Cancer Treatment Reviews 38 (2012) 379–386

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Cancer Treatment Reviews

journal homepage: www.elsevierheal th.com/ journals /c t rv

Antitumour Treatment

Electrochemotherapy of chest wall breast cancer recurrence

Gregor Sersa a,⇑, Tanja Cufer b, Snezna Marija Paulin a,c, Maja Cemazar a,d, Marko Snoj a,e

a Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Sloveniab University Clinic Golnik, SI-4204 Golnik, Slovenia

a r t i c l e i n f o

Article history:Received 2 May 2011Received in revised form 12 July 2011Accepted 25 July 2011

Keywords:ElectrochemotherapyBreast cancerChest wall recurrence

0305-7372/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.ctrv.2011.07.006

⇑ Corresponding author. Tel./fax: +386 1 5879 434.E-mail addresses: gsersa@onko-i.si (Gregor Sersa),

(T. Cufer), skosir@onko-i.si (S.M. Paulin), mcemazmsnoj@onko-i.si (M. Snoj).

c Tel.: +386 1 5879 501; fax: +386 1 5879 434.d Tel.: +386 1 5879 544; fax: +386 1 5879 434.e Tel.: +386 1 5879 110; fax: +386 1 5879 434.

a b s t r a c t

Chest wall breast cancer recurrence after mastectomy is a disease difficult to treat. Its incidence variesbetween 5% and 30% in different subset of patients. When possible, radical surgical therapy representsthe main treatment approach, however when the disease progresses and/or treatments are not success-ful, ulceration, bleeding, lymphedema and psychological distress of progressive disease significantlydecrease the quality of the remaining life of a patient. When surgical excision of chest wall recurrenceis not possible, other local treatments such as radiotherapy, radiotherapy with hyperthermia, topical che-motherapy and electrochemotherapy might be taken into account. Electrochemotherapy provides safe,efficient and non-invasive locoregional treatment approach for chest wall breast cancer recurrence. Sev-eral clinical studies have demonstrated high efficacy and a good safety profile of electrochemotherapyapplied in single or multiple consecutive sessions, till clinical response was reached. Electrochemother-apy can be performed either with cisplatin injected intratumorally or with bleomycin given intratumor-ally or intravenously. Furthermore, it can be effectively used in heavily pre-treated areas, after surgery,radiotherapy or systemic chemotherapy. These are the advantages that might demand its use especiallyin patients with pre-treated extensive disease and in frail elderly patients. With development of the tech-nology electrochemotherapy could even be suggested as a primary local therapy in patients not suitablefor surgical removal of the primary tumor.

� 2011 Elsevier Ltd. All rights reserved.

Introduction

Even though breast cancer became a highly curable disease dur-ing the last decade, around 30% of patients still experience localrecurrence of the disease. Breast cancer may recur locally as anisolated event or concomitantly with systemic spread of disease. Iso-lated local recurrences after breast conserving therapy are highlycurable by salvage mastectomy. On the other hand, local recurrencesafter mastectomy might present as a first sign of widespread meta-static disease. In this scenario palliation of symptoms, also the localones, represents one of the main goals of the therapy.1

Chest wall breast cancer recurrence (CWR) after mastectomy isa disease difficult to treat. Its incidence varies between in 5% and30% different subset of patients.2–5 The condition usually presentsitself in a form of multiple cutaneous and subcutaneous tumornodules, so called skin metastases. Recurrences invading deeper

ll rights reserved.

tanja.cufer@klinika-golnik.siar@onko-i.si (M. Cemazar),

chest wall structures are much less frequent. A number of factors,including tumor size, nodal status, tumor grade, lymphovascularinvasion and tumor grade predispose to the development of CWRafter mastectomy.6 It has been acknowledged that postmastec-tomy radiotherapy greatly reduces CWR, moreover some studiesshowed survival benefit when postmastectomy radiotherapy wasapplied in larger tumors and axillary lymph node involvement.3,4

