Beta-blockers in the Treatment of Infantile Hemangiomas 5yrs experience

Transcription

1 Beta-blockers in the Treatment of Infantile Hemangiomas 5yrs experience Josef Mališ V.Stará, S.Klovrzová, L.Nováková, M.Kynčl, A.Sukop, B.Kocmichová, Š.Čapková, K.Bláhová Dept. of Pediatric Hematology/Oncology University Hospital Motol Prague, Czech Rep.

2 Epidemiology 4-10% of infants < 1 year old > Up to 30% in prematured child* < 1.5kg birth weight The most frequent infantile tumor

3 ISSVA Vascular Anomalies Classification (1996 Enjolras O.) Vascular Anomalies «Angioma» = abusive term Vascular Malformations No regression GLUT-1 (-) Vascular Tumors Possible regression Slow flow Fast flow Complex & combined Infantile Hemangioma Others GLUT-1 (+) GLUT-1 (-) Lymphatic Malformations = vesicules or cysts Venous Malformations = blue and swelling Capillary Malformations = red Port-wine stains Sturge-Weber Syndrome RICH NICH Tufted angioma Kaposiform Hemangioendothelioma Kasabach-Merritt Phenom. Main vascular tumor

4 Infantile Hemangioma Types Deep «cavernous» Hemangioma involve the deep dermis and subcutis bluish to skin-colored nodules Smooth in surface 15% Superficial «strawberry» Hemangioma Combined Hemangioma 30% 55% features of both superficial and deep hemangiomas often with a red plaque overlying a bluish nodule All IH are hot to the touch bright red lesions plaquelike or more rounded papules or nodules. Uneven surface

5 Infantile Hemangioma characteristics By type By distribution By localisation Superficial Deep Combined Segmentary Localized Head Rest of body

6 Hemangioma Evolution Phases Nascent (resting) IH size Optimal time for starting treatment Proliferation & Plateau Involution Median age to ending involution*** The most rapid IH growth is between 1&2 months** Reach 80% of their final size by 3 months* 80% have completed growth by 5 months of age* 80% : size X2 5% : size X3 5% : dramatical growth Birth W1 W4 M6 M12 M18-20 Y3 Y7-Y9

7 Evolution Kinetics Reach 80% of their final size by 3 months* 80% have completed growth by 5 months of age* 100% of final size 6 months Status of hemangioma at 5 months 80% of final size = 3 months 80% 20% Completed growth Still proliferating

8 Hemangioma Evolution Phases in pictures Nascent (resting) Growing & Plateau Involution 12D 1.5M 3M 2.5Y 10W 3.5M 27M 3.5Y 5Y Birth W1 W4 M6 M12 M18-20 Y5-6

9 Disease Outcome Residues 30 % Residual Anomalies 70 % - 100% in segmental IH Telangiectasias Erythema Atrophic scars Anetoderma Fibro-fatty residue Hypopigmentation Scars

10 Infantile Hemangioma localisation Face (40%) Neck (20%) = 60% of the cases ie: eye nose lip neck «beard» - forehead - ears Breast Limbs - Hands Diaper area

11 Infantile Hemangioma localisation Eye Nose Ears Lip Neck Beard Forehead Limbs - Hands Breast Diaper area

12 Visceral hemangioma (liver)

13 IH compressing respiratory airways

14 Disease Complications 88% of cases = No treatment needed in early stage Natural resolution 88% 12% 12% of cases = treatment needed in early stage 1. Life-threatening conditions 2. Functional risks 3. Permanent disfigurement 4. Painful ulcerated or bleeding IH

15 IH requiring treatments in brief Vital Risks Functional Risks Respiratory failure Heart failure Visual function failure Maxillodental developpement Nose necrosis Ears closing infection deafness Impact on the future breast Painful ulcerated or bleeding IH Permanent disfigurement Ulceration Telangiectasias Fibro-fatty lesions Atrophic scars

16 Treatments historical development 1. Treatment options 1. Steroids 2. Interferon 3. Vincristine 4. Lasers 5. Surgery 6. Alternatives 2. β-blockers : Propranolol

17 2008 : The story begins Leaute-Labreze C et al. N Engl J Med 2008;358:

18 The story goes on

19 Propranolol vs placebo Propranolol is a safe and effective medication for treating IHs Significant volume reduction and redness/elevation reduction sufficient to justify the use of propranolol as the first-line option for potentially disfiguring or complicated IHs. There was a significant improvement in IH redness and elevation based on investigator scores from clinical photographs at weeks 12 and 24 in the propranolol group compared with placebo. The mean age at inclusion was 67 weeks in the Propranolol group and 71 weeks in the placebo group.

