A review of contemporary options for medical management of hemangiomas, other vascular tumors, and vascular malformations

Pharmacology & Therapeutics 139 (2013) 327–333

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Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera

A review of contemporary options for medical management of hemangiomas, other vascular tumors, and vascular malformations Julie Blatt a, c,⁎, Thomas W. McLean e, Sharon M. Castellino e, Craig N. Burkhart b, d a

Division of Pediatric Hematology Oncology, the University of North Carolina, Chapel Hill, NC, USA Division of Pediatric Dermatology, the University of North Carolina, Chapel Hill, NC, USA Department of Pediatrics, the University of North Carolina, Chapel Hill, NC, USA d Department of Dermatology, the University of North Carolina, Chapel Hill, NC, USA e Division of Pediatric Hematology Oncology, Wake Forest University Medical School, Winston-Salem, NC, USA b c

a r t i c l e

i n f o

a b s t r a c t Vascular anomalies include vascular tumors and vascular malformations. With growing pharmacologic options and parallels to cancer treatment and biology, the hematologist–oncologist has assumed a more prominent role in clinical care and research relating to these diagnoses. This also is a growing area for targeted therapies and drug repositioning. We performed a review of contemporary options for medical management of these lesions. PubMed was searched for “vascular anomaly”, “hemangioma”, “vascular malformation”, “arteriovenous malformation”, “capillary malformation”, “cerebral cavernous malformation”, “lymphatic malformation”, and “venous malformation”, each with “drug treatment” as a modifier. Manuscripts were reviewed to verify diagnoses, indications for treatment, dose-schedules, evidence of effectiveness, toxicities, and mechanisms of action. ClinicalTrials.gov also was reviewed for relevant trials. More than 20 agents were identified which have been used to treat vascular anomalies. Rigorous studies are lacking for many of these. The rarity of these tumors has limited development of medical approaches to treatment. Cooperative group trials will be needed to prove the effectiveness of drugs which have shown promise in cases and small series. The observant clinician remains a powerful tool for identifying potential new treatments for vascular tumors and malformations. © 2013 Elsevier Inc. All rights reserved.

Keywords: Vascular anomaly Vascular malformation Hemangioma Drug treatment

Contents 1. Introduction 2. Methods . . 3. Results . . . 4. Discussion . Financial support . Conflict of interest References . . . .

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1. Introduction Vascular anomalies are a heterogeneous group of diseases which include hemangiomas and other vascular tumors, intermediate and more aggressive malignancies, and vascular malformations of veins, arteries, capillaries and lymphatics (Enjolras & Mulliken, 1997; Blei, 2013). ⁎ Corresponding author at: Division of Pediatric Hematology Oncology, University of North Carolina School of Medicine, 170 Manning Dr., POB 1185A CB 7236 Chapel Hill, NC 27599-7236, USA. Tel.: 919 966 0590; fax: 919 966 7629. E-mail address: [email protected] (J. Blatt). 0163-7258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pharmthera.2013.05.001

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Hemangiomas are the most common of these lesions, with an incidence of 10% in white infants; vascular malformations as a group occur in 1–5% of children and adults (Hochman et al., 2011). Many centers have organized multidisciplinary clinics to manage patients with hemangiomas and vascular malformations (Mathes et al., 2004), inviting expertise in anesthesia, dermatology, dermatopathology, surgical, medical and pediatric subspecialties, diagnostic and vascular interventional radiology, rehabilitation medicine, cancer and vascular biology. With growing pharmacologic options and obvious parallels to cancer treatment and biology, there has been a paradigm shift in the pharmacologic approach to these lesions in the past decade. The