In spite of general opinion, CWR does not always bear a badprognosis, especially in absence of overt metastatic disease andwhen radical surgical treatment is possible.7 However when dis-ease progresses untreated, ulceration, bleeding, lymphedema andpsychological distress of progressive visible disease significantlydecrease the quality of life of a patient. Many factors as initial no-dal status, time of development of CWR after mastectomy, numberof nodules in CWR and size of CWR were associated with survivalafter the treatment of CWR, when CWR was initially isolatedevent.7

Many different treatment options for isolated CWR exist atpresent time. The best treatment option is surgical excision, how-ever it is seldom possible, sometimes the resection must encom-pass full thickness of thoracic wall and poor skin condition mayhamper surgical intervention.7 Surgical treatment was found tobe associated with a good prognosis when there is no systemic dis-semination of the disease, when CWR develops more than

380 Gregor Sersa et al. / Cancer Treatment Reviews 38 (2012) 379–386

24 months after mastectomy and patients are initially node nega-tive.8 Surgical excision might be followed by radiotherapy (RT)and systemic treatment. There is a role of systemic therapy inaddition to surgical excision of CWR in case of widespread meta-static disease, however the role of so called adjuvant systemic ther-apy after radical local treatment of loco-regional relapse has onlybeen investigated in small nonrandomized trials, with the datasuggesting its possible beneficial effect. The beneficial effect of che-motherapy after locoregional treatment for isolated locoregionalrecurrence is still an open question being currently investigatedin a joint study by the International Breast Cancer Study Group(IBSCG) and the National Surgical Adjuvant Breast and Bowel Pro-ject (NSABP), under the umbrella of the Breast International Group(BIG).

When surgical excision of CWR is not possible, radiotherapy,9

radiotherapy with hyperthermia,10 topical chemotherapy11 andelectrochemotherapy might be taken into account. Radiotherapycan only be applied if the area has not been previously irradiated.Topical chemotherapy with miltefosine represents another viableoption in the treatment of skin metastases associated with breastcancer. In a randomized, placebo-controlled trial the objective re-sponse rate in the miltefosine arm was 33%, compared to 4% inthe placebo arm. The most frequent side effect was skin toxicity,with grade 3 and grade 4 cutaneous reactions observed in 33.4%of patients.11 Electrochemotherapy is an excellent therapy fortreatment of CWR presenting as cutaneous and subcutaneous nod-ules which cannot be surgically removed or in case when irradia-tion is not possible or is unsuccessful.

In the present paper we will review a clinical experience oftreating the breast cancer CWR with electrochemotherapy. We willpresent an evidence of treatment with electrochemotherapy,which shows that it is effective, might be repeated several timesuntil a positive clinical response is reached, might be used in pre-treated area and is not invasive. These are the advantages thatmight demand its use especially in frail patients or patients withextensive disease.

What is electrochemotherapy?

Principles of action

Electrochemotherapy is nonthermal tumor ablation modalitythat is currently used for effective treatment of cutaneous andsubcutaneous tumor nodules of various malignancies.12–15 Theprinciple of the method is the application of electric currents (elec-tric pulses) to the tumors, in order to transiently permeabilize theplasma membrane of the cells in tumor tissues and thus facilitatetransport of the chemotherapeutics into the cells.16,17 Specifically,bleomycin and cisplatin have been proven to be the most suitablechemotherapeutics; their cytotoxicity was demonstrated to bepotentiated several 1000-fold and up to 80-fold, respectively.18–22

This therapeutic approach was extensively elaborated on differentlaboratory animal tumor types and good clinical results were alsoobtained in veterinary oncology in cats, dogs, and horses.17,23

Electrochemotherapy has predominantly a potentiating cytotoxiceffect on tumor cells in the tumor tissue that is electropermeabi-lized by application of electric pulses to the tumors.24,25 However,drug entrapment in the tumor tissue occurs due to the vascular lockthat is induced by the electric pulses, enabling prolonged exposureof cells to the chemotherapeutic used.26,27 Furthermore, electroche-motherapy also has a supplementary vascular-disrupting effectthat is due to the electroporative effect of electric pulses on endo-thelial cells and their apoptosis after drug exposure.28,29 Animmune response is also involved, as massive destruction of tumorcells may release tumor antigens systemically, which in turn can

elicit an immune response that can contribute to the overall treat-ment response of electrochemotherapy.30,31 All these mechanismssignificantly contribute to the overall treatment response of thetumors to electrochemotherapy.14,17,32

