Published online May 7, 2007
PEDIATRICS Vol. 119 No. 6 June 2007, pp. e1239-e1247 (doi:10.1542/peds.2006-2962)
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ARTICLE

Oral Versus High-Dose Pulse Corticosteroids for Problematic Infantile Hemangiomas: A Randomized, Controlled Trial

Elena Pope, MD, MSca, Bernice R. Krafchik, MB, ChBa, Colin Macarthur, MD, PhDb, Diana Stempak, PhDc, Derek Stephens, MScd, Miriam Weinstein, MDa, Nhung Ho, MDa and Sylvain Baruchel, MDc

a Section of Dermatology
c New Agents and Innovative Therapy Program
d Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
b Bloorview Research Institute, Bloorview Sick Kids Rehabilitation, Toronto, Ontario, Canada


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Oral systemic corticosteroids are the mainstay of treatment for problematic hemangiomas; however, current information is based on anecdotal experience and retrospective studies. We aimed to determine whether systemic steroids are efficacious in proliferating hemangioma and to compare the efficacy and safety of 2 corticosteroid treatment modalities.

PATIENTS AND METHODS. Twenty patients with problematic hemangiomas of infancy were randomly assigned to either daily oral prednisolone or monthly intravenous pulses of methylprednisolone. Their clinical outcomes (improvement using a visual analog score) and adverse events were compared at 3 months from baseline and 1 year of age. Data on possible surrogate markers of angiogenesis were available for the first 3 months.

RESULTS. At 3 months, orally treated patients had a median visual analog score of 70 compared with 12 in the intravenous group. This response pattern was similar at the patients' first birthday: 50.0 vs –1.5. Additional treatment beyond 3 months was needed for 65% of the patients (7 in the intravenous and 6 in the oral group). Six of 8 patients with impaired vision at enrollment had an improved function at 1 year (4 patients in the intravenous group and 3 patients in the oral group). Of the 4 surrogate markers of angiogenesis measured (plasma basic fibroblast growth factor, vascular endothelial growth factor, vascular cellular adhesion molecule 1, endoglin, and urine basic fibroblast growth factor), the only 2 that decreased over time were vascular cellular adhesion molecule 1 and endoglin. Patients in the oral group had a higher rate of adverse effects, such as hypertension (18.6% vs 13.1%), abnormal cortisol (78% vs 60%), and growth retardation.

CONCLUSIONS. Systemic corticosteroids are efficacious in stopping the proliferation of hemangiomas. The oral corticosteroids offered more clinical and biological benefit than the pulse steroids with higher risk of adverse effects.

Key Words: infantile hemangioma • corticosteroids • angiogenesis markers

Abbreviations: VEGF—vascular endothelial growth factor • VCAM-1—vascular cellular adhesion molecule 1 • bFGF—basic fibroblast growth factor • IH—infantile hemangioma • PI—principal investigator • VAS—visual analog scale • CBC—complete blood cell • BP—blood pressure • IQR—interquartile range

Hemangiomas are the most common benign tumors of infancy, occurring in ~10% of children by 1 year of age.1–3 These lesions are seen more frequently in females, premature infants, and twins.4–6 Endothelial proliferation is the hallmark of this condition. Proangiogenic factors, such as vascular endothelial growth factor (VEGF) and cellular adhesion molecules (intercellular adhesion molecule 3, E-selectin, and VCAM-1), are increased in the proliferative phase of hemangiomas, whereas basic fibroblast growth factor (bFGF) is higher in the resolution phases.7–10 It is unknown, however, how and when these angiogenesis factors are turned off. It is also unclear whether predictions of clinical behavior and/or therapeutic decisions could be made on the basis of the circulating levels of the angiogenesis factors.

Although most hemangiomas resolve spontaneously, 10% to 20%2 require treatment because of interference with function and/or significant disfigurement. Current guidelines2 recommend treatment for (1) life- and function-threatening hemangiomas (vision impairment, airway obstruction, congestive heart failure, and hepatic involvement), (2) large, disfiguring facial hemangiomas, (3) hemangiomas in locations that may lead to permanent scarring or deformity (eg, nose, ear, etc), and (4) ulcerated hemangiomas. Systemic corticosteroids administered orally are, at present, the mainstay of treatment for problematic hemangiomas. The mechanism of action of steroids is unclear but seems to be related to inhibition of angiogenesis.9 Information regarding dose, length of therapy, and weaning schedule for steroids is based on anecdotal experience and retrospective studies.2,11–16 Most children are treated with doses of 2 to 4 mg/kg per day for 4 to 12 weeks, followed by slow weaning over several months. This regimen is associated with a 30% to 84% response rate12,14,15,17 but leads to with various degrees of adverse events.18 Pulse steroids, supraphysiological doses of glucocorticoids, are usually used in conditions where rapid effects are desired and are associated with manageable, transient, short-term complications.19 Pulse steroids, alone or in combination with other modalities, have been used in diffuse hemangiomatosis20 and in other vascular tumors, such as hemangioendotheliomas.21,22