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hematologist–oncologist has assumed a more prominent role in clinical care and research. To provide an overview of growing options for management, we searched the literature for drugs which have been effective in the treatment of vascular anomalies. 2. Methods 2.1. Literature search procedure PubMed was searched for “vascular anomaly”, “hemangioma”, “vascular malformation”, “arteriovenous malformation” (AVM), “capillary malformation” (CM) (previously called “port wine stain”), “cerebral cavernous malformation” (CCM), “lymphatic malformation” (LM) (previously called “cystic hygroma”), and “venous malformation” (VM), each with “drug treatment” as a modifier. Where available online, abstracts of manuscripts whose titles indicated human experience with one or more specific medications were further screened for specifics of diagnoses and treatment. Relevant manuscripts were reviewed in an attempt to verify diagnoses, indications for treatment, responses, toxicities, and mechanisms of action. Only citations in English for which a manuscript was available on-line were included. For each drug, the strength of evidence for its effectiveness was reviewed: whether a drug had been used in one or more randomized or single arm clinical trials, in multiple case reports, or whether experience was limited to single case reports. Only representative citations are referenced but the body of literature was taken into account to determine quality of evidence. Drugs such as bleomycin which are used for sclerotherapy, or aminocaproic acid and tranexamic acid which have been reported as supportive care to treat bleeding but which have no effect on the vascular anomaly itself were not included. 2.2. Review of ongoing clinical trials ClinicalTrials.gov was reviewed for trials which were recruiting as of February 1, 2013. Additional studies on that website which were ongoing but not recruiting or which had been completed but not yet published were not included. Both PubMed and ClinicalTrials.gov were used to look for mechanisms of action. Most of the agents are thought to work through inhibition of one or more angiogenic pathways. 3. Results 3.1. Historical treatment — an overview Prior to 2008, corticosteroids, gamma or alpha interferon, and traditional chemotherapies (such as vincristine and cyclophosphamide) were typical medical therapies for vascular tumors (mostly hemangiomas and hemangioendotheliomas) that required treatment. Use of the most common agents has been reviewed elsewhere (Gottschling et al., 2006; Blei, 2013). These were used, as single agents or in combination, as adjuncts to excisional surgery, intralesional injection, pulse dye laser therapy, or sclerotherapy (Buckmiller, 2004; Gottschling et al., 2006). No randomized clinical trials ever compared these agents to each other or to placebo. However, they were used empirically and are considered to be effective in some patients with hemangiomas or hemangioendotheliomas with or without consumption coagulopathy (Kasabach–Merritt syndrome (KMS)). Newer conventional chemotherapies also have been applied to refractory vascular tumors (Pintoffl et al., 2009; Grenader et al., 2011). 3.2. Contemporary options for treatment Other, mostly newer, pharmacologic options are listed in Table 1. Because most of the agents we identified have been used to treat multiple different vascular anomalies, the table is arranged by drug rather than by diagnosis. Using our search criteria, PubMed identified several thousands