How to perform electrochemotherapy

The basic principle for effective treatment with electrochemo-therapy is that the pharmacological peak of the injected drug isreached in the treated tumors at the time of application of electricpulses and that the whole tumor mass is sufficiently covered byelectric field.14,32 The treatment procedure (protocol) has been al-ready extensively reviewed elsewhere, and is elaborated in Stan-dard Operating Procedures for Electrochemotherapy byCLINIPORATOR.14,15,33,34 Briefly, bleomycin or cisplatin can be in-jected intratumorally when few (<7) and small tumor nodules(<20 mm in diameter) are being treated. When multiple and biggernodules (>20 mm in diameter) are treated bolus intravenous injec-tion of bleomycin is given, in general anesthesia.33 Within fewminutes after intratumoral injection or 8 min after intravenousinjection of the chemotherapeutic, electric pulses are applied tothe tumor. Historically, during early clinical experiences differentelectric pulses generators have been used.35 In the EU, the Clini-porator™ (IGEA, Carpi, Italy) that is CE certified for clinical use, isexclusively employed to perform electrochemotherapy in clinicalpractice. Different sets of electrodes for different nodule size orthickness, plate and needle electrodes are available. Different elec-trode configurations enable adequate electric field coverage of thewhole tumor mass in order to permeabilize as many as possiblecells within the tumors.14 For adequate tumor coverage with theelectric field also treatment planning based on numerical modelingis used and was demonstrated to be a useful tool for thetreatment.36

Clinical use

Electrochemotherapy has proved to be effective in treatment ofvarious cutaneous tumor nodules; melanoma, Kaposi sarcomas,cervix leiomyosarcoma, breast cancer, head and neck cancer,hypernephroma, squamous cell carcinoma of the skin.14,15,37–67

Now it is used in treatment of melanoma metastases, in palliativeintent when all other treatment modalities have failed or provedinsufficient, providing improved quality of life of these patients.Predominantly, electrochemotherapy is used in treatment of mul-tiple cutaneous metastases, when they cannot be excised, due totheir number or localization.52 Electrochemotherapy may be alsoused as the treatment of choice for tumors refractory to conven-tional treatments like radiotherapy or unsuitable for surgery68, ascytoreductive treatment before surgical resection or in manage-ment of bleeding metastasis.69–72

Electrochemotherapy is now used in more than 80 cancer cen-ters over Europe and it is estimated that in the year 2011 about2000 patients will be treated by electrochemotherapy. In Europeexist also two patient’s databases; the International Network forSharing Practice in ElectroChemoTherapy (INSPECT) database andItalian Melanoma Group and Gruppo Italiano Dermatologico Onco-logico (GIDO). The clinical response was evaluated in several stud-ies.34,51,54 However, the prospective, international, multi-centerclinical trial ESOPE (European Standard Operating Procedures forElectrochemotherapy), reported in 2006 still represents the hall-mark of electrochemotherapy clinical development.68 The studyhas demonstrated that, based on the established SOP for electr-ochemotherapy, the same clinical responses can be obtained aswere reported in the previously published studies.73 Based on thisstudy several other studies have been published later on, confirm-ing the results of ESOPE study, predominantly on melanoma using

Gregor Sersa et al. / Cancer Treatment Reviews 38 (2012) 379–386 381

bleomycin in single or repetitive sessions.53,54 Repetitive electr-ochemotherapy in tumors bigger than 3 cm in diameter, that usu-ally do not respond completely to the first treatment proved to beeffective with even higher OR rate (96%). Also the quality of life ofthe patients was evaluated before and after electrochemotherapy,and demonstrated benefit in local disease related complaints andin activity of daily living. The sum of the scores obtained in sixitems (bleeding, ulceration, esthetics, pain, activity in daily living,social relations) registered after electrochemotherapy (at 1 monthand 2 months) were statistically different compared with thatregistered before treatment.54 Based on these clinical resultselectrochemotherapy was brought into clinical guidelines for pro-gressive cutaneous disease of melanoma on national and Europeanlevels.74 However, as mentioned before, several other tumors weretreated, with the same response rate as melanoma tumors.41–75 Among these, breast cancer CWR was the second predomi-nant type of tumors, which deserves attention because of itsfrequency and clinical significance.

