doi:10.1684/ejd.2018.3291
EJD, vol. 28, n◦3, May-June 2018
287
Review
Eur J Dermatol 2018; 28(3): 287-313S. Morteza SEYED JAFARI1,2,3 Fatemeh JABBARY LAK4 Amiq GAZDHAR2,5 Maziar SHAFIGHI2 Luca BORRADORI1 Robert E. HUNGER1,2
1Department of Dermatology, Inselspital, Bern University Hospital, Bern, Switzerland
2Department for BioMedical Research, University of Bern, Switzerland
3Graduate School for Cellular and Biomedical Sciences University of Bern, Switzerland
4Münsingen Hospital, Münsingen, Switzerland
5Department of Pulmonary Medicine, Bern University Hospital, Bern, Switzerland
Reprints: S. M. Seyed Jafari
<Seyedjafarism@yahoo.com>
Article accepted on 07/09/2017
Application of electrochemotherapy
in the management of primary and metastatic cutaneous malignant tumours: a systematic review and meta-analysis
Electrochemotherapy is becoming a promising technique for the man- agement of malignancies of skin and non-skin origin. The current review aims to clarify current knowledge on administration of elec- trochemotherapy for the treatment of various skin tumours. A systematic literature search was performed, up to the end of 2016, on studies in which the application of electrochemotherapy for management of pri- mary and metastatic cutaneous malignant tumours was assessed. Having selected appropriate studies, pooled estimates of mean objective (com- plete) responses, with 95% confidence intervals (CIs), were calculated to assess treatment efficacy. Finally, the main emerging themes from the papers were discussed in more detail. From 465 records identified through database searching, a total of 128 studies were screened, of which 70 were included for review. After a pooled analysis, the esti- mate for mean objective response following electrochemotherapy was 84.02% (95% CI: 80.08-87.61). Furthermore, the pooled estimate of objective treatment response of evaluated studies was 83.91% (95% CI:
79.15-88.17%) for bleomycin and 80.82% (95% CI: 66.00-92.36%) for cisplatin. Electrochemotherapy is a feasible, inexpensive, fast and easy technique to perform local treatment, regardless of tumour type, with a low level of adverse effects and patient discomfort. This method can be applied alone for patients with primary cutaneous lesions, or local or locoregional metastases, or as an additional treatment modality in patients with distant metastases.
Key words:
clinical trials, cutaneous malignant tumour, elec- trochemotherapy, metastasis
M
elanoma and non-melanoma skin cancer are now the most common types of cancer in Caucasian populations [1]. Surgery or radiotherapy is the elective treatment for most of the primary skin cancers, which provide high rates of local control and survival [2, 3].However, despite significant advances in treatment guide- lines, recurrence or metastases in the skin are often difficult to manage. As a result, the patients receive multimodal treatment including surgery, radiotherapy, and systemic chemotherapy. The poor response to these treatments could be due to the relative impermeability of the cell membrane to the therapeutic agents [2, 4, 5].
In the 1980s, it was discovered that the delivery of intense electric pulses can transiently and reversibly result in per- meabilization of the cell membrane to a large variety of molecules, which are otherwise unable to enter into the cell [2, 6-10]. Therefore, application of a combination of short intense electric pulses and chemotherapy, termed “elec- trochemotherapy”, has been proposed as a new treatment modality for cutaneous involvement of different malignan- cies [11-16], in which a local increase in plasma membrane permeability, i.e.exposure of the tumour nodule to elec-
tric pulses (electroporation), results in increased uptake of chemotherapeutics into the tumour cells [17-19]. Hence, by using this method, the intracellular concentration, and thereby the toxicity, of bleomycin and cisplatin (as the effective drugs for the treatment of different cutaneous tumours [20-22]) can be increased up to 10,000 times and 80 times, respectively [14, 23], which significantly potentiates their antitumour effectiveness, with lower doses required [15, 18, 24-26].
In order to shed more light on the clinical applications of electrochemotherapy in dermatology, the current review aimed to clarify current knowledge on the administration of this method in the management of primary and metastatic skin malignancies.
Material and methods
This review was conducted based on the PRISMA group statement [27]. A systematic literature search was per- formed in the PubMed Library and Cochrane electronic
databases, up to the end of 2016, taking all electropora- tion synonyms and skin tumours into account, using the following search terms or respective combinations: elec- troporation, electrochemotherapy, electropermeabilization, skin cancer, skin metastasis, melanoma, Kaposi’s sarcoma, Merkel-cell carcinoma, and basal cell carcinoma.