of manuscripts, of which a number appeared in multiple searches (e.g., in searches of both “hemangioma” and “vascular anomaly”). However, fewer than 600 met criteria for inclusion (under “vascular anomaly” (n = 83), “hemangioma” (n = 274), “vascular malformation” (n = 94), AVM (n = 26), CM (n = 4), CCM (n = 2), LM (n = 14), VM (n = 46)). In many cases, the literature searches incorrectly identified the type of vascular anomaly (e.g., “hemangioma/drug treatment” pulled up many articles relevant to the telangiectasias of hereditary hemorrhagic telangiectasia (HHT, Osler Weber Rendu syndrome)). Although not specifically searched for, treatments for primary lymphedema are included in these results since they were identified in searches for LM. Propranolol, a non-selective beta adrenergic blocker used for many years to treat hypertension, arrhythmias, and other cardiovascular abnormalities in children, is recently the most widely recognized agent for hemangiomas of infancy (IH). It has become first line therapy for IH in the proliferating phase in many centers (Blatt et al., 2011; Hogeling et al., 2011; Drolet et al., 2013) since the publication in 2008 of a series of 11 patients (Leaute-Labreze et al., 2008). The first patient had been given propranolol for treatment of obstructive hypertrophic myocardiopathy and dramatic improvement of her facial hemangioma was noted. This coincidental observation was duplicated in the other 10 children. Responses to propranolol since have been confirmed in over a thousand children with hemangiomas (Drolet et al., 2013). A single prospective randomized trial comparing propranolol to placebo proved efficacy and safety (Hogeling et al., 2011). Oral propranolol typically is started at doses of ≤1 mg/kg/day and escalated to 2 mg/kg/day divided in two or three doses. Responses can be noted within several days to two months of starting, and corticosteroids sometimes are continued as a bridge to achieving target dosing and initial responses. Side effects of propranolol generally are negligible, but rarely can be life-threatening. The overall frequency of complications has ranged from 0.1 to 10% (Blatt et al., 2011; Drolet et al., 2013). These include hypoglycemia, bradycardia and hypotension, hyperkalemia, somnolence or other sleep disturbances, respiratory embarrassment, and cool or mottled extremities — each of which can occur anytime during the course of treatment. Guidelines for treating and monitoring infants and children and hemangiomas with propranolol have been suggested (Drolet et al., 2013). Timolol maleate (0.5% gel forming solution), a topical beta-blocker, is an alternative in children with superficial lesions (Pope & Chakkittakandiyii, 2010; Blatt et al., 2011). Propranolol has been used anecdotally for related lesions including epithelioid hemangioma of the retina (Moss et al., 2012) and cavernoma (abnormal collections of vascular sinusoids that are lined by a single endothelial layer and lack intervening brain parenchyma) of the brain (Moschovi et al., 2010). It has been used with variable success for the treatment of tufted angiomas or Kaposiform hemangioendotheliomatosis with or without KMS (Chiu et al., 2012), and lymphangiomas (OzekI et al., 2011; Annabel et al., 2012). In vitro studies have suggested that it might have application to patients with HHT (Albiñana et al., 2012). Randomized trials of patients with hemangiomas or CM in Sturge–Weber syndrome comparing beta-blockers with corticosteroids or placebo are in progress (ClinicalTrials.gov; Table 2). Other beta-blockers with greater specificity (atenolol (Raphaël et al., 2011); acebutolol (Blanchet et al., 2010)) have been offered as alternatives to propranolol, but have been used much less commonly in this setting. In a recently published small prospective series, nadolol (which like propranolol is a non-selective beta-blocker) was found to be as effective as propranolol for hemangiomas in young children (Pope et al., 2013). Its favorable safety profile and longer half-life make this drug an attractive candidate for prospective head to head comparisons with propranolol. The mechanism by which beta-blockers work is multi-factorial, including vasoconstriction through beta blockade, anti-angiogenesis via decreased expression of vascular endothelial growth factor (VEGF) and β fibroblast growth factor (FGF), and apoptosis of capillary endothelial cells (Greenberger & Bischoff, 2011) (Fig. 1). Several small series indicate that captopril, an antihypertensive which is an ACE inhibitor, also may have anti-angiogenic activity (Tan et al., 2012).

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Table 1 Contemporary drugs in the management of vascular anomalies.a Drug

Lesions with responses

Highest Level of Evidence

Mechanism

pediatric dosing?/ pediatric usage for any vascular anomaly

Propranolol/ Timolol

Infantile hemangioma Epithelioid hemangioma Cavernoma KHE, TA Lymphangiomatosis

R C

Β blocker VEGF antagonist; Vasoconstriction; Down regulation of MMP and other pro-angiogenic cytokines

+/≥0 days

Atenolol Acebutolol Nadolol

Infantile hemangioma Infantile hemangioma Infantile hemangioma

C C S

Captopril Bevacizumab (Avastin)

Infantile hemangioma AVM in HHT Hemangioblastoma Hemangioma EHE

S S C C S

ACE inhibitor VEGF antagonist

+/≥5 weeks +/≥11 months

Pazopanib Sunitinib Semaxanib

Hemangioblastoma

C C S

Tyrosine kinase inhibitors

in phase I testing/+/ no published reports -/-/-

Infliximab Sirolimus (Rapamune)

AVM in HHT PTEN, hamartomas LM, VM/VLM VM (Blue rubber bleb nevus) Lymphangiomatosis Hemangioendothelioma CM

