Trial Information

A Comparative Study of the Use of Beta Blocker and Oral Corticosteroid in the Treatment of Proliferative and Involuting Cutaneous Infantile Hemangioma

1. Introduction Infantile Hemangioma (IH) is infancy's most common vascular tumor of
infancy and most frequent benign neoplasm. In 1996 the "International Society for the
Study of Vascular Anomalies" has defined the guidelines for the diagnosis and treatment
of vascular anomalies. Hemangioma is one of the many vascular tumors that were
classified. Clinically, it presents well defined characteristics and a natural history
divided into three phases. The proliferative phase represents an initial growth phase
through hyperplasia and hypertrophy, followed by a spontaneous regression phase called
the involuting phase. The involuted phase represents a final phase with no more
biological activity; however, it doesn't necessarily corresponds to the complete tumor
disappearance once there is a replacement by fibro-fatty tissue. IH affects one in
every 10 to 20 Caucasian infants.There is a predilection for females at a 3:1 to 5:1
proportion, a higher incidence in premature infants, in newborns with low birth weight,
in those whose pregnancy presented placentary anomalies and in neonates from mothers
with multiple pregnancies. Fifty to sixty percent of IH affect the head and neck area.

In the proliferative phase the tumor may reach considerable dimensions and depending on
its location and proximity to vital structures, it may result in the obstruction or
invasion of organs. This would cause a functional problem and even impose a threat to
infant's life. There is a variable incidence of local complications such as necrosis,
repetitive ulcerations, bleeding and infections, apart from systemic complications such
as coagulopathy and high output cardiac failure.

After involution, IHs may leave scars or contour deformities resulting in deformities
and eventual psychological damage. Treatment of IHs is indicated for approximately 10
to 20% of the cases. Two groups can be defined amongst indications for treatment:
patients with absolute indication and patients with relative indication for treatment.
Absolute or emergency indications comprise function or life threatening situations such
as obstruction of airways, obstruction of vision, congestive heart failure, hepatic and
coagulation problems.

The following are considered relative indications: cases of large and disfiguring
facial hemangiomas; locations that can result in a deformity and/ or permanent scar
(nose, ear, lip, glabellar area); extensive face hemangiomas, mainly when there is
dermal damage (more probable to scar); local complications such as ulceration,
infection and bleeding as well as small hemangiomas in exposed areas (hands and face),
mainly if pedunculated due to its ease of excision.

Treatment modalities vary according to the extension, location, presence of
complications and the evolutional phase. A combination of various treatments is
possible.

In cases of relative indication, surgical treatment is mostly indicated for lesions in
growing areas with disfiguring potential. For the other cases, pharmacological therapy
is being the routine. The mostly used option is prednisone, a systemic corticosteroid
administered orally. The therapeutic response to corticosteroids is variable and its
effectiveness rates fluctuate between 30 to 84%. Clearly effective responses or just a
reduction in the lesion's growth rate are possible. The effective response, when
observed, occurs on average a week after the beginning of use of medication. Side
effects are frequent, being the most common the cushingoid appearance, alterations of
personality, hypertension, gastrointestinal disorders, decrease in growth speed and
head circumference and weight gain.

For cases with no response to the corticosteroid, the most frequently used drug as a
second treatment line is subcutaneous alpha-interferon 2b. In spite of being very
effective, this medication presents a higher rate of side effects, being spastic
diplegia the most fearsome.

Other drugs are being used, such as chemotherapeutic drugs and immunomodulators.
However, published studies cover small casuistics, with no great population studies or
long term follow up to justify its routine use.

Recently, Léauté-Labrèze et al. reported the use of beta blockers (propanolol) for IH
treatment. The casual finding of a significant reduction in hemangiomas volume was
observed when this drug was used as an antihypertensive for the treatment of side
effects resulting from the use of systemic corticoids in the treatment of infantile
hemangioma. A significant reduction of tumor volume was observed after introduction of
the beta blocker, in a short period of time, with stable results after the end of
treatment, which suggested evidences of the benefits of this drug in the tumor
treatment. Other authors also reported the successful use of the medication. Recent
initial studies show the effectiveness of the isolated use of propanolol, suggesting
the presence of specific action mechanisms for this medication.

Beta blockers are being used in children for approximately 40 years, with proven
clinical safety and no cases of death or cardiovascular disease resulting from its
direct use. Side effects are already well established, such as bradycardia and
transitory hypotension, requiring monitoring from the beginning of treatment. Besides,
beta blockers reduce lipolysis, glycogenolysis and gluconeogenesis, predisposing to
hypoglycaemia. It has to be used with special attention in neonates, who can present
hypoglycaemia without medication.

Beta blockers, and more precisely propanolol, appear as one more therapeutic option
with apparent good results. So far in literature there are just some case reports and
initial protocols about the use of this medication.