Clinical application and outcome in chest wall breast cancerrecurrence

Clinical trials on electrochemotherapy

In spite of improved treatment possibilities of early breast can-cer, quite often (up to 45%) breast cancer recurs locally, presentingcutaneous and subcutaneous tumor nodules.1 The main problem ofthese patients with often incurable metastatic disease at recur-rence is that they present with multiple locoregional nodules andtheir quality of life might be compromised by invasive surgicalinterventions. These tumors often present as mutilating, painfuland malodorous. In this respect electrochemotherapy would be atreatment option because it is safe, easy to perform, also on outpa-tient basis.

Electrochemotherapy has been reported effective in manage-ment of breast cancer CWR several times. In the early period ofclinical application of electrochemotherapy of different tumortypes, some sporadic cases of successful treatment of breast cancerCWR were reported.13,42,44,49 However there were also some seriesof patients where efficiency of electrochemotherapy was moreextensively elaborated, which will be discussed in this review inmore details.61 The clinical reports dealing with breast cancerCWR are presented in Table 1.

Electrochemotherapy with cisplatin

The study performed at the Institute of Oncology Ljubljana in2004, reported the first series of six metastatic breast cancer pa-tients with CWR treated by electrochemotherapy with cisplatinpresenting 26 cutaneous lesions in whom all standard treatmentswere exhausted.61 The aim of the study was to compare the effi-ciency of electrochemotherapy with efficiency of intratumoraladministration of cisplatin alone after single treatment. Twelvelesions were treated by electrochemotherapy with intratumoralinjection of cisplatin (1 mg/100 mm3 of tumor), six lesions withintratumoral cisplatin administration, whereas eight were as con-trols. The control lesions were retreated during the clinical studywith electrochemotherapy or underwent other treatment. In allthe 12 electrochemotherapy lesions OR was obtained. Among theselesions 4 (33%) CR with median duration of response 10 weeks andin 8 (67%) PR with median duration of response of 5 weeks wasobtained. The study indicated on the differential efficiency ofelectrochemotherapy according to the size of the treated lesions.Namely, the mean size of the lesions before the treatment that ac-quired CR was smaller (72 mm3) than those with PR (192 mm3).

The increased antitumor efficiency of cisplatin by electroporationof tumors was demonstrated when its efficiency was comparedto intratumoral cisplatin administration alone. No CR wereobtained, in 5 of 6 lesions PR was obtained, with average durationof only 5 weeks, having 73 mm3 volume before treatment. In onelesion progression was observed. However, all of the lesions thatwere not treated were in progression. The treatment was per-formed on out-patient basis and with standard treatment protocol:injection of cisplatin intratumorally which proved difficult due tothe stiffness of the cutaneous nodules and application of electricpulses by plate electrodes in local anesthesia. The patients toler-ated electrochemotherapy well. Observed were standard reactionslike local pain due to application of electric pulses in local anesthe-sia and erythema and edema in the site of the treatment whichresolved in 2–4 weeks. The crust formation was observed in allpatients, which persisted 4–10 weeks. The late side effects of thetreatment were minimal scarring and depigmentation of the skinon the treated site, and persisted throughout the observation per-iod, however no early or late systemic side effects were observed(Fig. 1). The important finding was also that electrochemotherapywas effective on two patients pre-treated with cisplatin-based sys-temic treatment before electrochemotherapy.