C C rs C C C C

TNF-α inhibitor mTOR inhibitor, VEGF antagonist Apoptosis

+/ no published reports +/≥2 months

Tacrolimus Pimecrolimus

Hemangioma

S

Calcineuron inhibitor

+/6 months

Thalidomide

GI AVM, Epistaxis (HHT) Hemangioendothelioma

R S C

βFGF antagonist

+/ no published reports

Lenalidomide

GI AVM (+/HHT) Hemangioendothelioma

C

Doxycycline Minocycline Marimastat Imiquimod

CNS AVM CNS AVM AVM Infantile hemangioma CM Hemangioendothelioma

S S C rs C C

VEGF2R inhibition; MMP-9 inhibition MMP inhibitor MMP-1 inhibitor

+/≥15 years +/≥15 years +/3 years +/ all ages

Octreotide

GI angiodysplasias

S

+/ no published reports

Sildenafil

LM

C

Somatostatin analogue, down regulation of VEGF phosphodiesterase-5 inhibition

Tamoxifen Raloxifene Estrogen + Progesterone

AVM (HHT) AVM (HHT) AVM (HHT)

R S R

Anti-estrogen

+/ no published reports -/+/ no published reports

Pamidronate Kampo

Lymphedema LM

S S

unknown prostaglandin E2 inhibition

+/ no published reports +/2 years

Curcumin Tranilast

hemangioendothelioma

C C

NF-kβ inhibitor TNF-β inhibitor

+/6 months ?/ no published reports

C S C

+/≥3 months +/≥1.5 month +/≥1 month

-/ no published reports

C

+/≥9 months

a Abbreviations: AVM (arteriovenous malformation), CM (capillary malformation) cerebral CCM (cavernous malformation), LM (lymphatic malformation), VM (venous malformation); R (randomized clinical trial); S (single arm clinical trial); rs (retrospective series, ≥5 cases demonstrating efficacy); C (b5 cases demonstrating efficacy).

Bevacizumab (Avastin), a monoclonal antibody against VEGF which is approved for the treatment of several cancers, also is being explored in the treatment of vascular anomalies. Intravenous (IV) bevacizumab has been reported to be effective in the treatment of AVMs of patients with HHT (Dupuis-Girod et al., 2012), in several cases of central nervous system (CNS) hemangioblastomas (some in von Hipple–Lindau disease (Riklin et al., 2012)), and radiation-induced cavernomas

(Aguilera et al., 2010). Doses have ranged from 5 to 15 mg/kg IV every 2–3 weeks for 6–12 doses. Responses have been reported within several months of starting therapy, and lesions sometimes have regrown when drug was discontinued. Side effects have included paresthesias, bleeding, thromboembolic events, headache and alopecia. Intralesional administration has been effective in treating intraorbital hemangiomas (Shoeibi et al., 2011) as well as epistaxis in HHT (Karnezis & Davidson,

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Table 2 Clinical trials: recruiting as of 1/1/13. Trial number

Eligible diagnoses

Intervention

Institution

Age

NCT00967226 NCT01743885 NCT01408056 NCT01533376 NCT00975819

Phase 2 propranolol vs prednisone Acebutolol vs propranolol Topical timolol vs mupirocin Topical timolol vs placebo Phase 2 sirolimus

Children's Research Institute University Hospital, Montpelier CHOP Wills Eye Institute Children's Medical Center, Cincinnati

0–5 months b6 months 1–8 months 2–10 years ≤31 years

NCT01402531

Infantile hemangioma Infantile hemangioma Ulcerated infantile hemangioma Sturge Weber Port Wine Stain Kaposiform hemangioendothelioma Tufted angioma Capillary Venous Lymphatic Malformation Venous lymphatic malformation Microcystic lymphatic malformation Mucocutaneous lymphangiomatosis and thrombocytopenia Capillary lymphatic arterial venous malformations PTEN overgrowth syndrome with vascular anomaly Lymphangiectasia syndromes HHT epistaxis

UC San Diego

≥18 years

NCT01397695 NCT01314274

HHT epistaxis HHT epistaxis

Medical University of Vienna

≥18 years ≥18 years

NCT01507480 NCT01290484

HHT epistaxis Lymphangioma

Phase 2 bevacizumab — submucosal: 100 mg per nostril Topical bevacizumab Phase 2 bevacizumab — submucosal vs placebo Phase 1 bevacizumab nasal spray Phase 1–2 sildenafil

