Propranolol as first-line treatment for rapidly proliferating Infantile Haemangiomas

Journal of Plastic, Reconstructive & Aesthetic Surgery (2011) 64, 445e451

Propranolol as first-line treatment for rapidly proliferating Infantile Haemangiomas* W.J.M. Holmes*, A. Mishra, C. Gorst, S.H. Liew Department of Plastic Surgery, Alder Hey Children’s Hospital, Eaton Road, Liverpool, L12 2AP, UK Received 8 June 2010; accepted 16 July 2010

KEYWORDS Haemangioma; Hemangioma; Propranolol; Beta-blocker; Infantile; Haemangioma treatment

Summary Infantile haemangioma is the commonest childhood tumour and approximately 10% requires treatment.1,2 Recent reports have highlighted the impressive efficacy of propranolol in treating rapidly proliferating haemangioma. The aims of our study were to prospectively assess the efficacy of propranolol as a first line treatment for problematic haemangioma, and develop a treatment regime. 31 consecutive patients with rapidly proliferating infantile haemangioma with functional impairment or cosmetic disfigurement were treated with propranolol as a first line treatment. All patients had cardiovascular pre-treatment work-up and commenced on propranolol at 3 mg/kg/day. A rapid halt in haemangioma proliferation was seen in 100% of patients and significant regression in 87% of patients. This treatment is well tolerated and has little side effects. Since this study, our unit has adopted the policy of using propranolol as a first line treatment for all problematic proliferative infantile haemangiomas. ª 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Infantile haemangioma is the most common childhood tumour. Whilst most do not need treatment due to their inherent capability to regress with age, approximately 10% will require medical intervention. Problematic haemangioma can cause obstruction of vital structures such as vision and airways with potentially devastating effect. Haemangioma

* This data has been presented at: 1. BAPRAS December 2009, Royal College of Surgeons, UK. 2. 10th ISSVAe18th International Workshop on Vascular Anomalies Conference April 2010, Belgium. * Correspondence author. Tel.: þ44 7590539096. E-mail address: [email protected] (W.J.M. Holmes).

can also ulcerate, which is extremely painful and very slow to heal. Some haemangioma, if left untreated, can lead to disfigurement that is difficult to correct later in life. The gold standard for the treatment of infantile haemangioma has been the use of corticosteroid. Other treatments include vincristine and laser therapy. Whilst all these treatments are effective, their use has been overshadowed by the effective use of propranolol, which causes rapid halt of proliferation and promote regression of problematic haemangioma with apparent good safety profile.3e5 We conducted a prospective study evaluating the efficacy of propranolol as a first line treatment for 31 consecutive patients referred to a tertiary referral centre with problematic haemangioma. The aims of our study were to assess the efficacy and safety profile of propranolol and to assess an

1748-6815/$ - see front matter ª 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2010.07.009

446 effective treatment regime in terms of treatment dose and duration of treatment.

Methods This was a prospective clinical study. Consecutive patients at a tertiary referral centre for haemangioma who met treatment criteria were enrolled into the study (Table 1). Local ethical approval was obtained prior to commencement of this study.

Pre-treatment work-up Prior to treatment with propranolol, all patient underwent a cardiovascular work-up. This had been developed in conjunction with the paediatric cardiologists and involved baseline clinical observations (pulse, blood pressure, respiratory rate), electrocardiogram and echocardiogram.

Liverpool treatment regime Treatment was initiated at a starting dose of 0.5 mg/kg orally. All patients then underwent post-dose heart rate and blood pressure measurement every 15 min for 2 h. If tolerated a second dose was given at 4 h of 1 mg/kg orally. This was followed by post-dose heart rate and blood pressure monitoring every 15 min for a further 2 h. Blood glucose was measured if clinically indicated based on symptoms of clamminess, distress or irritability. If observations remained stable, the patient was observed for a further two doses and discharged at the target dose of 3 mg/kg/day given in three divided doses. Indications for withholding any further dose: 1. 2. 3. 4.