At that time it was not possible to compare the efficiency ofelectrochemotherapy with cisplatin with bleomycin-based electr-ochemotherapy, either given intravenously or intratumorally;namely only few reports dealing with one or two breast cancer pa-tients treated by bleomycin have been published before thattime.13,42,44,49 In the first report one patient with large CWR wastreated, but not successfully, due to its size and thickness(20 � 8 cm).42 Then in two other reports one and two patientswere treated in each, presenting one or two small CWR nodules(7 � 10 mm), both resulting in CR.13,44 Another report describedefficiency of electrochemotherapy with bleomycin given intratu-morally on two breast cancer patients with altogether 14 lesionsof CWR (mean size 21.3 ± 13 mm); CR was obtained in 58% oflesions and PR in 42% of lesions.49

Based on the results of the study on electrochemotherapy withcisplatin it was concluded that electrochemotherapy with cisplatinwas effective in the local control of cutaneous and subcutaneousbreast cancer CWR. Furthermore, electrochemotherapy with intra-tumoral cisplatin resulted in CR that could not be obtained byintratumoral cisplatin administration alone. The results were com-parable to the results published on sporadic cases of CWR treatedby electrochemotherapy with bleomycin.

ESOPE study

The international study that dealt with breast cancer CWR wasthe ESOPE study, where beside melanoma nodules; breast cancerCWR were the second most frequently treated tumors.68 The pri-mary goal of the study was to evaluate the response rate of themelanoma treated nodules to electrochemotherapy either withbleomycin given intravenously and those treated by electrochemo-therapy with bleomycin or cisplatin given intratumorally. How-ever, comparison of non-melanoma group of nodules tomelanoma nodules demonstrated no significant difference in effec-tiveness, but although not significant, there was a trend towardhigher antitumor efficiency in non-melanoma nodules (OR rate90.4% versus 80.6%, respectively and CR rate 83.6% versus 66.3%,respectively).

Among the non-melanoma group 14 patients with breast cancerCWR (58 nodules) were treated by electrochemotherapy. The ORrate of these nodules was 95% with 90% CR rate. There was nodifference in the response rate between the tumors that were trea-ted by electrochemotherapy with bleomycin given intravenously(seven patients; 26 nodules; OR = 96%; CR = 85%) and those that

Table 1Clinical trials treating or including treatment of breast cancer recurrences by electrochemotherapy.

References Patients (n)/tumors (n)

Breast CWR patients (n)/nodules (n)

Histotype Drug/route Response(%)

Response breastCWR n (%)

Domenge et al.42 7/53 Adenocarcinoma lung, SCC, breast BLM-i.v. CR 11;PR 11

1/1 Breast PR 1 (100)Heller et al.44 6/18 Melanoma, BCC, breast BLM-i.v. CR 33;

PR 391/2 Breast CR 2 (100)

Mir et al.13 20/107 Melanoma, SCC, adenocarcinoma,BCC, breast

BLM i.v./BLM i.t. CR 53;PR 17

2/10 Breast BLM i.v. CR 2 (20)NE 8 (80)

Rodriguez-Cuevaset al.49

15/38 BCC, melanoma, SCC, breast BLM-i.t. CR 49;PR 49

2/14 Breast CR 8 (58)PR 6 (42)

Rebersek et al.61 6/12 Breast CDDP-i.t. CR 4 (33)PR 8 (67)

Marty et al.68 41/171 Melanoma, carcinoma, sarcoma BLM-i.v.; BLM-i.t.;CDDP-i.t.

CR 74;PR 11

14/58 Breast CR 52 (90)PR 6 (5)

Larkin et al.51 30/111 SCC, melanoma, breast BLM-i.v.BLM-i.t.

CR 66;PR 22

12/127 Breast CR 89 (70)PR 38 (21)

Campana et al.54 52/608 Melanoma, SCC, sarcoma, breast BLM-i.v.BLM-i.t.

CR 80;PR 29

11/174 Breast CR 78 (50)PR 62 (36)

Total 171/1106 49/397 Average: CR52%PR 25%

Average: CR 235(59%)PR 121 (30%)

Fig. 1. Two tumor nodules of breast chest wall recurrence were treated byelectrochemotherapy with cisplatin. Cisplatin was injected intratumorally andthereafter to the tumor electric pulses were delivered by plate electrodes. Marks ofthe electrode are visible on skin after tumor electroporation. Several runs of electricpulses were delivered so that the whole tumor area was electroporated. During the2 weeks after electrochemotherapy a scab formed and thereafter fell off. Goodcosmetic effect is visible after 5 months, CR of the treated nodule lasted for 2 years.At that time progress of the disease in visceral organs was diagnosed and thepatient underwent systemic chemotherapy.

