suPERficial Slow-flow Vascular malFORMations Treated With sirolimUS
suPERficial Slow-flow Vascular malFORMations Treated With sirolimUS
The most recent classification, adopted by International Society for the Study of Vascular
 Anomalies (ISSVA) in 1996, and updated in Melbourne in 2014, divides these lesions into two
 broad categories: vascular tumors and vascular malformations. Vascular malformations (VMs)
 are subdivided into high-flow VM and slow-flow VM.

 Slow-flow VMs consist of congenital anomalies which may involve abnormal capillaries vessels,
 venous vessels, lymphatic vessels or combination of several of them. They can be superficial
 (involving cutaneous and subcutaneous tissues) and/or may have visceral involvement. They can
 be limited or diffuse, and are sometimes components of genetic hypertrophic syndromes.

 The diagnosis of slow-flow VMs is performed on physical examination (biopsy may be required
 for confirmation), and is completed with imaging (ultrasonography and magnetic resonance
 imaging (MRI)). Slow-flow VMs may be particularly voluminous; associated with underlying
 hypertrophy responsible for functional impairment; painful; associated with seepage or
 continuous cutaneous bleeding; complicated with visceral signs or hematologic disturbances
 (anemia, thrombopenia). Management requires dedicated multispecialty care. There are no
 guidelines for treatment, and management may include no intervention - but natural history of
 these VMs is progressive worsening -, compression by physical bandage, sclerotherapy,
 resection (when feasible),anti-inflammatory or anti-coagulation drugs.

 Case reports and series have provided evidence for supporting the need for a clinical trial
 of sirolimus by reporting successful treatment on several children with complicated vascular
 anomalies. The choice of sirolimus is rational. Mammalian target of rapamycin (mTOR) is a
 serine/threonine kinase regulated by phosphoinositide-3-kinase involved in cell mobility,
 cell growth and angiogenesis. Sirolimus inhibits mTOR, which induces inhibition of
 angiogenesis, in particular lymphangiogenesis, which has been demonstrated in several models.
Vascular anomalies include a heterogeneous group of disorders of newborns and children. While
 infantile hemangioma are common (10% of infants), generally not complicated and easily
 managed, the majority of other vascular anomalies are rare (<2% altogether) and have no
 guidelines for management. The most recent classification, adopted by International Society
 for the Study of Vascular Anomalies (ISSVA) in 1996, divides these lesions into two broad
 categories: vascular tumors and vascular malformations. Vascular malformations (VMs) are
 subdivided into high-flow VM and slow-flow VM.

 Slow-flow VMs consist of congenital anomalies which may involve abnormal capillaries vessels,
 venous vessels, lymphatic vessels or combination of several of them. They can be superficial
 (involving cutaneous and subcutaneous tissues) and/or may have visceral involvement. They can
 be limited or diffuse, and are sometimes components of genetic hypertrophic syndromes. They
 always result from defective embryologic vasculogenesis.

 The diagnosis of slow-flow VMs is performed on physical examination - a biopsy may be
 required for confirmation -, and is completed with imaging, which includes ultrasonography
 and magnetic resonance imaging (MRI). Slow-flow VMs may be simple to manage or can be
 complicated for several reasons: they may be particularly voluminous; associated with
 underlying hypertrophy responsible for functional impairment; painful; associated with
 seepage or continuous cutaneous bleeding; complicated with visceral signs or hematologic
 disturbances (anemia, thrombopenia). Management requires dedicated multispecialty care. There
 are no guidelines for treatment, and management may include no intervention - but natural
 history of these VMs is progressive worsening -, compression by physical bandage,
 sclerotherapy, resection (when feasible), anti-inflammatory or anti-coagulation drugs.

 The vast majority of literature reporting medical therapies consists of paediatric case
 reports, and is complicated by publication bias, inconsistent use of nomenclature and absence
 of clinical trials. Case reports and series have provided evidence for supporting the need
 for a clinical trial of sirolimus by reporting successful treatment on several children with
 complicated vascular anomalies. The choice of sirolimus is rational. Mammalian target of
 rapamycin (mTOR) is a serine/threonine kinase regulated by phosphoinositide-3-kinase involved
 in cell mobility, cell growth and angiogenesis. Sirolimus inhibits mTOR, which induces
 inhibition of angiogenesis, in particular lymphangiogenesis, which has been demonstrated in
 several models.

 Randomized observational-phase design (Feldman et al. J Clin Epidemiol 2001;54:550-557):

 -  each patient will be followed during a 12-month-period

 -  each patient will start by an observational period and will end being treated by
 sirolimus

 -  at a random date (between month 4 and month 8), each patient will switch from the
 observational period to the sirolimus period Therefore, each patient will be his/her own
 control, as in a cross-over trial (but the difference is that the cross-over is all in
 one direction, from observational period to treatment period). This explains why
 variation in volume will be standardized by period durations.

 As specified by Feldman et al, the randomized placebo-phase design is well adapted in
 situations where "a placebo controlled study would be perceived as being unacceptable by
 enrolling physicians and by patient" and "may be especially useful when highly potent
 therapies for rare diseases"
-  Patients aged from 6 years to 18 years

 -  With a slow-flow vascular malformation confirmed by MRI, included or not into a
 genetic disorder, among the following:

 -  microcystic lymphatic malformation

 -  mixed micro- and macrocystic malformation

 -  venous malformation

 -  combined lymphatic and venous malformation

 -  Malformation voluminous and complicated (pain, functional impairment, bleeding,
 seepage)

 -  Extended to the underlying subcutaneous tissue, to the fascias, the muscles and/or the
 underlying bone

 -  MRI of the VM performed within 8 months

 -  Vaccination schedule updated

 -  Informed, written consent of the subject's parents or the 18 years old subject

 -  Cooperative parent or subject, aware of the necessity and duration of controls so that
 perfect adhesion to the protocol could be expected

 -  Subjects or subject's parents covered by or having the rights to social security.

 Exclusion criteria:

 -  Slow-flow VMs which are only macrocystic lymphatic malformations

 -  Visceral life-threatening involvement

 -  Patients who received prior per os treatment with an mTOR inhibitor

 -  Immunosuppression (immunosuppressive disease or immunosuppressive treatment)

 -  Known chronic infectious disease

 -  History of cancer in the 2 previous years

 -  Brest feeding or pregnant women, or women on childbearing age without effective
 contraception, up to 12 weeks after treatment discontinuation

 -  Known allergy to mTOR inhibitor

 -  Concomitant treatment that inhibits or activates CYP3A4, and P-gp glycoprotein,
 cytotoxic drugs, antilymphocyte immunoglobulines and metoclopramide

 -  Intolerance to fructose, intolerance or malabsorption to glucose, galactose, metabolic
 insufficiency in sucraseisomaltase, metabolic defect in lactase

 -  Known allergy to peanuts or soyabean

 -  Liver insufficiency (elevated transaminases > 2.5 N)

 -  Anemia with Hb < 9 g/dl

 -  Leukopenia < 1000/mm3

 -  Thrombocytopenia < 80 000/mm3

 -  Hypercholesterolemia (LDL-cholesterol ≥ 2g/l)

 -  Patients with risk of opportunistic infections

 -  Contraindication of MRI

 -  Known allergy to lidocaïne

 -  Live attenuated vaccine up to 3 months after sirolimus discontinuation

 -  Subject already participating to a therapeutic study