Treatment of Low-flow Vascular Malformations With Bleomycin Electrosclerotherapy (BEST)

Vascular malformations are rare conditions caused by abnormally developed blood vessels. They can occur anywhere in the body and range from simple and benign lesions to complex conditions.

The latest and most commonly used categorization is the International Society for the Study of Vascular Anomalies (ISSVA) classification. This classification divides vascular anomalies into two main categories: tumors, defined as true proliferative neoplasms, and malformations, defined as morphogenetic defects. These two categories are further subcategorized: tumors are divided into benign, locally aggressive/borderline, and malignant tumors, whereas malformations are subdivided into simple, combined, or associated with other anomalies. Clinically, vascular anomalies can also be divided into low-flow and high-flow malformations.

Current treatment of vascular malformations varies depending on the type and anatomical location of the vascular malformation. Treatment options include observation, sclerotherapy, laser therapy, embolization, and surgery. Sclerotherapy involves the injection of sclerosing agents, such as bleomycin, pingyangmycin, absolute ethanol, ethanolamine oleate, polidocanol, doxycycline, cyanoacrylate, sodium morrhuate, and sodium tetradecyl sulfate (STS).

Current treatment options for low-flow vascular malformations remain suboptimal. Current therapies demonstrate limited clinical efficacy. Ethanol is widely used as a sclerosing agent and can induce substantial lesion regression; however, its clinical utility is limited by considerable safety concerns. In particular, ethanol may induce extensive tissue necrosis and damage to surrounding healthy structures, which limits its therapeutic use.

Another agent frequently employed for sclerotherapy is bleomycin. However, when administered as monotherapy, without the use of electroporation, bleomycin often shows insufficient therapeutic effectiveness. In many cases, treatment results only in minor reduction of lesion volume and fails to adequately alleviate patient-reported symptoms, including pain and functional discomfort.

Electrochemotherapy is a local ablative treatment in which electroporation is used to enhance the delivery of cytotoxic molecules, such as bleomycin or cisplatin, to treat cancer. The cytotoxicity of the drug is increased only at the site of electrical pulse application. This approach is often used to treat both skin tumors and deep-seated tumors, such as liver and pancreatic tumors. Several types of electrodes have been designed to optimize the delivery of electrical pulses to specific anatomical sites. The efficacy of electrochemotherapy ranges from 70% to 80%. Electrochemotherapy is included in many national and international guidelines as a local ablative therapy and is practiced in more than 200 centers throughout Europe.

There are three underlying mechanisms of electrochemotherapy. The first is enhanced drug delivery to tumor cells, which die due to the cytotoxicity of the drugs, either by apoptosis or necrosis. This is predominantly related to the drug used and its mode of action. Bleomycin, for example, induces mitotic cell death, which leads to slow resolution of the tumor mass.

The second mechanism is the induction of an immune response due to immunogenic tumor cell death induced by the drug. It is well established that certain ablative therapies induce immunogenic cell death that can attract and enhance the immune response of the organism.

The third mechanism is the vascular disrupting effect of electrochemotherapy. In early preclinical research, it was established that the application of electrical pulses only temporarily abrogates blood flow within tumors. This phenomenon was termed vascular lock and lasts less than an hour. Furthermore, the effect is enhanced when the drug is present during the application of electrical pulses. Investigations have shown that this results in vascular disruption that occurs within hours in tumors. Endothelial cells start to die, blood flow is obstructed, and secondary tumor cell death is induced within days due to tumor hypoxia.

The phenomenon is predominantly confined to the tumor vasculature, sparing the normal vasculature around the tumors. This is because of the high proliferation rate of endothelial cells in tumors compared with the vasculature in normal tissues, where the endothelial proliferation rate is very slow. The vascular disrupting effect of electrochemotherapy is not fully understood. To date, the proportion by which this vascular disrupting effect contributes to the overall effectiveness of electrochemotherapy in specific tumor types is not fully understood. The effect appears to depend on the distribution and extent of tumor vascularization, with better vascularized tumors generally responding better to electrochemotherapy.