Symptomatic bradycardia or hypotension Symptomatic hypoglycaemia Symptomatic wheeze Heart rate fall to <70% of acceptable age related minimum post-dose with child awake 5. Systolic blood pressure fall of >25% of baseline postdose with child awake.

Table 1 List of inclusion and exclusion criteria for enrollment in study Inclusion criteria Any rapidly growing lesion defined as doubling in size over one to two weeks Any functional or significant cosmetic deformity Any lesion that is likely to compromise normal physiological functions Any lesion likely to cause significant cosmetic deformity in the future No previous treatment for haemangiomas No cardiac anomalies as per cardiac work-up (see below) Exclusion criteria Any child with a cardiovascular disorder Significant asthma Previous treatment with laser or steroid

W.J.M. Holmes et al.

Follow-up Patients were followed up at 1 week, then 2 weekly throughout the duration of treatment. During each visit patients underwent formal photographic and clinical evaluation. Compliance to treatment and baseline observations were measured to assess tolerance. Body weight was measured with the dose adjusted accordingly. In any patient with eyelid or airway involvement, ophthalmological or ENT specialist input was arranged. Response to treatment was measured by blind assessment of serial photographs. These were taken prior to initiation of treatment, at 24 h, at 48 h and at every follow-up visit. Data was collected for time to halt proliferation of haemangioma, and time to regression. Time to halt progression was defined as the time when a haemangioma stops growing in size. Time to regression was defined as the time to produce a 25% reduction in diameter of the original lesion, or time for ulceration to epithelialize. Any side effects associated with propranolol treatment was recorded. Treatment was stopped after a sustained plateau of the growth of the haemangioma. This was determined by clinical assessment by the senior author. Relapse episodes after stoppage of treatment were defined as rapid increase in size, worsening of the colour, or the re-emergence of ulceration. Propranolol was restarted on a dosage of 3 mg/kg/day for these patients.

Results A total of 31 patients were treated with propranolol. Mean age at the start of treatment was 3.9 months (median 3 months, range 1.2e9.7 months). The mean age was skewed by two patients who were treated at 9 months old when their haemangioma was in static growth phase. 74% of patients treated were female and 26% were male. Location of the haemangioma was as follows: 81% Face (n Z 25), 10% Upper limbs (n Z 3), 6% perineum (n Z 2) and 3% Lower limbs (n Z 1).

Indication for treatment Indication for treatment was as follows: rapid growth 51% (n Z 26), ulceration in 26% (n Z 8) and functional impairment 23% (n Z 7). Of the seven cases of functional impairment, five involve the obstruction of vision, one obstruction of nasal cavity, and one obstruction of the urethra, causing difficulty in micturation. Three patients were treated while their haemangioma were in static growth phase. This is early in the study, to evaluate if propranolol is effective in inducing further regression.

Treatment regime All patients were treated with propranolol at 1 mg/kg/tds (3 mg/kg/day). Mean duration of treatment, including treatment following relapses was 12.5 weeks (median 12 weeks, range 1e58 weeks). Age at cessation of treatment was 6.5 months (median 6 months, range 4e11.7 months). This data was skewed by the three patients who started

Propranolol as first-line treatment treatment at 9 months of age. Five patients were still undergoing propranolol therapy at time of publication. Mean follow-up was 6 months (median 7 months, range 0.7e12 months) e Figure 1. Time to halt lesion proliferation was less than 48 h in 74% (n Z 23) of patients. This was directly observed during their in patient stay, and accompanied by a palpable softening and change in colour from a deep red to a blue/ purple. The remaining 26% (n Z 8) of haemangioma demonstrated halt of proliferation by two weeks (Figure 2). Evidence of regression was seen in 55% (n Z 17) of patients within two weeks, 16% (n Z 5) within 4 weeks and 16% (n Z 5) within 10 weeks. 13% (n Z 4) failed to show signs of regression and remained static in size during the course of therapy. In one case of early regression, spontaneously eye opening was achieved in 5 days (Figure 3). Epithelialization was achieved in seven of the eight cases of ulceration within three weeks of commencement of therapy (Figure 4). The other case of ulceration had only received treatment for one week at time of preparing the manuscript. Of the three patients who were treated at an older age (>9 months) when their haemangioma were in static growth phase, no significant improvement was seen.