The objective of this study was to determine whether high-dose intravenous pulse corticosteroids are more efficacious in reducing the size of hemangiomas and safer than oral corticosteroids. A secondary objective was to measure changes in the putative surrogate markers of angiogenesis over time.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population and Study Design
The study was conducted between July 2002 and July 2005 at the Hospital for Sick Children (SickKids), an academic pediatric tertiary referral center. The study received ethical approval from the institution's research ethics board and has been registered at www.clinicaltrials.gov (NCT 00312520).

Eligible infants were between 1 and 4 months of age and had "problematic" facial infantile hemangiomas (IHs), defined as periorbital/orbital tumors with visual impairment and/or large size/disfiguring hemangiomas. Infants >4 months of age, those with concomitant congenital heart disease, and those with nonfacial IHs were excluded.

The families and the principal investigator (PI) who followed the patients were not blinded to the intervention. However, the assessors who measured the primary outcome were blinded to the patient's intervention allocation.

Intervention
The study had 2 treatment groups. In the oral group, infants received oral prednisolone, 2 mg/kg per day, in 2 divided doses for 3 months. This dose was followed by a tapering schedule (decreasing the dose by 1 mg per month) over 6 to 9 months to prevent rebound. The IV group received pulses of intravenous high-dose corticosteroids monthly for 3 months. A pulse consisted of methylprednisolone in doses of 30 mg/kg per day infused over 1 hour daily for 3 days. The study design allowed for infants to receive additional treatment beyond the 3 months if there was evidence of rebound or ongoing proliferation. For the oral group it meant retreatment with a second course of oral corticosteroids, whereas for the IV group it involved either monthly pulse steroids if, in the opinion of the PI, the infant had response but needed additional treatment or oral corticosteroids if there was no response with the IV pulse steroids (treatment failure).

The study design allowed for these patients to have oral steroids added to their regimen if there was significant rebound or worsening of the lesion between pulses (such patients were considered treatment failures for the final analysis). Patients were offered continuation of the pulses if they responded but required additional treatment beyond the 3 months. Patients in the oral group were prescribed concomitant oral ranitidine to minimize steroid-related gastrointestinal adverse effects.

Subjects were allocated randomly to each group by the research pharmacist who prepared blocks of 4. The PI monitored all of the subjects every 2 weeks for the first month then monthly for 6 months and every 2 months thereafter. The study had 2 major end time points: 3 months from the enrollment (time point 1) and at the subjects' first birthday (time point 2).

Outcomes
The primary outcome was change in the size of the hemangioma. Serial photographs (front and side view) were taken using a standardized approach (background, distance, and angle from the patient). Assessors (blinded to patient allocation) and parents were asked to compare photographs and rate change in the hemangioma at 3 months versus baseline and at 1 year versus baseline, using a 100-mm visual analog scale (VAS)23,24 with a range of –100 to +100, where "0" represented no change, "+" represented a decrease in size and "–" represented an increase in the size of the hemangioma.

Secondary outcomes included (1) change in the visual function at 1 year in infants with periorbital hemangiomas, (2) adverse events captured using parent diaries (behavior changes, irritability, crying, hyperactivity, apathy, insomnia, vomiting, and abdominal pains), medical charts (blood pressure, heart rate, and respiratory rate), and investigations (complete blood cell [CBC] count, blood sugar, renal function tests, electrolytes, and morning cortisol), and (3) changes over time in angiogenesis markers. All of the blood pressure (BP) readings were done manually with size-appropriate cuffs. If an abnormal reading was obtained, second and third readings, 15 minutes apart, were performed. The lowest value of the 3 readings was recorded. Hypertension was defined as persistent BP readings >95th percentile for the patient's age.

