Electrochemotherapy in Breast Cancer: a Review of References Elektrochemotherapie Beim Mammakarzinom: Eine Literaturübersicht
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DGGG Review 557 Electrochemotherapy in Breast Cancer: A Review of References Elektrochemotherapie beim Mammakarzinom: eine Literaturübersicht Authors G. Schmidt, I. Juhasz-Böss, E.-F. Solomayer, D. Herr Affiliation Uniklinik Homburg, Homburg Key words Abstract Zusammenfassung l" breast cancer ! ! l" metastasis Electrochemotherapy is a new method for the lo- Die Elektrochemotherapie ist eine neue Methode l" mammary cal treatment of cutaneous and subcutaneous me- zur lokalen Behandlung von kutanen und sub- Schlüsselwörter tastases. If surgery and/or radiotherapy are no kutanen Metastasen. Sind Operation und/oder l" Mammakarzinom longer possible, this innovative technology can Radiatio nicht mehr möglich, so kann diese inno- l" Metastasierung be used effectively for local tumour control. The vative Technik effektiv zur lokalen Tumorkontrol- l" Mamma minor side effects of the therapy and the low in- le eingesetzt werden. Die geringen Nebenwirkun- traoperative duration of treatment make it possi- gen der Therapie und die geringe intraoperative ble to admit patients to hospital for just a short Behandlungsdauer machen eine kurze Hospitali- time. Thus, the repeated use of electrochemother- sation möglich. Durch wiederholten Einsatz der apy has allowed for an increase in the rate of com- Elektrochemotherapie kann dabei die Rate an Deutschsprachige plete remissions. In fact, in 2013, this form of Komplettremissionen erhöht werden, sodass Zusatzinformationen treatment, which consists of a low-dose cytostatic 2013 diese aus einem niedrig dosiertem Zytosta- online abrufbar unter: and electroporation, was also included in the tikum und Elektroporation bestehende Therapie- www.thieme-connect.de/ mammary guidelines of the Working Group for form auch in die Mamma-Leitlinien der AGO/DKG ejournals/toc/gebfra Gynaecological Oncology (AGO) and the German aufgenommen wurde. Die günstige Kosten-Nut- Cancer Society (DKG). The favourable cost-benefit zen-Relation macht dieses Behandlungsverfahren ratio makes this method of treatment very inter- in der klinischen Praxis sehr interessant, sodass es esting in clinical practice and, as a result, it is al- bereits erfolgreich in zahlreichen deutschen Kli- ready being used successfully in many German niken eingesetzt wird. hospitals. Fundamentals and Technical Require- sults in changes in the structure of the mem- ments of Electrochemotherapy brane. This can cause small “pores” in the mem- ! brane, which in turn make the membrane perme- Electrochemotherapy is a combination of electro- able to molecules which would otherwise be un- received 23.2.2014 poration and low-dose chemotherapy. The first able to penetrate it. In this way, the increased per- revised 24.3.2014 clinical (phase I/II) studies were already being meability can allow cytostatic agents to cross the accepted 25.4.2014 carried out at the beginning of the 1990s [1]. Thus cell membrane and then enter into the cytosol by Bibliography far, this innovative technology has established it- diffusion. The increased permeability also allows DOI http://dx.doi.org/ self mainly in the dermatological field. New study the cytostatic to reach the cytosol at much higher 10.1055/s-0034-1368538 results, however, have been able to prove the concentrations, leading to increased cytotoxicity Geburtsh Frauenheilk 2014; 74: 557–562 © Georg Thieme treatmentʼs high degree of effectiveness when [2]. As electroporation is limited to the tumour- Verlag KG Stuttgart · New York · used for gynaecological tumours, with electro- affected area, there is no increase in systemic tox- ISSN 0016‑5751 chemotherapy now being increasingly employed icity caused by the chemotherapeutic agent, re- Correspondence in the field of gynaecology as a result. sulting in the good tolerability of this method. Dr. Gilda Schmidt Electrochemotherapy utilises the phenomenon of The permeability of the cell membrane, however, Uniklinik Homburg electroporation. By applying an external electric does not persist for an unlimited period, and is Kirrbergerstraße100 66421 Homburg field, the membrane potential of the cell can be suspended once again a few minutes after the [email protected] changed. At a sufficiently high intensity, this re- electrical impulse (l" Fig. 1) [3]. Schmidt G et al. Electrochemotherapy in Breast… Geburtsh Frauenheilk 2014; 74: 557–562 558 GebFra Science Fig. 1 Schematic representation of electroche- motherapy: Phase 1: Injection of the cytostatic: bleomycin (i.v./intratumoural) or cisplatin (intra- tumoural); Phase 2: high-frequency electroporation results in a permeable cell membrane and the cyto- static agent reaches up to 10000 times higher con- centrations in the tumour