Rebound growth Of the 25 patients who had completed the propranolol course, 24% (n Z 6) patients showed evidence of rebound growth after cessation of treatment. Looking specifically at this group: age at commencement of treatment was 3.2 months (median 3 months, range 1.2e5 months), duration of treatment was 8.7 weeks (median 7 weeks, range 4e16 weeks) and age at cessation of treatment was 5.1 months (median 5.6 months, range 4e6.5 months). Evidence of

447 rebound growth developed at 2.3 weeks following cessation of treatment (median 2, weeks range 1e4 weeks) and all responded when propranolol was re-introduced. Propranolol was re-introduced at 3 mg/kg/day for a further 9.3 weeks (median 9 weeks, range 6e54 weeks) with good response. Propranolol re-introduction was stopped at age 7.9 months (median 8, range 6.5e9) with no further episodes of rebound growth. Comparing those patients who developed rebound growth to those who did not, there is no significant difference in age at commencement of treatment (3.2 months þ/1.1 vs. 4.3 months þ/1.4 p Z NS). However those who developed rebound growth had their propranolol stopped when they were significantly younger compared to those who did not develop rebound growth (5.1 months þ/0.9 vs. 7.2 months þ/1.0, p Z 0.047 (2 sample student t-test)).

Side effects Out of all 31 patients, no major side effects were noted. One patient had transient asymptomatic hypotension that occurred during a propranolol loading dose that resolved before the subsequent dose. The same patient went on to complete a full course of propranolol with no further side effects. One patient developed gastro-oesophageal reflux during his propranolol treatment and required concomitant treatment with proton pump inhibitor. It is not sure if this was related to his propranolol treatment. Again, the same patient went on to complete the full course of propranolol with no further side effects. One patient who had rebound growth and had propranolol restarted was reported by his parents as being more restless at night while he was on propranolol. One patient developed bronchiolitis that was

Figure 1 Haemangioma timeline for each patient enrolled in the study with the patient’s age on X (horizontal) axis. Green bars represent timing and duration of propranolol treatment and total no of weeks. Light green bars represent propranolol treatment that remains on-going. The red bars represent relapse/rebound growth episodes with the number of weeks it occurred post cessation of therapy. The black bar represents withdrawal of treatment.

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Figure 2 This patient was referred aged 4 months with a rapidly growing haemangioma that was causing significant breathing problems (A). Propranolol was commenced at 3 mg/kg/day. The Immediate halt in lesion progression can be noted at 24 h (B) and significant regression at 18 weeks (C). Treatment was stopped at 21 weeks and the lesion has continued to resolve (Follow-up 10 months).

unrelated to the propranolol therapy but treatment was discontinued as a precaution.

Discussion Infantile haemangioma is the commonest childhood tumour, affecting 4e10% of Caucasians newborns.6 Haemangiomas have a self-limiting course consisting of a proliferative phase lasting up to approximately nine months followed by an involution phase that is mostly completed by 5e7 years of age.7 Although benign, and known to regress with age, its variable growth pattern can lead to significant functional and cosmetic deficits in 10% of patient.8 Haemangioma can ulcerate, which is extremely painful, and very slow to heal.9 This is particularly common in the anorectal region. Rapidly proliferating haemangioma can also obstruct vital structures

such as vision and airways. Large lesions can also cause significant cosmetic deformity, which is sometimes difficult to correct surgically. Very rarely, systemic sequelae such as hearth failure can occur. The gold standard for the treatment of rapidly proliferating haemangioma has been corticosteroid, which has been used used since the 1960s. Administered either orally or intralesionally at a dose of 2e3 mg/kg/day, the response rate is quoted at 84% with a 36% rebound rate after cessation of therapy.10,11 Unfortunately, adverse effects of steroid treatment are commonly observed, with up to a third of patients developing reversible cushingoid facies, mood disturbances and gastric irritation.12 35% can develop diminished growth and weight gain that can be permanent in 12% of patients.12,13 Adrenal Suppression is apparent in up to 6% of patients treated with corticosteroids despite