382 Gregor Sersa et al. / Cancer Treatment Reviews 38 (2012) 379–386

were treated by electrochemotherapy with bleomycin given intra-tumorally (seven patients; 32 nodules; OR = 94%; CR = 94%). Themean size of the nodules treated with intravenous bleomycinwas 108 mm3 and that of intratumoral injection of bleomycin94 mm3. Based on the published results of this study it is not pos-sible to draw further conclusions, except that breast CWR that

were treated by single electrochemotherapy session and were lessthan 3 cm in diameter responded in the range of melanoma tumornodules. Compared to the previously published study performedwith electrochemotherapy and intratumoral cisplatin, the antitu-mor effectiveness of electrochemotherapy with both ways of bleo-mycin administration observed in the frame of the ESOPE trial wassimilar. Namely, electrochemotherapy with intratumoral cisplatinadministration on smaller tumors (mean size 72 mm3) resultedin 100% CR.61

Electrochemotherapy with bleomycin

The study of Cork Cancer Research Center after the ESOPE studyin 2007 analyzed efficiency of electrochemotherapy with bleomy-cin given intravenously or intratumorally on a cohort of patientsdealing with different types of cancer, including breast carcinomaand treating tumors smaller and larger than 3 cm in diameter.51

The general conclusion was: 60% of tumors (66 of 111) presentedCR, 22% PR and 18% NC, no tumors progressed. Analysis of theresults of only breast CWR in that study showed in 12 evaluablepatients with 127 tumors were included, 48% were smaller than3 cm (n = 58) and 52% were bigger than 3 cm (n = 66). The OR rateof smaller tumors was 97%, from these 76% were CR. Among thebigger tumors 91% responded with OR and 68% with CR. In mostof the patients there was no progression within the treated areafollowing electrochemotherapy and amelioration of symptoms ofbleeding and pain was achieved. Only four of the patients devel-oped further chest wall lesions outside the treated field. Thepatients that requested further treatment of these lesions hadretreatment with electrochemotherapy and regression of thetumors was seen again. This study confirmed that electrochemo-therapy with bleomycin either given intratumorally or intrave-nously is effective in local tumor control of breast cancer CWR.

Gregor Sersa et al. / Cancer Treatment Reviews 38 (2012) 379–386 383

The response rate was high; higher with tumors smaller than 3 cmin diameter that were treated intratumorally with bleomycin thanwith bigger tumors that were treated by bleomycin given intrave-nously. It also proved the efficacy of electrochemotherapy and fea-sibility of repeated electrochemotherapy on newly developednodules. Very indicative how useful electrochemotherapy can bein extensive CWR (4.5 � 5 cm) is also a case report, where afterthree consecutive electrochemotherapy sessions the tumor areahas reduced dramatically, and the patient after further systemicchemotherapy remained tumor free for 10 months.76 Furthermore,it has to be stressed that electrochemotherapy provided substan-tial symptomatic relief of big, painful and bleeding nodules.

The study of Instituto Oncologico Veneto in 2008 reported on 11patients with 174 nodules with breast CWR within the study deal-ing with 52 patients and 608 nodules.54 In that study, electroche-motherapy with bleomycin intravenously or intratumorally wasperformed according to the published guidelines.33 It is difficultto extract the data only for CWR, but the overall response of thetreated lesions was 96% (50 nodules). CR rate was 50% (26 nodules)and 46% (24 nodules); the patients were followed up to 9 months.Again the study indicated on possibility and efficiency of repeatedtreatment of not completely responding tumors and those thatgrew out of previously treated area. In the patients up to five re-peated electrochemotherapy sessions were performed. Unfortu-nately, electrochemotherapy did not affect the course of thedisease; as reported considerable number of patient’s experiencedvisceral progression or the reappearance of new superficial meta-static lesions. However, authors stress that the patients benefitfrom electrochemotherapy by having good local tumor controland better quality of life.