cell; Phase 3: reversible poration, the cell membrane closes and the cyto- static drug accumulates in the tumour cell (courtesy of IGEA, Carpi, Italy). Phase 1 Phase 2 Phase 3 in minutes 030 Practical Implementation and Technical Requirements fects [6]. Cytotoxic agents can be administered both intravenous- ! ly and intratumourally [3]. With respect to response rates, there Electrochemotherapy is performed using an electrical impulse was no significant difference found between intratumoural and generator, the Cliniporator™ (IGEA, Carpi, Italy). The device is intravenous administration of cisplatin and bleomycin (l" Fig. 3). shown in l" Fig. 1 and consists of a console unit, a power supply unit for supplying the current and an applicator for placement Bleomycin on the skin. The Cliniporator™ allows for electroporation by Bleomycin is an anti-cancer antibiotic from the group of glyco- means of the generation of an electrical low and an electrical high peptides with minimal myelotoxic effect [7]. In the case of bleo- voltage impulse, which are applied to the tumour cells using spe- mycin, it is important to note that it is primarily excreted renally, cific electrodes. This makes possible the transfer of intracellular and that it is rendered inactive by the enzyme bleomycin hydro- substances or molecules which would not normally be able to lase. This enzyme is present in all cells of the human body, how- pass through the cell membrane. The emitted impulse lasts ever the concentration of the enzyme is reduced in skin cells and 100 µs. The number of impulses varies between 1–20 and their in alveolar epithelial cells in the lung. amplitude between 100–1000 volts. The frequency used is be- The administration of bleomycin can cause subacute or chronic tween 1–5000 Hz. During implementation, both the applied volt- interstitial plasmacytic pneumonia, which can also lead to inter- age and the corresponding current curve are shown on the dis- stitial fibrosis in the worst case. Pulmonary toxicity is reported in play in real-time, thus allowing for the effectiveness of each indi- approximately 10% of patients and approximately 1% of patients vidual electroporation to be seen on the monitor. develop a pulmonary fibrosis from the bleomycin-induced non- Prior to the start of the impulse generation, a low-dose cytostatic specific pneumonitis; this can also be fatal in the worst case [8]. – usually bleomycin at a dosage of 15 mg/m2 – is administered in- Risk factors that promote pulmonary fibrosis include advanced travenously over one minute. Following a recommended time in- age, pre-existing pulmonary disease, smoking, renal insuffi- terval of 8 minutes, the administration of the electrical impulses ciency, previous radiotherapy of the lung, increased oxygen con- begins. Special electrodes are used to generate an electrical field centration in the air inhaled, etc. [9] (bleomycin drug information around the tumour. The cell membrane then opens and the cyto- sheet). static agent is able to accumulate in the cell at a high concentra- A connection has been established between bleomycin adminis- tion. Different needle electrodes and plate electrodes are used tration and pulmonary toxicity. Therefore, a bleomycin dose of depending on the size, depth and shape of the tumour (l" Fig. 2) 400 IU/m2 should not be exceeded. [3]. The procedure is performed under local anaesthesia, regional It is also important that 2⁄3 of the bleomycin dose administered is anaesthesia or general anaesthesia, depending on the location of excreted unchanged in the patientʼs urine. In conclusion, patients the tumour. In the case of large surfaces, painful muscle contrac- with impaired renal function have greatly increased plasma con- tions are to be expected: as a result, it is wise to carry out the pro- centrations when standard doses are administered. Therefore, cedure under general anaesthesia. The best results are obtained patients with moderately reduced renal function (glomerular fil- when the impulse is applied within 25 minutes following admin- tration rate [GFR] 10–50 ml/minute) should receive only 75% of istration of the chemotherapeutic agent [3–5]. the usual dose at normal dose intervals, while patients with se- vere renal impairment (GFR < 10 ml/minute) should receive 50% of the usual dose at normal dose intervals. No dosage adjustment Cytotoxic Agents Used is necessary in patients with a GFR > 50 ml/minute (bleomycin ! drug information sheet). Several cytotoxic agents have been tested in preclinical studies An overdose can cause hypotension, fever, an increase in pulse, (e.g. doxorubicin, daunorubicin, paclitaxel, etoposide, bleomycin difficulty breathing and general symptoms of shock. It is impor- and cisplatin, etc.). In principle, following electroporation, the tant to note that there is no specific antidote and that bleomycin anti-tumour