Hospices Civils de Lyon Stanford

NCT01485224

Epistaxis HHT

Phase 2 — thalidomide

IRCCS Policlinico S. Matteo (Pavia)

2012). Bevacizumab also appears to have activity against vascular malignancies including epithelioid hemangioendotheliomas and angiosarcomas (Agulnik et al., 2013). Several tyrosine kinase inhibitors (including semaxanib, sunitinib, pazopanib), which like bevacizumab are small molecules, have had success in single cases or small series of adults with CNS hemangioblastomas (Capitanio et al., 2013; Kim et al., 2012). Another small molecule, infliximab, was used for its anti-TNF-α activity in a 21 year-old male with Crohn's disease and was found incidentally to treat his HHT-related epistaxis (Papa et al., 2010). Sirolimus (Rapamune®), or rapamycin, an inhibitor of mammalian target of Rapamycin (mTOR), has been used to treat hamartomas in patients with PTEN mutations (Marsh et al., 2008; Hammill et al., 2011; Iacobas et al., 2011) as well as vascular malformations including VM and LM (Hammill et al., 2011; Reinglas et al., 2011; Yuksekkaya et al., 2012). An ongoing single arm prospective trial at the Children's Hospitals in Cincinnati and Boston is recruiting patients with a range of vascular malformations (Hammill et al., 2011; Table 2). Sirolimus also has been effective based on a growing number of case reports for the management of hemangioendotheliomas with or without KMS (Blatt et al., 2010; Hammill et al., 2011). In vitro data support its potential for treatment of hemangiomas (Greenberger et al., 2011). A recent study reports that sirolimus may enhance the efficacy of laser treatment for the CM of Klippel Trenaunay Weber syndrome (Nelson et al., 2011). Sirolimus has been given orally at doses of 0.1 mg/kg/day divided every 12 h or 0.8 mg/m 2/dose, twice daily, titrated to reach serum trough levels of 5–15 ng/mL. The dose and targeted levels reflect experience with the drug in tuberous sclerosis and Proteus syndrome. Responses often occur slowly compared to those seen with propranolol in treating hemangiomas, and often are not noted for 2–9 months. Length of treatment is not defined, and lesions have regrown in several cases when drug was weaned after a year of successful treatment. Side effects are dose dependent and include mouth sores, diarrhea, peripheral edema, and respiratory distress. Anti-angiogenesis is one likely mechanism of action of these agents, as mTOR intersects with several angiogenesis pathways (Fig. 1). Apoptosis may be another yet unexplored mechanism of action in this setting, as endothelial cells of vascular malformations actually appear to disappear in some situations (Miyake et al., 2012). Tacrolimus and pimecrolimus are calcineuron inhibitors which are available in the US and Europe and which have been used topically to treat superficial vascular anomalies (Lazaridou et al., 2010). Like sirolimus, these agents are immune