In some cases, the same article could be found in both databases, however, the evaluation for each database was performed separately and reported in the table of results of the search.
Additionally, no geographical restrictions were imposed in this study. Both qualitative and quantitative studies were chosen. From these manuscripts, those that fulfilled the fol- lowing inclusion and exclusion criteria were considered in the current review:
– Studies focused on the clinical application of electropo- ration in the management of primary and metastatic skin tumours.
– Studies restricted to English language and limited to humans. As a result,in vitrotreatments and veterinary stud- ies were excluded from full-text assessment.
– Scientific letters, review articles, and meta-analysis were not considered for this study.
After evaluation of the selected studies, these were then summarised in a table and subclassified under publi- cation year, authors, patient number, tumour number, type/dose/route of chemotherapy, settings of electropora- tion, outcome, and side effects. The studies were then ordered chronologically to reveal any changes and particu- larly advances made over time (table 1). Finally, the main emerging themes from the papers were discussed in more detail.
Statistical analysis
Pooled analysis was conducted using MetaXL Version 5.3 (EpiGear International Pty Ltd, Australia). The presence of heterogeneity among these studies was evaluated with Cochran’s Q test, and inconsistency was assessed with I2 test that describes the percentage of the variability in effect estimates that is due to heterogeneity, where p<0.05 indi- cates significant heterogeneity. Pooled estimates of mean objective (complete) responses, with 95% confidence inter- vals (CIs), were calculated to assess the overall efficacy. In order to calculate the pooled estimate of mean objective (complete) response for each tumour or specific adminis- tration route, only the relevant papers were considered for the analysis. The random-effects model was defined as the preferred method due to diversity and heterogeneity of the studies, patients, and treated tumours [28].
Results
A total of 465 articles were identified. All abstracts were examined and screened, excluding 308 articles regardingin vitroor veterinary treatments, or non-English papers. Full- text assessment of the remaining 128 articles resulted in 70 eligible articles (figure 1).
Considering objective responses, significant heterogene- ity was detected among all studies (I2 = 68%;
p-heterogeneity<0.001). After a pooled analysis, the estimate for mean objective response was 84.02%
(95% CI: 80.08-87.61%), which suggests efficacy of electrochemotherapy in the management of primary and metastatic cutaneous malignant tumours (figure 2).
Choice of chemotherapeutic agent for electroporation
Bleomycin and cisplatin are the most commonly admin- istered drugs for the treatment of skin tumours with electrochemotherapy [29], which can be given systemically or locally [30].
Bleomycin is a water-soluble antibiotic with toxicity to mammalian cells due to the capability to induce DNA breaks [7, 13, 31]. Electropermeabilization of cells allows bleomycin to enter the cytosol and exert its cytotoxic potential. Therefore, bleomycin is an ideal candidate for combining with electric pulses because it is non-permeant, but highly cytotoxic once inside the cell [7, 21, 31-35].
It can therefore be used at lower doses than those needed for classic chemotherapies [7, 13, 31]. In previous stud- ies, electrochemotherapy with bleomycin was found to be effective for primary and metastatic malignant melanoma [2, 5, 17, 20, 30, 36-49], primary and metastatic basal cell carcinoma [2, 21, 38, 44, 50-52], primary and metastatic squamous cell carcinoma [44, 47, 49, 53], Kaposi’s sarcoma [41, 43, 49, 54-59], Merkel cell carcinoma [41, 60, 61], cutaneous primary and metastatic lesions of breast cancer [49, 62-68], soft tissue sarcoma [49, 69], cutaneous B-cell lymphoma [70], superficial angiosarcoma [71], metastatic cutaneous nodules and transitional cell carcinoma (bladder cancer) [72], locally advanced and metastatic angiosarcoma [71], and as a palliative therapy for tumour complications [12, 36, 73-75].
Cisplatin is a nuclear DNA-damaging agent with the capa- bility to form DNA crosslinks. Cisplatin transport through the plasma membrane is also limited [76]. Neverthe- less, exposure of cutaneous tumours to electric pulses after intravenous or intratumoural non-toxic cisplatin doses potentiates its antitumor effectiveness several-fold [24, 77, 78]. Electrochemotherapy with cisplatin was first introduced by Sersaet al. in 1998 [78]. Subsequently, fur- ther studies showed its treatment efficacy for malignant melanoma [17, 78, 79], squamous cell carcinoma [78], basal cell carcinoma [78], cutaneous lesions of breast cancer [80], and as a palliative therapy [79]. Efficacy of elec- trochemotherapy with cisplatin was proven to be dependent on the cisplatin dose, the amplitude of the electric pulses, and the sequence and interval of cisplatin administration [24, 78].