The angiogenesis markers tested were plasma bFGF, VEGF, VCAM-1, endoglin, and urine bFGF at baseline and 1, 2, and 3 months. All of the blood and urine samples were placed on ice and centrifuged at 2000 rpm for 10 minutes at 4°C within 15 minutes. The plasma and sediment-free urine was aliquoted and frozen at –80°C until analyses using the following commercially available enzyme-linked immunosorbent assay kits, Quantikine human VEGF, bFGF, VCAM-1, and endoglin immunoassay kits (R&D Systems, Inc, Minneapolis, MN), according to the manufacturer's directions. Plasma results were expressed in picograms per milliliter for VEGF and bFGF and in nanograms per milliliter for VCAM-1 and endoglin. Urine bFGF results were expressed as picograms per gram of creatinine.

Statistical Analysis
A total of 20 patients (10 in each group) provided a power of 80% (2-tailed {alpha} level of .05) to detect a difference between the 2 groups of ≥20% in their VAS scores. Descriptive statistics included means, medians, and proportions. The intraclass correlation coefficient was used to assess the reliability of assessments. For the primary outcome (VAS), the nonparametric Mann-Whitney U test was used to test the differences between groups. For the secondary outcomes, continuous variables were tested using the Mann-Whitney U test, whereas differences between groups on categorical variables were tested using Fisher's exact test. Repeated-measures analyses were used to test differences between the 2 groups on the surrogate angiogenesis markers. A 2-sided P of .05 indicated statistical significance. Statistical analyses were conducted using SAS 9.1 (SAS Institute Inc, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Characteristics of the Study Population
Twenty patients, 10 in each study group, met the inclusion and exclusion criteria. The mean age at enrollment was 12 (±4) weeks, with female predominance (85%). Hemangiomas were present at birth in 45% of patients. All of the patients had mixed, superficial and deep facial hemangiomas, with an equal segmental distribution (Table 1). 25 There were 2 patients with prematurity, 1 of them having a birth weight of <1500 g. Four patients had a family history of hemangiomas. Two patients, 1 in each group, presented with ulcerations. The 2 groups were not statistically different in their baseline characteristics (Table 1); however, the IV group had more subjects with periorbital involvement at enrollment (5 vs 3). Imaging to assess the depth of the lesions and associated abnormalities was performed in 7 patients (3 patients had MRIs, 1 patient had computed tomography, and 1 patient had ultrasonography). One patient had evidence of prominent extra-axial cerebrospinal fluid spaces related to prematurity. All of the patients completed the study.


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  		TABLE 1 General Characteristics by Randomized Treatment Group

 
Efficacy
Clinical Improvement Using VAS
At both time points, the infants in the oral group had greater improvement in the size of the hemangiomas compared with the IV group. For example, at time point 1 (3 months compared with baseline) the median VAS score was 70 (interquartile range [IQR]: 54 to 80) in the oral group compared with a median VAS of 12 (IQR: –18 to 39) in the IV group (P = .002). At time point 2 (1 year of life compared with baseline), the median VAS was 50 (IQR: 35 to 67) in the oral group versus a median of –1.5 (IQR: –35 to 22) in the IV group (P = .005). There was good agreement between the 2 blinded assessors (intraclass correlation coefficient: 0.6; 95% confidence interval: 0.21–0.81). Similarly, there was good correlation between assessors' and parents' VAS scores (0.92). At 3 months, patients with periorbital hemangiomas had less improvement compared with other areas of facial involvement, with a median VAS of 11 (IQR: –19 to 55) versus a median of 61 (IQR: 23 to 78; P = .049). Similar findings were noted at 12 months, with a median VAS of 4 (IQR: –24 to 36) versus a VAS of 48 (IQR: 9 to 72; P = .049).

Functional Improvement
Forty percent (8 of 20) of the patients had evidence of eye involvement at enrollment as determined by a pediatric ophthalmologist (3 in the oral group and 5 in the IV group). This consisted of amblyopia in 6 (75%) of 8 patients, astigmatism in 3 (38%) of 8, and increased intraocular pressure in 5 (63%) of 8. Two patients had no change in their eye findings at 1 year, 1 in each treatment group. The other patients (6 of 8) had improvement in their eye findings (4 patients in the IV group and 2 patients in the oral group), suggesting that despite the lack of significant changes in the appearance of the lesions (as assessed by VAS), treatment was efficacious.

Need for Additional Treatment
Thirteen patients required additional treatment (65%). Seven patients (54%) belonged to the IV group, and 6 patients (46%) were in the oral group. In the oral group, the additional treatment consisted of a second course of 2 mg/kg per day of corticosteroids for 4 to 6 weeks during the weaning phase and was because of regrowth of the lesion. For the IV group, 6 patients required an average of 2.6 additional pulses (range: 1–6) until 1 year of age. In addition, 2 patients received intralesional steroids after their last pulse. One patient in the IV group required surgery because of the inability of the corticosteroids to significantly decrease the size of the lesion.

