Sans, 2009; Holmes, in press). Most patients respond well to treatment, with rapid reduction in hemangioma volume. The first effects (change in color and texture) are noticed in days, while a noticeable reduction can already be identified in 1-2 months. Although this has yet to be proven by adequate studies, our preliminary results indicate that patients can be divided into two groups regarding the speed and intensity of response: a group that responds rapidly and completely, with complete remission within a few months (rapid responders), and a group with a much slower and incomplete response, and may take up to six months to have an objective partial response (slow responders). Some of our patients in the first group responded immediately with low doses and completed treatment with 1.0 mg/kg/day of propranolol, with complete remission. However, in the second group, some patients only responded when the dose was increased to 4.0 mg/kg/day, or when low dose corticosteroid was associated. Possibly, addition of corticoid and/or dose increase may represent ways of reversing partial primary resistance to treatment. In our series, we did not observe cases of secondary resistance. All cases of recurrence after early termination of treatment by the family were adequately treated with re-initiation of propranolol.
The incidence of side effects has been low and virtually no patient with hemangioma had to discontinue treatment because of adverse reactions. We contraindicated propranolol therapy for children with heart failure or a history of severe asthma. We received a child whose treatment with propranolol was initiated by another colleague at another health facility who had a severe adverse event episode (severe bronchospasm requiring tracheostomy). For this patient, the dose was started without progressive increase at the maximum level we use. We reiterate the need for close monitoring of the patient in the initial phase of treatment. The American choose to increase the dose gradually with the hospitalized patient and then discharge to continue ambulatory (Siegfried, 2008). The French start at the maximum dose, without progressive increase, keeping the patient monitored for a few hours (Sans, 2009). In our experience, progressive outpatient setup dosing was safe and effective, avoiding serious adverse events. Another concern in the literature has been the possible occurrence of hypoglycemia, although only anecdotal reports associate the use of propranolol with this event. We performed a routine blood glucose test, as well as cardiac evaluation (physical examination and chest X-ray) and abdominal ultrasonography (to detect visceral lesions), as well as transfontanelar ultrasonography in young infants. We did not identify any cases of hypoglycaemia, hypotension or bradycardia that necessitated discontinuation of treatment. Some patients, however, did not tolerate a dose greater than 1-2 mg/kg/day.
The optimal treatment of complicated childhood hemangiomas should be rapid, effective and safe, and perhaps the advent of beta-blockers is the answer to this need. Clinical trials are under way worldwide to clarify their efficacy and safety. At first glance, the existing alternatives do not have characteristics that can rival this new treatment, due to the lack of quality evidence and the high profile of adverse effects (for example, high-dose corticosteroids). It should be noted, however, that propranolol showed efficacy in typical infantile hemangiomas in the proliferative phase. There is no evidence yet of effect on hemangiomas of children outside this age group (although our preliminary results corroborate good response to residual lesions as well). To date, there are no reports of use of this drug in other types of hemangiomas (cavernomas, hemangioendotheliomas), nor in lymphangiomas or mixed complex lesions. Isolated cases that we are following indicate that the latter lesions are refractory to propranolol. We are planning a clinical trial to evaluate the response of patients with typical childhood hemangiomas treated with beta-blockers.
In conclusion, infantile hemangiomas are common and most of the lesions involute with time, not justifying treatment. Despite maternal anxiety, expectant behavior should be advocated in most cases. Topical or intralesional treatments are seemingly ineffective, as well as countless non-scientific treatments (such as topical silver nitrate, prescribed to a patient!). The fact that it is a self-limiting disease in most cases leads to the false impression of efficacy for many potentially harmful treatments that should be avoided. Complicated cases should be treated, the first choice is still oral corticosteroid at high dose, the second choice is vincristine for refractory cases. The recent introduction of propranolol promises to modify the landscape of the treatment of these lesions, being fast, effective and safe. The treatment should ideally be through referral to specialized services. In the future, however, treatment with beta-blockers may become a therapy used in primary care for such lesions.
References:
Adams DM, Wentzel MS. The Role of the Hematologist/Oncologist in the Care of Patients with Vascular Anomalies. Pediatr Clin N Am 2008;55:339-355.
Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a complication of interferon alfa-2a treatment of hemangiomas of infancy. J Pediatr 1998;132:527–30.
Boon LM, MacDonald DM, Muliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg 1999;104:1616–23.
Curado JH. Tratamento dos hemangiomas e linfangiomas. In: Mélega JM, Zanini AS, Psillakis JM, editores. Cirurgia Plástica: reparadora e estética. 2a. ed., São Paulo: MEDSI; 1992. p. 177.
Ezekowitz RAB, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 1992;326:1456– 63 [errata: N Engl J Med 1994;330:300, N Engl J Med 1995;333: 595–6].
Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Newell B, Nopper AJ, Frieden IJ. Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr. 2007;150(3):291-294.
Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Newell B, Nopper AJ, Frieden IJ. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics. 2006;118(3):882-887.
Holmes WJ, Mishra A, Gorst C, Liew SH. Propranolol as first-line treatment for rapidly proliferating Infantile Haemangiomas. J Plast Reconstr Aesthet Surg. 2011 Apr;64(4):445-451
Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649-2651.
Marler JJ, Mulliken JB. Current management of hemangiomas and vascular malformations. Clin Plastic Surg 2005;32:99-116.
Perez J, Pardo J, Gomez C. Vincristine—an effective treatment of corticoid-resistant life-threatening infantile hemangiomas. Acta Oncol 2002;41:197-199.
Pope E, Krafchik BR, Macarthur C, Ho N, Baruchel S. Oral Versus High-Dose Pulse Corticosteroids for Problematic Infantile Hemangiomas: A Randomized, Controlled Trial. Pediatrics 2007;119:e1239-e1247.
Sadan N, Wolach B. Treatment of hemangiomas with high doses of prednisone. J Pediatr 1996;128:947-948.
Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, Mazereeuw-Hautier J, Lipsker D, Dupuis E, Ezzedine K, Vergnes P, Taïeb A, Léauté-Labrèze C. Propranolol for severe infatile hemangiomas: follow-up report. Pediatrics. 2009;124:e423-e431
Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med 2008;359:2846, author reply 2846–2847
Originally published in Rev. Saúde Criança Adolesc., 3 (2): 39-45, jul./dez., 2011 [Portuguese], http://bit.ly/alt-pub2zH
Comments
comments powered by Disqus