Route of drug administration
According to the findings of the previous trials, either bleomycin or cisplatin can be used as treatment due to their good antitumour effectiveness. Clinical data have proven antitumour effectiveness of bleomycin and cisplatin when given intratumourally, however, intra- venous injection is only recommended for bleomycin [24, 37, 77, 78, 81]. The estimates for objective response fol- lowing electrochemotherapy with intravenous bleomycin, intra-lesional bleomycin, and intra-lesional cisplatin were
Table1.Summaryoftheselectedstudiesforthereview. StudyNo.of patients (lesions) Tumour characteristicsAnaesthesiaTreatment (drug/dose/ route) Interval betweendrug administra- tionand electricpulse Pulsecharac- teristics(field strength,no. ofpulses, duration, frequency) ORCRCommentson outcomeSideeffectsand drawbacks Belehradek etal.(1993) [98]
8(40)Permeation nodulesofhead andneck squamouscell carcinomas SIntravenous bleomycin (10mg/m2) 3.5min1300V/cm,8 or4pulses, 100s,1Hz
7257-Nomajorlocalor generalsideeffects. Localinstantaneous contractionof muscleswas observed. Rudolf etal.(1995) [30]
2(24)Malignant melanoma nodule LAIntravenous bleomycin (10mg/m2) 8min1300V/cm, 2×4pulses, 100s,1Hz
9292-Nomajorlocalor generalsideeffects. Musclecontractions wereobservedafter eachpulse.Several hoursafter treatment,erythema andslightoedema wasdetectedatthe treatedarea.These symptoms disappearedwithin oneday. Domenge etal.(1996) [85]
7(53)Multipleand/or largepermeation nodulesofhead andneck squamouscell carcinomaorof salivary,lung cancer,breast adenocarcinoma SorGAIntravenous bleomycin (10or 15mg/m2)
8-28min1000or 1300V/cm,8 or4pulses, 100s,1Hz
2211Inalmostallthe cases,progressionof thetreatednodules wasatleaststopped, comparedwiththat oftheneighbouring nodulesnot subjectedto electroporationbut exposedtothesame doseofbleomycinin. Clearantitumour effectswere obtained,especially inthesmallnodules. Inthelargest nodules,extended tumournecrosiswas seen.
Nolocalorgeneral sideeffects,except foronepatient,who developedtransient heartfrequency accelerationand increaseinmaximal bloodduringthe treatment,which returnedto pre-treatmentValues withinafew seconds.
Table1.(Countinued) StudyNo.of patients (lesions) Tumour characteristicsAnaesthesiaTreatment (drug/dose/ route) Interval betweendrug administra- tionand electricpulse Pulsecharac- teristics(field strength,no. ofpulses, duration, frequency) ORCRCommentson outcomeSideeffectsand drawbacks Glassetal. (1996)[38]2 (multiple)Nevoidbasalcell carcinoma syndrome
LAIntravenous bleomycin (10mg/m2) 12-15min1300V/cm,8 pulses,99s, 1Hz
NMNMPartialresponses wereobservedin tumoursfromboth ofthepatients treatedwithelec- trochemotherapy; threepartial responseswere observedinone patient,andone partialresponsewas observedintheother patient.Complete responseswereseen fortwolesions.
Onlyminimallocal orsystemicside effectswerenotedin responsetothe therapy. Glassetal. (1996)[97]5(23)Cutaneous metastatic melanoma
LAandEIntratumoural bleomycin,at adoseof 0.5-1.0mg (basedon tumoursize) 10min1300V/cm,8 pulses,99s, 1Hz
9678-Thetreatmentwas welltolerated,with theexceptionofthe sensationofmuscle contractionduring thetherapy.Also,a slightburningofthe skinwiththecalliper electrodes. Helleretal. (1996)[39]6(18)Metastatic melanoma,basal cellcarcinoma, nevussyndrome, ormetastatic breast adenocarcinoma withcutaneous nodules
LAIntravenous bleomycin (10mg/m2) 5-15min1300V/cm,8 pulses,99s, 1Hz 7833-Allpatientstolerated thetreatmentwell withnoresidual effectsfromthe electricpulses.