Surrogate Markers of Angiogenesis
Four angiogenesis markers, plasma bFGF, VEGF, VCAM-1, and endoglin, as well as urine bFGF, were measured at baseline and every month for the first 3 months of the study in a subgroup of 13 patients (7 in the oral group and 6 in the IV group). The angiogenesis markers that decreased significantly over time were VCAM-1 (P < .001) and endoglin (P = .03), whereas the others did not change over the study period (Fig 1). Moreover, a statistical difference between the oral group and IV group values for VCAM-1 and endoglin was found in 2 of 3 follow-up visits, mirroring the clinical regression of the hemangiomas (Fig 2).


Figure 1
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  		FIGURE 1 Entire study-population plots of angiogenic markers over time.

 

Figure 2
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  		FIGURE 2 Confidence interval (CI) plot analysis over time of VCAM-1 and endoglin according to randomization group.

 
Safety
Parental Reports
There was no difference between the 2 groups with respect to irritability, excessive crying, apathy, insomnia, vomiting, abdominal pain, or behavioral changes (Table 2). One patient in the oral group had persistent vomiting over several weeks, which required changing the formulation of prednisolone to dose-equivalent dexamethasone.


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  		TABLE 2 Parental Reports of Adverse Events

 
Physician-Documented Adverse Events
There were no adverse events noted during pulse steroid infusions. In the oral group, 72% of BP measurements were ≤90th percentile (31 of 43), 9.4% were 75th to 95th percentile (4 of 43), and 18.6% were ≥95th percentile (8 of 43). In the IV group, 76% of BP measurements were ≤90th percentile (35 of 46), 10.9% were 90th to 95th percentile, and 13.1% were ≥95th percentile. The patients with measurements ≥95th percentile were asked to have their BP monitored by their regular doctor on a weekly basis. Only 1 patient (in the oral group) required antihypertensive medication for persistent high BP. Two patients experienced serious adverse events (respiratory distress) requiring hospital admission, 1 in each group. Both patients had uneventful recoveries. The patient in the oral group also developed uncomplicated chickenpox infection. There was no difference between the patients' growth parameters at 3 months (P = .13 for weight and P = .3 for height). However, infants in the oral group had evidence of growth retardation at 1 year of age as documented by the differences in their weight (P = .003) and height (P < .001) (Fig 3).


Figure 3
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  		FIGURE 3 Confidence interval (CI) plot of weight and height changes over time.

 
Investigations
Renal function tests, serum electrolytes, CBC count, morning cortisol, and blood sugar were measured in all of the patients at baseline and monthly for 3 months. There were no clinically significant abnormalities noted in the renal function tests, electrolytes, and CBC counts. Fifty-two plasma morning cortisol tests (n = 73 [71%]) were found to be abnormal, 31 in the oral group (n = 38 [82%]) and 21 in the IV group (n = 35 [60%]). Twelve cortisol levels in the oral group and 1 in the IV group were in the undetectable range, suggestive of significant adrenal suppression. Blood sugar was found to be mildly elevated in 2 of 38 tests in the oral group and 3 of 32 tests in the IV group. In all of the patients with an abnormal blood sugar, the abnormality was transient.


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Approximately 10% to 20% of infants with hemangiomas require intervention to prevent or decrease complications related to their proliferation.2 Systemic corticosteroids are the most common treatment modality used in the management of problematic hemangiomas. This is the first randomized, controlled trial to demonstrate the efficacy of corticosteroids in halting the proliferation of IHs clinically (decrease in hemangioma size and improved visual function) and biologically (decrease in the circulating proangiogenic proteins). The effect, measured over the first year of life, was more pronounced with continuous, daily doses of prednisolone than with high-dose, intermittent pulses with methylprednisolone. One of the biggest limitations in designing studies in IHs is quantifying the response to treatment. To date, there are no good clinical, laboratory, or imaging tools that can accurately size these lesions. We adapted a validated tool (VAS) to estimate size differences between visits by comparing digital photographs. However, medical photography has its own limitations (the inability to quantify the volume of the lesion, the difficulty in standardizing the photographs, and the difficulty in accurately distinguishing changes because of the natural growth of the face from changes related to proliferation).