≥18 years 6 months– 20 years ≥18 years

modulators. They are thought to act by blocking T-cell activation through VEGF-mediated pathways. Thalidomide has been shown to be effective in the treatment of gastrointestinal bleeding and epistaxis from telangiectasias, in patients with or without HHT (Ge et al., 2011; Franchini et al., 2013). A recent randomized trial demonstrated efficacy of thalidomide compared with iron therapy for patients with gastrointestinal vascular malformations (Franchini et al., 2013). During a 1-year follow-up, response rates (defined as a decrease in bleeding episodes of 50%) were 71% for thalidomide compared with 4% for the iron therapy arm. Thalidomide is thought to exert anti-angiogenic activity through inhibition of βFGF (D'Amato et al., 1994). It also is said to stimulate vessel maturation (Lebrin et al., 2010). The drug has been used in combination with interferon alpha in the management of diffuse hemangiomatosis (Adam et al., 2010) and with bevacizumab anecdotally in patients with HHT (Amanzada et al., 2010). Lenalidomide (Revlimid®), an analog of thalidomide, has been reported to be effective in single cases of GI bleeding in HHT (Bowcock & Patrick, 2009). Thalidomide and lenalidomide each has been used successfully to treat cases of epithelioid hemangioendothelioma (Sumrall et al., 2010; Salech et al., 2011). Both drugs are known teratogens. Other side effects include peripheral neuropathy, somnolence, thrombosis, and cytopenias. Dosing of lenalidomide in adults is 25–100 mg orally daily and responses have been noted within a month of starting. Phase I pilot data also suggest that tetracyclines such as doxycycline and minocycline, are reasonably well-tolerated, and may be effective in the management of vascular malformations (Frenzel et al., 2008). These are non-specific inhibitors of matrix metalloproteinases (MMPs). MMP-9 has been most consistently associated with vascular wall instability and hemorrhagic brain disorders, and it is hypothesized that doxycycline and minocycline may enhance vascular stability, thus reducing the risk of spontaneous hemorrhage in brain vascular malformations by decreasing MMP-9 activity. A placebocontrolled correlative study in which doxycycline in a dose of 100 mg orally twice a day was given to patients over 13 years of age with cerebral AVMs, cavernous angiomas, or aneurysms for two weeks pre-operatively and tumor tissue tested for MMP activity is listed in ClinicalTrials.gov (NCT00783523) with results pending. Side effects include tooth discoloration in children under 8 years, rashes and other allergic reactions, gastrointestinal distress. Marimastat, also a broad spectrum metalloproteinase inhibitor, was used for more than 10 years after compassionate release as an adjunct to embolization therapy in a single child with an AVM of the arm (Burrows et al., 2009). After 8 weeks of marimastat therapy, the patient no longer

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Fig. 1. Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Clin Oncol. Albini A, Tosetti F, Li VW, Noonan DM, Li WW. Cancer prevention by targeting angiogenesis. 9:498-509 (2012) http://www.nature.com/nrclinonc/. Angiogenesis signaling pathways. Many of these are known to be important in the pathogenesis of vascular anomalies. Some, but not all, of the agents shown in the figure already have been applied to treatment of one or more vascular anomalies.

required analgesia. Pain recurred with the interruption of drug administration and remained in good control with the reintroduction of the drug but without major change in the size of the lesion. It is of interest that imiquimod, a topical immune modifier which may have antiangiogenic properties via induction of tissue inhibitor of matrix metalloproteinase-1, has been reported to cause resolution of cutaneous hemangiomas (Barry et al., 2008), single cases of CM (Kouba et al., 2007) and epithelioid hemangioendotheliomas (Sanchez-Carpintero et al., 2006). Octreotide, a somatostatin analog, has been used in small series of patients with angiectasias (Brown et al., 2010), but without comparison to control or placebo therapy. Postulated mechanisms of action include inhibition of angiogenesis, decreased splanchnic blood flow, increased vascular resistance. Improved platelet aggregation may be contributory, since it has been shown that most patients with bleeding angiectasias have an acquired form of von Willebrand's disease. One 9 month-old girl with a microcystic LM of the neck and lungs was treated for pulmonary hypertension with sildenafil (Viagra®), a known inhibitor of phosphodiesterase-5 which is approved for the treatment of pulmonary hypertension in adults and is used off-label in children. She improved clinically, and within 4 months of starting treatment the LM had almost disappeared (Swetman et al., 2012). The same report describes two additional children with LM who had a partial response to 3 months of sildenafil with mild enlargement after discontinuation of the drug. A phase 1–2 clinical trial is underway at Stanford to expand upon these findings (Table 2). The natural history of a number of types of vascular anomalies has suggested a role for hormonal mediation. IH develops at a time when estrogen and other maternal hormones are in flux in babies, and resolve spontaneously over the first few years of life, possibly related to hormone withdrawal. Vascular malformations, present from birth, are