Table1.(Countinued) StudyNo.of patients (lesions) Tumour characteristicsAnaesthesiaTreatment (drug/dose/ route) Interval betweendrug administra- tionand electricpulse Pulsecharac- teristics(field strength,no. ofpulses, duration, frequency)
ORCRCommentson outcomeSideeffectsand drawbacks Glassetal. (1997)[93]20(54)Primarybasal cellcarcinomaLAandEIntralesional bleomycin, 0.5-1.0mg (basedon tumoursize)
10min1300V/cm,8 pulses,99s, 1Hz
10098Norecurrenceswere recordedwitha mean18monthsof observation.Two weeksaftertherapy, thehistopathological appearanceconsisted ofcutaneous ulcerationand scale-crust formation,butno tumour.
At1to2daysafter electrochemother- apy,painless erythemaand oedemaoccurredat thetreatmentsite. Ulcerationappeared within2to3days, withathick, scale-crustappearing afterwards. Completewound healingbysecond intentionrequired4 to6weeks. Kubota etal.(1998) [72]
1(17)Metastatic cutaneous nodules, transitionalcell carcinoma (bladdercancer) GAIntralesional bleomycin (0.5mg/5mm ofnodule diameter) 10min1000V/cm,8 pulses, 100s,1Hz
10082.3Alllesionsgradually dried,forming yellowishcrusts,and 14completely disappeared.The other3lesions partiallyregressed andshowedthin, lustrousskin.
Localexudateand oedemawerepresent for5days,and exudatefromthe lesionsinthehead remainedfor20 days. Helleretal. (1998)[42]34(143)Basalcell carcinoma, advanced melanoma (metastaticto localordistant softtissueand skinsites), squamouscell carcinoma,or Kaposi’s sarcoma
LAandEIntralesional bleomycin (0.5- 4mg/cm3) 10min1300V/cm,8 or6pulses, 99s,1Hz
9991-Musclecontraction wasseenduring administrationof eachelectricpulse, butpromptly disappearedafterthe pulse.
Table1.(Countinued) StudyNo.of patients (lesions) Tumour characteristicsAnaesthesiaTreatment (drug/dose/ route) Interval betweendrug administra- tionand electricpulse Pulsecharac- teristics(field strength,no. ofpulses, duration, frequency)
ORCRCommentson outcomeSideeffectsand drawbacks Sersaetal. (1998)[78]4(30)Melanoma, squamouscell carcinoma,basal cellcarcinoma
NMIntratumoural cisplatin (0.25- 2mg/cm3)
1-2min1300V/cm, 100s,1Hz100100-Electrochemotherapy waswelltolerated withgoodcosmetic outcomeand onlyminimal scarring,andaslight depigmentationof theskin. Miretal. (1998)[21]50(291)Cutaneousor subcutaneous tumoursofbasal cellcarcinoma, malignant melanoma, adenocarcinoma andheadand necksquamous cellcarcinoma
LAorGAIntravenous bleomycinin (10mg/m2or 15mg/m2),or intratumoural bleomycinin (0.25- 1.0mg/cm3 oftissue) 3minafter intravenous and10min after intratumoural injection 1300V/cm,8 or6pulses, 100s,1Hz
85.356.4-Localinstantaneous contractionof muscleswas observed,which disappeared immediatelyafter theendofeach electricpulse. Gehletal. (2000)[12]1(9)Ulcerated cutaneous metastasesof malignant melanoma(5-20 mm)
LAandE0.5mgof bleomycin10min1200V/cm,8 pulses,99s100100Bleeding immediatelystopped onadministrationof theelectricpulses anddidnotrecur. Thetreated metastases developedcrustsand thelesionshealed overweeks.
Patientdiscomfort wasbriefand modest. Rolsetal. (2000)[13]4(55)Cutaneous metastasesof malignant melanoma(2-35 mm)
SorGAIntravenous bleomycinin (10mg/m2) 5-45min1000and 1300V/cm,8 pulses, 100s
909-Contractionswere seenduring applicationofeach pulse.Inonepatient, slighthyperthermia wasnoticed,which disappearedafter2 days.Theacute reactionswere maximalonthefifth dayandhad completely recoveredafter2-3 weeks.