Based on these studies a new clinical study in Herlev Hospital inCopenhagen has been launched. The aim of the study is to relievesymptoms related to CWR in breast cancer patients with tumorsbigger than 3 cm in diameter.77 The patients are treated usingintravenously administered bleomycin. Considerable reduction oftumor mass was seen in all treated patients, and five out of thesix patients did not experience progress in the treated area aftertreatment in a follow up period of 2 months, whereas progressionwas seen in non-treated areas. Symptomatic relief was achievedespecially in three of the four patients who had ulcerating tumors.No serious adverse events were observed. The study is still recruit-ing patients, 11 patients were included so far, in 8 patients (73%)OR was obtained. Due to large dimensions of the nodules PR wasobtained in 7 (63%) of patients (personal communication).

Fig. 2. Subcutaneous breast CWR treated by electrochemotherapy with bleomycin. Bleowere delivered to the tumor nodule. Several runs of electric pulses were delivered in orderecurrence on the chest wall where the electrochemotherapy was applied. The patient d

In addition to these trials there are some short reports indicat-ing that electrochemotherapy is being utilized for treatment ofbreast cancer CWR in additional cancer centers that have not beenutilizing this therapeutic approach before, like Instituto Oncologico‘‘Giovanni Paolo II’’ Bari and Instituto Oncologico Veneto, Padova,Italy.78 No definitive published data on their results are currentlyavailable; however in conference reports they have indicated thatthey have treated a substantial number of patients. Recently re-sults of the Hellenic Group of Electrochemotherapy on 52 patientswas published. Among these also nine patients with recurrences ofbreast cancer were treated. However, there is no data whetherthese were CWR; in two patients CR, in six patients PR was ob-tained and one patient was not assessed.67

Based on the published results it is difficult to recommendeither intramural or intravenous drug administration. However,from the data it can be extracted, that smaller and low numberof tumor nodules can be effectively treated by intratumoral drugadministration. Breast cancer CWR are usually very stiff tumors,therefore it may be sometimes difficulty to infiltrate the drug intosuch metastases. In addition, bigger tumor nodules may be alsorecommended to be treated by intravenous bleomycin administra-tion. This route of drug administration provides a therapeutic win-dow of at least 20 min, usually sufficient to treat all the metastases.Intravenous drug administration also provides adequate drug dis-tribution throughout the tumor nodules. However, in the case ofirradiation pre-treated metastases these may have hampered per-fusion and in such cases intratumoral drug administration wouldbe recommended.

Summarizing the results of the clinical trials that have includedbreast cancer CWR it can be observed that the response rate is sim-ilar to other tumor types. The OR rate of all tumors that were trea-ted in these clinical trials was 78% with 52% of CR, among these theOR rate of breast cancer CWR was 89% with 59% of CR. This simpli-fied comparison at least indicates that breast CWR are as respon-sive to electrochemotherapy as other tumor types. Taking intoaccount that the lesions treated were of various sizes and treatedin different cancer centers, the results are more than encouraging.

Toxicity of electrochemotherapy

So far all the clinical studies have reported satisfactory toxicityprofile of electrochemotherapy with only locoregional side effects.No systemic side effects were recorded. The most often reportedside effect was minimal pain associated with application of electric

mycin was injected intravenously in bolus and after 8 min interval electric pulsesr to electroporate the whole tumor area. The nodule gradually regressed without theied after 16 months due to lung and bone metastases.

384 Gregor Sersa et al. / Cancer Treatment Reviews 38 (2012) 379–386

pulses, treated in local anesthesia and in tumors located in the sen-sitive areas of the body.34 In ESOPE study muscle contractions wererecorded in 78% of the patients.68 The muscle contractions, whichare induced by the applied electric field, occur at each applicationof electric pulse, when the repetition frequency of the deliveredpulses is 1 Hz. However, it was demonstrated that by increasingthe frequency to 5 kHz, there is only one sensation of the appliedpulses and the effect is the same as with delivery at 1 Hz.68,79,80

Therefore, most of the treatments performed in clinical practicenow utilize 5 kHz repetition frequency for the application of elec-tric pulses.