known to grow disproportionately at puberty. Estrogen and progesterone receptors have been documented on endothelium of IH (Liu et al., 1999) though not of vascular malformations (Kulungowski et al., 2012). A randomized double-blind placebo-controlled trial of the anti-estrogen tamoxifen in patients with HHT provided good evidence for the role of hormonal control of bleeding (Yaniv et al., 2009). Raloxifene, another anti-estrogen, has been used in an uncontrolled series of postmenopausal women with osteoporosis and HHT, and found to result in possible improvement of epistaxis (Albiñana et al., 2010). Whereas estrogen itself does not appear to be beneficial in HHT, the combination of estrogen and progesterone in a small but doubleblind placebo-controlled cross-over study has been found to be effective in men and women with that diagnosis (van Cutsem et al., 1990). Pamidronate, like Raloxifene, has been used to treat osteoporosis. Based on beneficial reports of pamidronate use for reflex sympathetic dystrophy in reduction of pain and swelling, that drug was used and found to demonstrate efficacy in a small single arm trial in patients with refractory lymphedema (Beigi et al., 2011). 4. Discussion 4.1. Diagnostic pitfalls and treatment Simplified terminology and classification have improved consistency in diagnosing vascular anomalies (Enjolras & Mulliken, 1997; Blei, 2013). Nonetheless, these remain heterogeneous groups of diseases and precision in diagnosis can be difficult. For example, a number of references in this review used the term “hemangioma” generically for lesions which, based on case descriptions, probably were hemangioendotheliomas. Hemangioendotheliomas as a group are heterogeneous and range from inflammatory lesions to low

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grade sarcomas. This is an important issue because the natural history, diagnosis-specific complications, as well as inheritance and how best to counsel family members vary considerably. Treatment also is partly diagnosis-specific, despite some overlap of efficacy for classes of anti-angiogenic agents. 4.2. Summary of findings Historically, medical management of vascular anomalies has been empiric. Vascular tumors variably respond to an armamentarium of drugs which included corticosteroids, conventional cytotoxics, and interferon (Buckmiller, 2004; Gottschling et al., 2006). In this review, we identified more than 20 agents which have been used more recently to treat vascular anomalies. These agents are therapeutically promiscuous, and appear to be able to treat several types of lesions which are distinct clinically and pathologically. Nonetheless, all vascular anomalies share a histopathology consisting of a single layer of endothelial cells surrounded by one or more layers of vascular smooth muscle cells or pericytes. Most defects leading to the development of these lesions appear to affect the endothelial cell. Most therapies have been linked to one or more angiogenic pathways which affect the endothelial cell, although the operative mechanisms of action have not always been clear. These include inhibition of VEGF, mTOR, MMP, tyrosine kinase, FGF, NF-κ, calcineuron, somatostatin, phosphodiesterase, PG, and sex steroid hormones. A growing understanding of the genetics of vascular anomalies is anticipated to result in the development of targeted therapies, as has been the case for cancers. Already, anecdotal reports and small series have demonstrated that drugs such as rapamycin with known molecular targets can improve or even completely reverse the phenotypic abnormalities of vascular malformations and vascular tumors. Our review did not include discussion of a long list of agents including tranexamic acid, aspirin and dipryidamole, desmopressin, or recombinant factor 7a, which are not thought to have a direct effect on vascular anomalies but which have been useful for supportive care to limit bleeding with or without consumption coagulopathy. We also did not include several complementary or “alternative” medicines, since their chemical composition is less well-described in Western literature. These include Kampo (a system of herbal combinations which are commercially available in Japan by prescription as different oral formulations (www.naturalstandard.com)) which reportedly has been effective in the treatment of a 2 year old boy with a lymphangioma (Ogawa-Ochiai et al., 2011); curcumin, which is available in the United States, and has been thought to cause resolution of an infantile hemangioendothelioma in a 6 month-old baby treated with 400 mg daily (Hassell & Roanh le, 2010); and tranilast, an inhibitor of TNF-β which like Kampo is commercially available in Japan and Korea, and has been associated with near-complete regression of a recurrent epithelioid hemangioma in one adult who simultaneously received indomethacin (Ogura et al., 2012). A role for benzopyrones (which include alpha-benzo-pyrones (coumarin derivatives), gamma-benzo-pyrones (flavones and flavonols such as diosmin and rutin), and flavanes (such as hesperidin)) in the treatment of lymphedema also has been suggested, though efficacy remains anecdotal (Badger et al., 2004). Such medications may deserve attention in the future. 4.3. Approach to new drug discovery That vascular anomalies are so rare likely will be a major factor in limiting new drug development for their treatment. The observant clinician and drug repurposing (the use of old drugs for new indications) have been powerful tools for identifying new treatments for vascular tumors. The applications of propranolol and sildenafil to the treatment of vascular anomalies are impressive examples of this approach. In these cases, drug repurposing relied on chance