Table1.(Countinued) StudyNo.of patients (lesions) Tumour characteristicsAnaesthesiaTreatment (drug/dose/ route) Interval betweendrug administra- tionand electricpulse Pulsecharac- teristics(field strength,no. ofpulses, duration, frequency)
ORCRCommentson outcomeSideeffectsand drawbacks Sersaetal. (2000)[17]10(82)Recurrent melanoma metastases refractoryto chemoim- munother- apy,Visceral metastases
NMIntratumoural cisplatin (0.25-2mg basedon tumoursize)
1-2min1300V/cm, 100s,1Hz7868At124weeksof follow-up,a77% controlrateofthe tumournodules treatedby electrochemotherapy wasobserved, comparedto19%for thosethatwere treatedwithcisplatin only.
Localinstantaneous contractionof muscleswas observed,which dissipated immediately afterwards. Erythemaand oedemawere observedinpatients treatedwith electrochemotherapy whichremainedfor 2weeks. Sersaetal. (2000)[20]9(27)Cutaneous metastasesof malignant melanoma
NMIntravenousVin- blastine (4mg/m2), oral lomustine (80mg/m2) onDay1, intravenous cisplatin (20mg/m2) onDays 2±5,and interferon- ␣2b 3mg/m2on Days4-7.
Atleast3h afterthe beginningof theinfusion 1300V/cm,8 pulses,99s, 1Hz
4811Fourweeksafter treatment,objective responsewas obtainedfor48%of tumournodules, comparedwith22% oftumournodules treatedwith Vinblastin-based chemoimmunother- apy alone.
Localinstantaneous contractionof muscleswas observed,which dissipated immediately afterwards.Slight erythema surroundingthe noduleand sometimesformation ofasuperficialscab weredetected. Rodriguez- Cuevas etal.(2001) [2]
15(38)Basalcell carcinomas, in-transit metastasisof melanoma, squamouscell carcinomasof theupper aerodigestive tract(metastatic totheskin),and skinmetastases frombreast cancer LAIntralesional bleomycin (0.5- 4mg/cm3)
10min1300V/cm,8 pulses, 100s,1Hz 9849-Nocomplications weredocumented relatedtothe treatment,and tolerancewas adequate.
Table1.(Countinued) StudyNo.of patients (lesions) Tumour characteristicsAnaesthesiaTreatment (drug/dose/ route) Interval betweendrug administra- tionand electricpulse Pulsecharac- teristics(field strength,no. ofpulses, duration, frequency)
ORCRCommentson outcomeSideeffectsand drawbacks Sersaetal. (2003)[92]14(211)Progressive diseaseof malignant melanoma
NMIntratumoural cisplatin (1mg/100cm3 oftissue) NM1300V/cm,8 pulses, 100s,1Hz
8270.1-Painwasalimiting factorformostofthe patients. Rebersek etal.(2004) [80]
6(26)Cutaneous tumourlesionsof breastcancer LAIntratumoural cisplatin (1mg/100 mm3of tissue) 1-2min1300V/cm, 2×4pulses, 100s,1Hz
10033Forlesionstreated withintratumoural applicationof cisplatinalone, objectiveresponse wasobtainedfor 83%oflesions.
Onlyminimallocal sideeffectswere observed. Snojetal. (2005)[79]1(1)Anorectal malignant melanoma
GAIntralesional cisplatin (6mgand 4mg) 2-5min730V,5× (and3the secondtime) 192pulses, 100s, 5000Hz 100100Fourteenmonths afterthebeginning oftreatment,the patientwaswithout signsoflocal recurrence.
NM Kubota etal.(2005) [74]
1 (multiple)Perineal malignant melanoma GAIntralesional bleomycin (0.1mg/cm3 oftissue) 10min1000V/cm,8 pulses, 100s,1Hz
100100Fivemonthsafterthe secondtreatment,no recurrenceof pigmentationor subcutaneous noduleswas detected.
Electrochemotherapy ofmucosal malignantmelanoma waswelltolerated. Byrneetal. (2005)[94]19(36)Visibleand/or palpable cutaneousand/or subcutaneous secondary melanoma deposits(Stage IIIandStageIV)
LAandEIntralesional bleomycin (1mg/cm3of tissue)
2-20min560-1500V, 100s7872-Electroporation causedunpleasant electricshock sensationsinthe limbduetospasmof underlyingmuscles ortopainrelayedby localnerves. Garbay etal.(2006) [56]
1 (multiple)Unresectable Kaposi’s sarcomanodules GAIntravenous bleomycin (27mg)
8-30min730V,31×8 pulses, 100s, 5000Hz(for typeIII electrode), 960V,15×8 pulses, 100s, 5000Hz(for typeI electrode) 100100Repetitive electrochemotherapy sessionscombined withtheuseof imiquimod applicationledtoan excellentlocal controlwithno secondaryeffect.