Mild edema and erythema of the treated area is also frequentside effect.34 The erythema disappears usually after a few days,and the crust sometimes forms on the treated nodule. The crustmay persist for several weeks, so the treatment effectiveness can-not be determined before it falls off. In relation to this, repetitivetreatment of the same tumor nodule is not recommended in short-er intervals than 4 weeks (Fig. 2).

The treated area is without scarring after regression of the tu-mor nodule, only with slight depigmentation of the skin, whichwas demonstrated in several clinical studies.47,68 Electrochemo-therapy has well documented effect predominantly on dividingcells; therefore the effect on the normal tissues around the tumoris minimal. This enables treatment of tumors with the safety mar-gin without normal tissue damage.72

In principle, the application of electric pulses to the chest wallmay interfere with heart function if the electric field is close tothe heart. A strict cardiac monitoring was applied in most of trials,but no such adverse events were reported so far in electrochemo-therapy of cutaneous nodules, also when being on the chest wallabove heart area. Due to the small gap between the electrodes, itis not possible to expect the penetration of the electric field lowerthan a few mm below the lower level of the electrodes.81 Therefore,electric field may not penetrate below the rib cage. In order to fur-ther avoid this possible side effect new electric pulse generatorproduced by IGEA, provides the option of synchronizing algorithmso that electric pulses are delivered outside the vulnerable periodof the ventricle and no heart arrhythmias or any other pathologicalchanges could be observed.

Conclusion

Electrochemotherapy can be proposed as an effective and safelocoregional therapy for breast cancer CWR as alternative treat-ment modality to conventional therapies, especially in case of mul-tiple cutaneous and subcutaneous lesions. It has been proven toameliorate the symptoms of locoregional relapse and to improvepatients’ quality of life.

Electrochemotherapy is spreading through Europe for treat-ment of melanoma and other tumors’ metastases in the skin. Thetherapy is safe, easy to perform and has good cost/benefit ratio.82 It has been recognized as a valid treatment approach; over 80cancer centers routinely use it and have reported positive results.Although the controlled randomized trials are missing, still electr-ochemotherapy offers an important and more efficient alternativeto other local treatment modalities in these patients.

In relation to this, breast cancer CWR are interesting target toevaluate electrochemotherapy efficiency in controlled clinical tri-als, and to provide evidence of its effectiveness and utility in com-prehensive care of breast cancer patients. Most of the studies havereported on efficacy and safety of electrochemotherapy in breastcancer patients with loco-regional skin metastases after mastec-tomy. Therefore, with further development of the electrodessuitable to be accurately guided into the soft mammary tissuesand accurately target the tumor nodules, the therapy could be

implemented also for treatment of primary mammary carcinoma.Such an attempt is already being evaluated at the Institute GustaveRoussy, Villejuif in an ongoing clinical study (EUDRACT number:2009-A00971-56).

Electrochemotherapy of breast cancer might represent an alter-native treatment to conventional ablation techniques and topicalchemotherapy in the therapy of CWR, especially in patients thatare not candidates for radical surgery and/or radiotherapy.1 Its spe-cific advantage is that it is effective in previously surgically orradiotherapy treated area, and in patients pre-treated with thesame cytostatic, such as cisplatin, used as systemic therapy.61,68

In case of overt metastatic disease local electrochemotherapy rep-resents an additional therapeutic option to systemic therapy. How-ever, the local regression of skin metastases achieved byelectrochemotherapy can be extremely beneficial to patients withpredominant loco-regional disease which might prove to be a ma-jor psychological burden for these patients. Furthermore, electr-ochemotherapy could also be developed for treatment of otherclinical indications, such as primary local therapy in frail elderlypatients that are not suitable for surgical removal of the primarytumor.

Conflict of interest statement

The authors declare no potential conflicts of interest.

Acknowledgement

This research was funded by a research grant from the ResearchAgency of the Republic of Slovenia P3-0003.

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