20 Propranolol versus Corticosteroids Propranolol therapy was more clinically effective and more costeffective than oral corticosteroids in treating IHs Propranolol resulted in fewer surgical interventions and demonstrated better tolerance, with minimal adverse effects, compared with oral corticosteroids Propranolol should be considered a first-line agent

21 Propranolol vs Prednisone : a retrospective comparative study Prednisone Propranolol T = 0 1 month 2 months 6 months

22 The β-blockers Discovered in the 50 s. Propranolol: The first clinically useful β-blocker in angina pectoris Discovered in the 50 s by Sir James W. BLACK against angina (1988 Nobel Prize) β1-β2 adrenergic receptors blocker How it works? HR BP (2h after administration) Cardiac contractility cardiac excitability Renin Angiotensin II = Arterial Pressure Bronchoconstriction

23 Propranolol Mechanism of Action (3 paths) Nascent & Proliferation Plateau Involution Hypoxi c stress HIF CD133 Mesenchymal Stem Cells VEGF bfgf VEGF bfgf Birth W1 W4 Vasoconstriction M6 M12 M18-20 Y3 Y7-Y9 Β-blocker Apoptosis CD133 stem cells Immature endothelial cells Pericyte Adipocyte Mast cell Léauté-Labrèze C, Taïeb A. [Efficacy of beta-blockers in infantile capillary haemangiomas: the physiopathological significance and therapeutic consequences]. Ann Dermatol Venereol Dec;135(12): Epub 2008 Nov 20. Review. French. PubMed PMID:

24 Side effects due to Propranolol in hemangioma patients 25,00% 20,00% 15,00% 10,00% 5,00% 0,00% Sleep disturbance Hypotension Somnolence Cool or mottled extremities Pulmonary symptoms Bradycardia Hypoglycemia Diarrhea Gastrointestinal disease

25 Propranolol Efficacy - Conclusion Propranolol was initiated at a mean age of 6.6 months Mean treatment duration of 6.4 months Response rate for patients with IHs treated with propranolol was 98% (range 82% 100%) IH rebound growth in 17% of patients. Adverse events reported in 31% (changes in sleep = 11% - acrocyanosis = 5%) Propranolol for IHs showed a high rate of efficacy and a low rate of serious adverse events

26 Randomized study design Adaptive Design: Phase II/III Trial Double-Blind Randomized Controlled Trial in Parallel Groups Infants with proliferating infantile hemangiomas requiring systemic therapy and located anywhere on the body except on the diaper area, with largest diameter of at least 1.5 cm Age at initiation = 1 to 5 months (proliferating phase only) Placebo versus 4 propranolol Regimens, Administration twice daily (Dose escalation in 2 weeks D7 D14) No corticosteroid comparator arm ( Not FDA/EMA approved in IH)

27 Study design Patients 102 Regular patients pictures 1 mg/kg/day Main efficacy endpoint 98 1 mg/kg/day Placebo mg/kg/day Follow-up mg/kg/day Placebo 55 Placebo Randomization 3 months 6 months 24 months Doses and durations discussed with European and US Health Agencies

28 N Engl J Med 2015; 372: February 19, 2015 In conclusion, this trial shows that oral propranolol at a dose of 3 mg per kilogram per day for 6 months is effective in the treatment of infantile hemangioma.

29

30 Our experience Since children were treated Head + face % Thorax % Liver (only 6 4 % Liver + skin. 4 2 % Extremities % Multipl. lesion (more than 10) % Neck + mediastinum 6 2 % Mucosal (mouth) 5 2% Treatment duration: med. 10,7 měs. (4 mths; 2,5 yrs) 6mths age 4,7 mths 6mths to 1 y age - 8,1 mths Response very good in 98%, in 3% the surgery needed for removal of residual lesions In 5% regrowths after completion of propranolol, preferably in deep IH

31 Management of infants with IHs (2 )- 4 days hospitalization Initial investigation: history of the child search for risk factors blood pressure (BP), heart rate (HR) electrocardiogram, ECHO glycemia, basal biochemistry Dose escalation: 0, (3) mg/kg/d in 2 (3) doses Propranolol administration close to feeding BP and HR 1 hr after drug administratin HR monitoring after target dose achieving during sleeping

32 IH treatment in our Hospital

33 Conclusions: Superficial IH most gratefull for treatment, responding well, rapidly and almost without any ressiduals Mixed and deep (particularly) have tendency for regrowth after treatment completion The best effects of BBs th can be achieved when the treatment is started during first 4(5) mths of life Whenever the features of spontaneous involution of IH appear, the chance for succesful treatment (without any residues) decreases.

34 Hemangioma Evolution Phases Nascent (resting) IH size Optimal time for starting treatment Proliferation & Plateau Involution Median age to ending involution*** The most rapid IH growth is between 1&2 months** Reach 80% of their final size by 3 months* 80% have completed growth by 5 months of age* 80% : size X2 5% : size X3 5% : dramatical growth Birth W1 W4 M6 M12 M18-20 Y3 Y7-Y9

35 Side effects: Slow dose escalation in preterm or lowbirth weight babies (hypoglycemia) Sleep disturbancies Colder extremities Only once allergic reaction to BBs in sirup

36 Who? Where? When? Who? Oncologist/dermatologist + other specialists: radiologist, cardiologist, neonatologist, surgeon, etc. Where? Institutions where all these specialists and facilities are available When? ASAP as soon as possible during the rapid growth phase

37

38

39

40

41

42

43

44

45

46

47 Thank you! Josef Mališ Dept. Of Pediatric Hematology/Oncology University Hospital Motol, Prague, Czech Rep.