Our efficacy data are comparable to previous reports. Several case series have shown that 30% of patients have a significant improvement after steroid initiation, 30% show no change requiring additional dose increases to 5 mg/kg per day, and 40% have an equivocal response.12,17 In a recent meta-analysis,15 using a mean steroid dose of 2.9 mg/kg per day, 84% of patients had cessation of growth or regression of the hemangiomas, and the rebound (increase in the size of the mass after an initial shrinkage) rate was 36% (95% confidence interval: 29%–44%). Several retrospective studies suggested that higher doses are associated with a higher clinical response.14,15 In a study using high-dose oral methylprednisolone (30 mg/kg per day for 5 days with tapering every 5 days for a total of 6 weeks), a high initial response rate with high doses was noted; however, the overall response seemed to be similar to 5 mg/kg per day.26 Given the lower rate of adverse effects and shorter duration of treatment, this regimen was preferable to longer, lower-dose courses.26 In our study, the superiority of higher doses could not be duplicated (median VAS of 12 vs 70 at time point 1 and –1.5 vs 50 at time point 2). Another surprising finding was the fact that VAS scores were lower at 1 year compared with 3 months in both groups. A possible explanation is that as the facial contour normalizes (losing the "moon face" as a result of weaning), the relationship between the mass and the rest of the facial structures changes, making hemangiomas more noticeable. Functionally, 6 of 8 patients had an improved visual function at 1 year despite lower VAS scores in patients with periorbital lesions compared with other facial areas. This suggests either that periorbital lesions are less steroid responsive or that their functional impairment is because of a deeper component that is not easily discernible on photographs.

We were also able to document biological changes in the circulating levels of angiogenic markers as result of intervention. Several factors, such as VEGF, VCAM-1, proliferating cell nuclear antigen, and interleukin 16 were implicated in the early proliferation phase.7,27–29 As hemangiomas involute, other growth factors seem to play a more significant role, such as bFGF.8 Two studies documented decreasing levels of proangiogenic factors, such as VEGF, with steroids and interferon.9,10 In our study, the only 2 markers that decreased significantly as the hemangiomas stopped proliferating were VCAM-1 and endoglin, suggesting that they are the most sensitive markers of endothelial proliferation and may be used as surrogate markers. The magnitude of the changes was more significant in the oral group than in the IV group correlating with the clinical response. The lack of changes noted in the VEGF values is possibly explained by the short duration of follow-up data (3 months). The serum and urine bFGF values did not change over the 3 months of follow-up as expected. Each infant served as his/her own control, considering that disease-specific and age-matched levels are ethically unjustified.

The safety data were similar to published studies.30,31 Parental reports of adverse events attributed to the medication were not different between the 2 study groups. The frequency of hypertension was 18.6% in the oral group and 13.1% in the IV group. Abnormal cortisol values were more frequently found in the oral group (78% vs 60%), with 32% of the abnormal tests in the oral group suggestive of severe adrenal suppression. This finding did not clinically translate into increased infections. The growth retardation was more pronounced in the oral group, similar to previous studies. Although our data suggest that the oral group had overall more adverse effects than the IV group, the sample size of our study was not sufficient to clearly establish a difference.


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This randomized, blinded study showed that corticosteroids are efficacious in reducing the size of hemangiomas. Oral corticosteroids offered more clinical and biological benefit than the pulse steroids, however, with an increased risk of adverse effects. The pulse steroids may play a role in hemangiomas where a fast therapeutic response is needed (eg, eyelid hemangioma with complete visual axis occlusion) followed up by a shorter oral steroid regimen. Our data suggest that angiogenic proteins, such as VCAM-1 and endoglin, may have clinical use in monitoring clinical response and making therapeutic decisions. More prospective studies on the clinicobiological dose response of various corticosteroid regimens are needed.


   ACKNOWLEDGMENTS
 
This study was awarded the 2002 William Weston Grant from the Society for Pediatric Dermatology.

We thank Dr Robert C. Pashby, pediatric ophthalmologist, who assessed all of the patients with visual compromise; dermatology nurses Lesley Eisel and Alejandra Stuparich and research assistants Susan Britton and Nicole Brown for navigating us smoothly through the study process; and Marg Mather for administrative support.


   FOOTNOTES
 
Accepted Nov 28, 2006.

Address correspondence to Elena Pope, MSc, FRCPC, University of Toronto, Section of Dermatology, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: elena.pope{at}sickkids.ca

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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Right arrow Allergy & Dermatology