Anti-angiogenic therapy

On account of case study observations, accidentally discovered side effects, but also  fundamental pathophysiological considerations based mainly on recent genetic findings, new drug therapy modalities for patients with vascular anomalies are currently being tested clinically and in studies.

With the discovery of new somatic or germline mutations about 10 years ago, hyperactivation of two important intracellular signaling cascades was identified as the reason for the development of vascular malformations: the RAS/MAPK/ERK and/or the phosphatidylinositol-3-kinase (PIK3) /ACT / mammalian target of rapamycin (mTOR) signaling pathway.

Various targeted molecular inhibitors for these signaling cascades have been developed primarily in cancer therapy, since the same signaling cascades play a role in certain tumor types. In particular, the mTOR inhibitor sirolimus has been investigated in many studies for its efficacy in vascular anomalies with regard to clinical changes, quality of life and improvement of radiological findings. Similar drugs used in cancer therapy are currently being intensively investigated for their effectiveness in vascular anomalies.

However, none of the therapeutic approaches described here has yet become part of routine clinical practice.

None of the following drugs can therefore be used outside an individual therapeutic attemptwith an individual risk-benefit assessment at specialist centers and/or outside a study.

In addition, the actual efficacy or possible undesirable side effects have not yet been fully clarified.

None of the drugs listed here has marketing authorization or certification for the indication mentioned here.

Therefore it will only be possible for them to be administered in special cases by appropriately specialized and experienced physicians, mostly in the context of therapy studies, for which high requirements apply in terms of patient information and education as well as implementation and follow-up.

Thalidomide has a strong anti-angioneogenic effect. Among other things, a suppressive effect on vascular endothelial growth factor (VGEF) has been demonstrated.

A reduction in bleeding severity during epistaxis in patients with hereditary hemorrhagic teleangiectasia (HHT - Osler’s disease) has been published several times.

Several small series have also been published in which gastrointestinal bleeding caused by vascular malformations has been improved.

Combinations with interferon and zoledronate have been used in studies, but without a clear superiority of the additional medication. This is not recommended anymore.

There are no published results regarding the efficacy of thalidomide in slow-flow malformations (venous or lymphatic).

The high anti-angiogenic potential of thalidomide is currently being investigated in further studies in patients with severe complications from vascular malformations, mostly bleeding or rapid proliferation of arteriovenous malformations.

Serious side effects are known to exist:

• The known teratogenic effect.
• Up to 20% of patients develop peripheral neuropathy.
• According to personally communicated experiences, high doses of the drug can cause drug-induced psychiatric disorders, especially depression.

This points to a potential efficacy in very difficult cases, but serious side effects are also possible. Use of thalidomide in clinical routine is prohibited today.

Sirolimus (also called rapamycin) was originally developed as a macrolide antibiotic and then, after proof of an immunosuppressive and antiproliferative effect, was used in the prophylaxis of tissue rejection, especially after kidney transplantation. To this day, it is one of the standard combination drugs used for immunosuppressive therapy in kidney transplantation medicine.

However, sirolimus is also successfully applied as a surface-active coating on vascular stents and vascular dilatation balloons in order to prevent restenosis of the vessel after dilatation treatment by means of its local antiproliferative effect in the vessel wall.

The antiproliferative effect via inhibition of angioneogenesis has also been investigated in several studies with concomitant inhibition of the growth of certain tumors and metastases. This effect seems to be mediated via a change in the vascular endothelial growth factor (VGEF).

Positive reports of the use of sirolimus in individual case studies and smaller series of patients with extensive vascular malformations and corresponding severe clinical presentations have been published since 2011.

Sirolimus seems to be especially effective in the case of extensive, severe micro- or macrocystic lymphatic malformations.

There are also positive reports of the treatment of intraosseous lymphatic malformation in Gorham-Stout disease or generalized lymphatic anomaly. In the meantime, several publications report the use of sirolimus in kaposiform hemangioendothelioma with positive results so far. An international prospective multicenter phase II and phase III study has been initiated.