Lesions located on the cervicofacial region with relative indication for treatment are
more susceptible to visual exposure, causing discomfort to the patient and family,
apart from the possibility of distortion of growing anatomical structures which will
eventually evolve into deformities. The best management for these cases is debatable:
on one hand the possibility of pharmacological treatment with corticosteroids with a
variable success rate and significant side effects; on the other hand the conservative/
expectant treatment, in other words, waiting for evolution, expecting a complete
spontaneous regression. Therefore, a drug with known reduced side effects could be a
good alternative of treatment, accelerating tumor involution and allowing a quick
problem solution in comparison to the expecting conduct and to the conventional
pharmacological treatment.

In this context, the proposal is to assess the use of propanolol in IH treatment,
quantifying its effectiveness and safety under continuous monitoring and comparing it
to the use of oral corticosteroid.

In the present study we propose the assessment of the betablockers' use in comparison
to the use of corticosteroids in infants with IH in the proliferative or involuting
phases, with indication for clinical treatment, and that are not alarming nor urgent;
in other words, the current relative indications for treatment.

2. Patients and Methods

Patients are going to be recruited at the Instituto de Tratamento do Câncer Infantil (Itaci)
- (Infantile Cancer Treatment Institute) - ITACI - ICr-HCFMUSP and the Division of Plastic
Surgery, Hospital das Clinicas, University of Sao Paulo,once eligibility, inclusion and
exclusion criteria are assessed and after signature of informed consent by legally
responsible parties.

2.1. Type of Study See detailed information below

2.2. Eligibility: Infants with ages up to 2 years, of both genders, carriers of clinically
diagnosed infantile hemangioma in proliferative or involutive phases and relative indication
for treatment.

2.3. Inclusion Criteria: see below on separate item

2.4. Exclusion Criteria: see below on separate item

2.5. Data Gathering

Once included in the study, patients are going to be subject to:

2.51. Gathering of epidemiological data concerning pregnancy, birth and family history;

2.5.2. Determination of anatomical location and dimensions of hemangioma through direct
measurements and photographic study.

- Measures in centimeters on lesion's larger axis and another one perpendicular to this
axis;

- Photographic measures with a measuring tape for reference on anterior and bilateral
profile positions with the same photo camera and obtained by the same technician.

2.5.3. Pediatric clinical assessment of health conditions prior to the beginning of
treatment, comprising the following follow-up parameters:

- Blood pressure

- Heart rate

- Oxygen Saturation

- Weight and height

2.5.4. Laboratory assessment

- glucose blood levels

- complete blood count

- assessment of renal function

2.5.5. Specific cardiac assessment

- rest electrocardiography

- echocardiography

- PA and profile thoracic radiography

2.6. Clinical Treatment Patients in Groups A and B will undergo a treatment for an initial
60-day period, unless in the presence of criteria for medication suspension (item 2.9).

The total length of the treatment is going to be determined by the effective response to the
treatment. The effective response is going to be defined as a volumetric reduction of the
lesion.

2.6.1 Outcome

Reduction on volume is going to be considered as effective response. It will be evaluated
based on direct measurement and photographic analysis, as mentioned in item 2.5.2.

The absence of effective response after the initial 60-day period is going to be considered
as treatment failure; Group A patients' medication (propanolol) is going to be suspended and
Group B (prednisone) patients are going to begin a progressive dose reduction regimen until
the suspension of the medication.

2.7. Follow up during treatment

During the whole period of treatment patients will be periodically evaluated as described
below:

- Clinical control and lesions measure control:

- weekly in the first two months,

- twice a week in the following months.

Considering the same parameters obtained in items 2.5.2 and 2.5.3

- Monthly laboratory control until the end of treatment considering the same parameters
obtained in item 2.5.4,

- Electrocardiographic examination and echocardiography at the end of the 60-day initial
treatment.

2.8. Follow up after conclusion of treatment

After suspension of treatment, patients are going to maintain a periodic outpatient
treatment returning after 14 days, 21 days, 1, 2 and 6 months for evaluation of clinical
parameters and lesion dimensions.

Six (6) months after the conclusion of the treatment, electrocardiography, echocardiography
and chest radiography are going to be repeated.

2.9. Criteria for treatment interruption:

In the event of an indication for suspension of treatment, the patient is going to be
excluded from the study and is going to follow a treatment according to the group's routine
indications.

2.9.1. Group A - Propranolol:

- Hypotension below percentile 90

- Bradycardia with heart rate below percentile 90

- Bronchospasm

- electrocardiographic alterations

- echocardiographic alterations

- hypoglycaemia.

2.9.2. Group B - Prednisone

- Difficult-to-control hypertension