It is a paradox that general improvement of cancer treatment today is both leading to prolonged survival of cancer patients and to an increased number of patients who live long enough to develop brain metastases. The risk of developing brain metastases increases in breast cancer patients, when there are metastases to the liver, lungs and lymph nodes (Ryberg et al. 2005), i.e. with the advancing stage of the cancer. The treatment of brain metastases are, for single or a limited number of metastases, surgery or stereotactic radiosurgery. For multiple brain metastases the evidence based treatment is whole brain radiation therapy (WBRT) and in some cases systemic chemotherapy or other anti-cancer drugs. Still, the overall prognosis is poor with a reported median survival of 10–12 months after treatment with surgery or stereotactic radiosurgery and a reported median survival of 4–6 months after WBRT (Videtic et al. 2009).

The patient’s quality of life is related to their neurocognitive function, which is the ability to do daily activities (ADL), such as recognizing safe and unsafe behavior, memory, and compliance with medical treatments. It has been established, that tumor regression of brain metastases after whole brain radiation therapy (WBRT) is correlated with an increased survival and preservation of neurocognitive function (Li et al. 2007). Another study concluded that the tumor volume before treatment was the only predictor of decreased neurocognitive function (Meyers et al. 2004). Some patients have a better prognosis than others, and several positive prognostic factors have been found, including good performance status, age > 60 years; less than three brain metastases and no extracranial metastases (Sperduto et al. 2008). Some cancer histologies also have a better prognosis, for example, in a study of 43 patients with metastatic breast cancer the median survival was 23 months after the diagnosis of brain metastases (Gori et al. 2007). Still, the effect of the available treatments is limited, and when the brain metastases progresses after whole brain radiation therapy, there are no additional standard treatments left to offer for a large number of the patients.

The role of re-irradiation of the whole brain for recurrent/progressive brain metastases is controversial, mainly due to the data on the subject being retrospective and published over a large number of years while the oncological treatments have evolved. These studies of re-irradiation of the brain may therefore have underestimated the toxicity of the treatment and treated different types of patients, with respect to disease status and performance status, which is known to influence patient survival. Response to treatment and median survival differ among the studies, probably reflecting both the difference in radiation doses, patient characteristics and period of time, respectively (AbdelWahab et al. 1997; Cooper et al. 1990; Hazuka and Kinzie 1988; Kurup et al. 1980; Sadikov et al. 2007; Shehata et al. 1974; Wong et al. 1996). The most recent studies indicate that a majority of the patients may benefit from re-irradiation of the brain in the form of complete or partial resolution of symptoms (Cooper et al. 1990; Sadikov et al. 2007; Wong et al. 1996). Opposed to these results is Hazuka et al.’s cohort treated from 1975–1986, where over half the patients failed to respond or deteriorated and 2 patients died from brain necrosis, possibly as a direct consequence of the re-treatment (Hazuka and Kinzie 1988).

Previously, cancer patients died of general disease progression, but today it is not uncommon that the only site of progression is the brain, while the cancer elsewhere in the body is controlled. For example, in the previously mentioned study of 43 breast cancer patients, 60 % of the patients only had disease progression in the brain (Gori et al. 2007). It is therefore increasingly important to prevent brain metastases and explore better treatment options for these patients.

Electroporation (sometimes referred to as electropermeabilization) is basically a technique used to transfer exogenous molecules into cells, by applying a voltage difference across the target tissue. The technique stems from observations made in the 1960s and 1970s showing that cell membranes are made transiently more permeable by the action of voltage pulses thus allowing diffusion of hydrophilic molecules and ions from the extracellular space to the cell cytosol and eventually to the cell nucleus (Gehl 2003). With electroporation a substantial enhancement of transport across cellular membranes can be achieved for certain molecules.

The chemotherapeutic drug of choice in the performance of electrochemotherapy is in our opinion bleomycin. Other chemotherapeutic drugs have been tested regarding the magnitude of enhancement of the cytotoxicity when using electroporation. When testing drugs commonly used in the clinical setting, results show an increase of cytotoxicity by a factor 300–700 for bleomycin (Gehl et al. 1998; Orlowski et al. 1988), a factor 3 and 2.3 for carboplatin and cisplatin, and for the drugs daunorubicin, doxorubicin, etoposide, and paclitaxel no effect of electroporation was found (Gehl et al. 1998). In concordance with this, other results show an enhancement of the cytotoxicity of bleomycin by a factor 5,000, and confirmed a much more limited effect of electroporation when using the drugs carboplatin and cisplatin (Jaroszeski et al. 2000). The next paragraph will clarify the nature of bleomycin, and explain additional reasons why we prefer this drug to others for electrochemotherapy.