There are also publications on the use of sirolimus to reduce gastrointestinal bleeding in venous malformation of the intestinal mucosa, especially in blue rubber bleb nevus syndrome. Reductions of the volume of the lesions have also been reported in this situation.

A questionable effect or no effect in reducing bleeding frequency and proliferation activity in severe, complicated arteriovenous malformations has also been reported. The treatment outcome in fast-flow malformations appears to be significantly smaller and could not be demonstrated in all studies. The reason for this may lie in the genetic basis of arteriovenous malformations where dysregulation of another signaling pathway (RAS/MAPK/ERK signaling cascade) seems to be affected. By contrast, in slow-flow malformations upregulation of the PIK3CA/AKT signaling pathway is causative in the development of vascular anomalies. Sirolimus (rapamycin) is a central inhibitor of this mammalian target of rapamycin (mTOR) pathway, which may explain its effect.

However, sirolimus also has potentially severe, undesirable side effects. Its use in individual cases at appropriately experienced centers and/or outside studies is therefore not advisable today. Furthermore, it takes a lot of experience to adjust for the ideal therapeutic blood level of sirolimus.

The most important side effect is the dose-dependent immunosuppressive effect. This effect also leads to the primary application of sirolimus in transplantation medicine. In practice, there is a dose-dependent tendency to more frequent and more severe infections, especially pneumonia and urinary tract infections. More common side effects are aphthae, i.e., inflammatory mucous membrane lesions of the oral mucosa. The skin can become impure on the face and some patients develop acne.

Gastrointestinal side effects are also relatively common, and these usually subside after several weeks.

The number of red and white blood cells can decrease significantly, even dangerously so. Therefore, appropriate laboratory tests (incl. liver, kidney, blood lipids) are regularly required.

In the long term, there is also the possibility of tumor induction. Patients of reproductive age must therefore practice reliable contraception.

Sildenafil, a phosphodiesterase inhibitor used in the treatment of pulmonary arterial hypertension, among other things, and which has vasodilatory effects, is said to have a positive effect on lymphatic malformations according to case reports. The underlying pathophysiological mechanism is unclear and the vasodilatory effect proposed in the publications is implausible. Lymphatic malformations, in particular, do not have smooth muscle cells in their walls and therefore cannot dilate after drug administration. These effects of sildenafil have not been confirmed in systematic applications.

A positive effect in the sense of a reduction of chronic bleeding in vascular anomalies of the gastrointestinal tract by the somatostatin analogue octreotide was reported and an anti-angioneogenic potential was proposed. However, the same effect could also be caused by a general reduction in intestinal blood flow. Octreotide is used in this indication, e.g., for ascites in the presence of portal venous hypertension in liver cirrhosis.

Based on the well-known observation that epistaxis bleeding episodes in patients with hereditary hemorrhagic teleangiectasia sometimes improve during pregnancy and worsen after menopause, a possible role has been postulated for progesterone and estrogen in reducing chronic gastrointestinal bleeding from intestinal angiodysplasias in HHT - Osler’s disease. Unfortunately, a prospective multicenter randomized trial could not confirm this effect.

Bevacizumab, an antibody directed against vascular endothelial growth factor, has anti-angioneogenic activity and, when injected systemically or locally, has been shown to reduce bleeding episodes in patients with hereditary hemorrhagic teleangiectasia (Osler’s disease) in severe epistaxis. An improvement up to 12 months has been repeatedly published. However, there are potentially serious side effects, especially bleeding, impaired wound healing, gastrointestinal side effects through to perforation, cardiac insufficiency, proteinuria, thromboembolism, etc.

Gene-specific or mutation-specific drug therapy options, developed in tumor therapy, are being discussed after decoding of the genetic basis of vascular anomalies. They have already been used on a case study basis as proof-of-principle. In particular, inhibitors of the PIK3CA/AKT/mTOR and the RAS/MAP kinase signaling pathways have to be mentioned. Substances such as trametinib, selumetinib, infliximab and MEK162 are undergoing intensive scientific testing.

The direct PIK3CA inhibitor alpelisib, which has already been investigated in tumor therapy for breast cancer, is currently being tested in prospective studies on vascular malformations with  confirmed PIK3CA mutation and PROS.