observations in single patients with more than one diagnosis. Fortuitously, a drug known to be effective in treating one problem caused regression of the vascular anomaly. Recent preclinical work with retinoids, which are drugs used in the treatment of both solid tumors and leukemias, suggests that these may have repurposing potential for the treatment of lymphedema (Choi et al., 2012). Itraconazole, an antifungal agent, has demonstrated in vitro anti-VEGF receptor capabilities (Nacev et al., 2011) and therefore may have application to patients with vascular anomalies. Clinical trials to study these rare entities are beginning to emerge, and will be needed to prove the effectiveness of interventions which have shown promise in cases and small series. ClinicalTrials.gov and other on-line forums may be powerful tools in recruiting patients. However, they share the limitation of other websites in their need for ongoing updates. The need for a multidisciplinary approach to manage patients with hemangiomas and vascular malformations is clear. Many centers have organized multidisciplinary clinics (Mathes et al., 2004), inviting expertise in anesthesia, dermatology, dermatopathology, surgical, medical and pediatric subspecialties, diagnostic and vascular interventional radiology, rehabilitation medicine, cancer and vascular biology. 4.4. Conclusions With growing pharmacologic options and obvious parallels to cancer treatment and biology, the pediatric and adult hematologist–oncologist will have increasingly prominent roles in clinical care and research. Updates on medical management, supported by a more evidence-based literature, will be important. Financial support The authors received no financial support for the preparation of this manuscript. Conflict of interest The authors declare that there are no conflicts of interest. References Adam, Z., Pour, L., Krejcí, M., Pourová, E., Synek, O., Zahradová, L., et al. (2010). Successful treatment of angiomatosis with thalidomide and interferon alpha. A description of five cases and overview of treatment of angiomatosis and proliferating hemangiomas. Vnitr Lek 56, 810–823. Aguilera, D., Tomita, T., Goldman, S., & Fangusaro, J. (2010). Incidental resolution of a radiation-induced cavernous hemangioma of the brain following the use of bevacizumab in a child with recurrent medulloblastoma. Pediatr Neurosurg 46, 303–307. Agulnik, M., Yarber, J. L., Okuno, S. H., von Mehren, M., Jovanovic, B. D., Brockstein, B. E., et al. (2013). An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol 24, 257–263. Albiñana, V., Bernabeu-Herrero, M. E., Zarrabeitia, R., Bernabéu, C., & Botella, L. M. (2010). Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): effects of raloxifene on Endoglin and ALK1 expression in endothelial cells. Thromb Haemost 103, 525–534. Albiñana, V., Recio-Poveda, L., Zarrabeitia, R., Bernabéu, C., & Botella, L. M. (2012). Propranolol as antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia. Thromb Haemost 108, 41–53. Amanzada, A., Töppler, G. J., Cameron, S., Schwörer, H., & RamadorI, G. (2010). A case report of a patient with hereditary hemorrhagic telangiectasia treated successively with thalidomide and bevacizumab. Case Rep Oncol 3, 463–470. Annabel, M., Shanna, B., Gerard, L., Soizick, P. L., Denis, H., & Allan, E. (Sept 25). Lack of effect of propranolol in the treatment of lymphangioma in two children. Pediatr Dermatol, http://dx.doi.org/10.1111/j.1525-1470.2012.01864.x (Epub ahead of print).. Badger, C., Preston, N., Seers, K., & Mortimer, P. (2004). Benzo-pyrones for reducing and controlling lymphoedema of the limbs. Cochrane Database Syst Rev 2, CD003140. Barry, R. B., Hughes, B. R., & Cook, L. J. (2008). Involution of infantile haemangiomas after imiquimod 5% cream. Clin Exp Dermatol 33, 446–449. Beigi, A. A., Sadeghi, A. M., Masoudpour, H., Shirazinejad, S., & Mottaghi, P. (2011). Intravenous pamidronate for refractory lymphedema. Iran Red Crescent Med J 13, 263–266.

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