Bleomycin ElectroScleroTherapy (BEST)

Sclerotherapy of slow-flow malformations (venous, capillary and lymphatic) is under constant development, as it is safe but limited in its effectiveness. Standard sclerotherapy often requires several treatment sessions. In early studies and initial clinical application, reversible electroporation was introduced as a new development in sclerotherapy of slow-flow malformations. This completely new procedure will be briefly described here.

Reversible electroporation involves delivering multiple, short (approx. 100 µs) and strong current surges (up to 1,000 V/cm) to the target tissue via thin needles. This temporarily makes cell membranes more permeable to certain charged molecules, e.g. the sclerosing agent bleomycin. The aim is to increase considerably the intracellular concentration of bleomycin and thus its effect in the target tissue, while at the same time reducing systemic side effects due to the lower overall dose required. The procedure has long been familiar from the therapy of skin tumors and was first used for vascular malformations in 2017. Early anecdotal reports showed that the use of bleomycin in combination with reversible electroporation might increase the sclerosing effect. This even occurred with a dosage of 25% compared to standard bleomycin sclerotherapy. This effect is achieved by a reversible (approx. 45 to 60 min) local increase of cell membrane porosity, resulting in an increased intracellular bleomycin concentration in the pathological vascular endothelia of the vascular malformation. There are currently no substantial study results available regarding bleomycin electrosclerotherapy (BEST), so that the procedure still needs to be evaluated in terms of its effectiveness and safety.

The most important mechanism of action is to enhance the cytotoxic effect at the intracellular level by increasing the intracellular concentration of the delivered drug. In view of their different molecular structure, electrochemical charge properties, as well as pharmacokinetic and pharmacodynamic properties, not all drugs are equally well suited for this purpose. However, bleomycin has proven particularly suitable in this situation.

Another important effect results from pronounced vasoconstriction in the treated tissue after electroporation. This temporary vascular constriction, also known as the “vascular lock effect”, sets in almost immediately and appears to be mediated by stimulation of the sympathetic autonomic nervous system at the precapillary level.

In addition, there is a direct vascular damaging effect on vessels smaller than 5 mm, which happens slightly later and is mediated by evidently greater sensitivity of vascular endothelia to the current impulses. These vascular effects are also used to prolong the contact time of bleomycin with the lesion (less wash-out) and possibly stop malformation-related or puncture-related vascular bleeding during and after the intervention.

Bleomycin, which was originally developed as an antibiotic in the 1960s, leads to cell proliferation arrest in the G2/M phase at low intercellular concentrations and to programmed cell death (apoptosis) at higher concentrations. It is only with high intracellular bleomycin concentrations that necrosis finally occurs as a result of direct destruction of the DNA. It is comparatively inexpensive, has been tried and tested for a long time and is included in the WHO list of essential tumor drugs. Furthermore, bleomycin is currently the world’s most commonly used agent for the sclerosing treatment of slow-flow vascular malformations.

Animal experiments showed that the simultaneous application of reversible electroporation increases the intracellular bleomycin concentration by up to > 700 times. The plasma half-life of bleomycin is about 3 to 4 hours, and it is mainly excreted via the kidneys. Therefore the dose should be reduced in case of renal insufficiency. Possible side effects are allergies and a mild immune reaction with fever. In higher concentrations from approx. 150,000 to 200,000 IU, it can cause skin and mucous membrane reactions with stomatitis and ulcer, hair loss, as well as a reduction in cell count. The skin may become discolored (hyperpigmentation), itchy and blistered, and even form wounds. The most feared side effect is interstitial pneumonitis, which is very rare and limits the cumulative dose (no more than 400,000 IU in people under 60). This dose, however, is generally not even close to being reached with reversible electroporation.

In the largest prospective observational study on the treatment of superficial skin tumors with bleomycin-assisted reversible electroporation (n = 376 patients), G3 skin reactions such as hyperpigmentation, redness through to skin ulcers were found in 7.8% of patients. These were treatable on an outpatient basis. The skin ulcerations healed over 6 to 10 weeks.

Before electroporation, bleomycin must reach the vascular malformation. A distinction must be made here between the simpler, systemic administration of bleomycin, in which the drug is administered intravenously and is thus distributed in lower concentrations in the lesion, and direct local intralesional application. In the case of intralesional injection, the malformation to be treated is located, by ultrasound guidance in the case of deeper lesions, and bleomycin is injected directly.

For the subsequent reversible electroporation, there is a variety of different needle geometries and applicators available to suit the particular patient. Electrodes can be selected according to the size, type, location, extent and accessibility of the individual lesion. The thin needles are then inserted into the target lesion under ultrasound guidance, sometimes also under fluoroscopy, and connected to the pulse generator. The exact needle geometry of the specific applicator then determines not only  conductivity measurements in the lesion but also the final impulse protocol to be employed. The applied pulses are adapted to the specific malformation in the individual patient and its tissue characteristics.

In summary, reversible electroporation in combination with bleomycin (bleomycin electrosclerotherapy; BEST) seems to increase local efficacy while reducing the total concentration of the sclerosing agent required. According to initial findings, this selective effect known from tumor therapy is able to increase local effectiveness and at the same time reduce side effects in the body. In addition to established indications, especially in the treatment of skin tumors, new and promising indications are emerging with the treatment of vascular malformations.