Figure 3 this child present at 4 weeks with a large facial haemangioma that was causing visual occlusion. He was commenced on propranolol 3 mg/Kg/day (A). By day three the child could open his eye (B), and by 4 weeks his haemangioma had significantly regressed (C). Patient stopped treatment after 16 week. There has been no adverse affect to vision (follow-up 11 months).

Propranolol as first-line treatment

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Figure 4 This child presented aged three weeks with an ulcerated perineal haemangioma (A). Propranolol 3 mg/Kg/tds was commenced and no side effects were noted. There was an almost immediate halt in lesion progression and near total complete ulcer epithelialisation by two weeks (B). Treatment was continued for 15 weeks and then stopped. There have been no episodes of rebound growth of ulceration following treatment (C). e follow-up 7 months.

adequate weaning.14 Subclinical adrenal suppression is more prevalent and many require replacement therapy.15

Propranolol as a new therapeutic modality Labreze first reported the serendipitous effect of propranolol on a child with a facial haemangioma.5 Since then many more case reports and small cohorts have reported similar results.16e21 A recent review of case reports reporting the role of propranolol in the treatment of haemangioma confirmed a rapid halt in lesion progression and evidence of regression in the majority of cases.4 In this study, we have shown propranolol to halt haemangioma proliferation in 74% of patients within 48 h and 97% of patients within 2 weeks. This was associated with marked change in colour of the haemangioma within the first 24 h from an intense red to dark blue/purple. This was irrespective of size or location of the haemangioma. This is in keeping with the observed changes seen in the published case reports so far 4 and is more efficacious than the traditional use of corticosteroid. Besides halting the proliferation of haemangioma, propranolol also seems to have the ability to cause early regression of haemangioma, thus altering its natural clinical course, in agreement with published datas (Mousa, Kues et al. 2010, Buckmiller 2009; Michel and Patural 2009; Sans, De La Roque et al. 2009). 55% of haemangioma in this study demonstrated clinical evidence of regression within 2 weeks of treatment and 71% by four weeks. 13% of lesion showed no evidence of regression during the treatment course, but remain static.

Ideal treatment regime There is as yet no generally accepted consensus on the ideal treatment regime with propranolol. The main

differences between different published reports were the dosage of propranolol used, and the duration of treatment. Whilst our study has used the highest dose of propranolol reported (3 m/Kg/day), many case reposts have shown successful results doses ranging from 1e2 mg/Kg/day and with differing mode of administration.4, 22e24 In the largest study to date, Qin et al report the use of 1e1.5 mg/kg/day in 58 infants and found a response rate ‘good to excellent’ in 67% of patients.25 This response rate was lower than in our study. Healing of haemangioma related ulcers has been reported to range from 8 to 18 weeks with propranolol treatment at 1 mge2 mg/kg/day.17,20,21 Again, this response rate was lower than the complete healing at three weeks in our study. We speculate that our better clinical results could be dose related. Recent in vitro studies had suggested that propranolol efficacy is dose-dependent in reducing proliferation of tumour stem cells 26 and placental endothelial cells.27 Further studies are needed in determining the optimum treatment dosage of propranolol. This study has given us some insight to the ideal treatment duration with propranolol. All patients with rebound growth in this study (n Z 6, 24%) were significantly younger at the time of cessation of treatment compared with those who did not develop rebound growth (5.1 months vs. 7.2 months p Z 0.047). We know that for most haemangioma, by 7 months of age, the proliferative phase is coming to an end and the balance between pro-angiogenic and pro-apoptopic factors is shifting.28 We therefore conclude that in order to avoid rebound growth, optimum treatment should cover the majority if not all the proliferative phase, i.e. till the child is at least 7e8 months old. In fact, most of the rebound patients were treated early in the study. In subsequent cases, the decision to stop propranolol was based on observed plateau of regression for 4 weeks or when the child was older (7.2 months þ/1.0). Using these principles we observed no further rebound growth (mean follow-up 6 months).