NM
Table1.(Countinued) StudyNo.of patients (lesions) Tumour characteristicsAnaesthesiaTreatment (drug/dose/ route) Interval betweendrug administra- tionand electricpulse Pulsecharac- teristics(field strength,no. ofpulses, duration, frequency)
ORCRCommentson outcomeSideeffectsand drawbacks Gaudyetal. (2006)[95]12(54)Cutaneous metastasesof malignant melanoma(Stage IIIandStageIV)
LAandEIntralesional bleomycin (1mg/mm3 oftumour lesion) 10min>600V/cm, 6pulses 100s,4Hz
4636-Patientsreported localpainand musclespasmwith myocloniaafter electroporation. Gehletal. (2006)[36]1(8)Disseminated malignant melanoma presentedwith severalbleeding, ulcerated metastasesonthe headandscalp
GAIntravenous bleomycin (15mg/m2) 8minAccordingto theESOPE protocol.
10087Bleedingmetastases ceasedtobleedand formedacrust withinafewhours aftertreatment.
NM Whelan etal.(2006) [64]
1(1)Recurrent inflammatory breastcancer, unresponsiveto systemic chemotherapy SIntravenous (20mg)and intratumoural bleomycin (5mg) 8min1400V/cm,a consecutive seriesof pulses, 100s
100100Followingthethird treatment,adramatic reductioninthe tumourmasswas accompaniedby reliefofpainand bleeding, culminatingina completeelimination oftumouronthe chestwall.
NM Tijinketal. (2006)[96]7(17)Squamouscell carcinoma, sarcoma, melanoma, Merkelcell carcinoma
LAorGAIntratumoural bleomycin (1mgmg/cm3 oftissue)
8-10minNM10082Withinafewdays aftertreatment, crustingoccurredat thetumoursite,with necrosisofthe tumourunderneath; thecrustthen disappearedafter 10-14weeksandthe tumourwasreplaced byscartissue.
Musclecontraction wasobservedinthe treatedarea.
Table1.(Countinued) StudyNo.of patients (lesions) Tumour characteristicsAnaesthesiaTreatment (drug/dose/ route) Interval betweendrug administra- tionand electricpulse Pulsecharac- teristics(field strength,no. ofpulses, duration, frequency)
ORCRCommentson outcomeSideeffectsand drawbacks Martyetal. (2006)[15]41(171)Cutaneousand subcutaneous metastasesof malignant melanoma tumournodules, carcinomaand sarcoma
LAorGAIntravenous bleomycin (15mg/m2) or intratumoural bleomycin (0.25- 2mg/cm3of tissue)or intratumoural cisplatin(0.5- 2mg/cm3of tissue) 8-28minafter intravenous, orafter intratumoural injectionof either bleomycinor cisplatin
1300V/cm,8 pulses, 100s,1or 5000Hz(for typeI electrode), 1000V/cm,8 pulses, 100s,1or 5000Hz(for typeII electrode), 1000V/cm, 96pulses, 100s, 5000Hz(for typeIII electrode)
84.873.7-Sideeffects wereminorand acceptable. Larkinetal. (2007)[62]30(111)Squamouscell carcinoma, primaryandskin metastaticbreast carcinoma,and others
SandLAor GAIntravenous bleomycin (15mg/m2) or intratumoural bleomycin 8minafter intravenous and immediately after intratumoural injection 1400V/cm,8 pulses, 100s,1to 5000Hz
8260-Onlymildpain relatedtothe treatmentwas reported,which dissipatedwithin48 hours. Snojetal. (2007)[89]1(224)Unresectable cutaneous metastasesof malignant melanoma
GAIntravenous bleomycin (15mg/m2) 8-28min1300V/cm,8 pulses, 100s,1or 5000Hz
100100-Onlymuscle contractionwas reported. Quaglino etal.(2008) [11]
14(233)Cutaneous metastasesof malignant melanoma(Stage III relapsed/refractory patients) GAIntravenous bleomycin (15mg/m2)
8-28minAccordingto theESOPE protocol
9358-Localerythemaand slightoedema disappearedwithina fewdays.Moreover, marksfromthe electrodesand superficialepidermal erosionswerenoted, followedbyscars healingwithina month.