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Is propranolol the best beta-blocker to use? Propranolol has been the most widely reported beta-blocker agent used so far in the treatment of haemangioma. Other beta-blockers, such as acetabutolol, that has a differing beta-adrenoceptor affinity, have been shown to be efficacious in the treatment of haemangioma when used in conjunction with corticosteroids.29 Propranolol has a very good safety profile, and has been used extensively in the paediatric population for a wide range of medical conditions in doses as high as 7 mg/kg/ day.30 The known side effects of propranolol include bronchospasm, hypoglycaemia, mood disturbances, bradycardia and hypotension.31 In this study, there was no major side effects associated with the use of propranolol. In fact, propranolol toxicity in children is very rare, and is usually associated with the accidental ingestion of adult pharmacological doses. Nevertheless, even with ingestion of up to 1.2 g of propranolol, side effects are minimal.32 A 40-year review of propranolol toxicity in children found no fatalities and side effects that either resolved once propranolol was stopped, or resolved spontaneously.33 However, It is important to perform a full cardiovascular work-up prior to initiation of propranolol therapy, to identify patient in whom the commencement of propranolol could be dangerous.19,34 We have proposed a treatment regime that is easy to follow, both in the hospital and in the community.

Mechanism of action of propranolol The mechanism of action of propranolol remains largely speculative. It may cause haemangioma resolution via vasoconstriction, inhibition of angiogenesis, apoptosis or a combination of all these mechanisms.35 Propranolol is a beta-adrenoceptor antagonist. Beta-adrenoceptors are part of the G-protein coupled receptor super family and exert their effects through activation of adenylyl cyclace. Beta-blockers such as propranolol block this signalling and cause their pharmacological effects. We’ve shown that propranolol produces a rapid halt in haemangioma proliferation and concomitant change in colour within the first 48 h of treatment. It is likely that these rapid changes are due to the vasoconstrictive properties of propranolol on vascular endothelium.36 Haemangioma regression takes longer to achieve and we hypothesize that this may be due to altered angiogenesis induced by propranolol. Stromal cells, mast cells and dendritic cells, present in all haemangioma, produce a soup of growth factors such as vascular endothelial growth factor (VEGF), cytokines, fibroblast growth factor (FGF2) that are key to the aggressive angiogenesis seen during the proliferative phase.37,38 Stimulation of ß-adrenoceptors has been shown to stimulate VEGF formation in the murine placenta39 and in brown adipocytes.40 It is therefore likely that propranolol exerts its effect via altered VEGF expression. Whether propranolol induces a direct down-regulation of VEGF or whether it initiates altered gene splicing between pro- and anti-angiogenic isofroms of VEGF remains an exciting area for further research.41,42

W.J.M. Holmes et al. This study shows that propranolol is an extremely effective first line treatment for proliferative haemangioma when commenced early and continued throughout its proliferative phase. Propranolol at a dose of 3 mg/kg/day in three divided doses produces a rapid halt in haemangioma proliferation in 97% of cases and significant regression in 87%. This treatment is well tolerated and has little side effects. Since this study, our unit has adopted the policy of using propranolol as a first line treatment for all problematic proliferative infantile haemangiomas. Further comparative studies are needed in determining the most effective treatment dosage, and optimum treatment duration. It is also important to determine the exact mechanism of action of propranolol in future scientific studies, in order to exploit its potential further.

Conflict of interest None.

Funding None.

Acknowledgement Many thanks to Dr R Johnson, consultant paediatric cardiologist, for developing the treatment regime and his invaluable advice.

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