Radiol Oncol 2020; 54(1): 79-85. doi: 10.2478/raon-2020-0009
79
research article
Long term response of electrochemotherapy 
with reduced dose of bleomycin in elderly 
patients with head and neck non-melanoma 
skin cancer
Crt Jamsek1, Gregor Sersa2,3, Masa Bosnjak2, Ales Groselj1,4
1 Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia
2 Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
3 Faculty of Health Sciences, University of Ljubljana, Ljubljana, Slovenia
4 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Radiol Oncol 2020; 54(1): 79-85.
Received 15 December 2019
Accepted 4 February 2020
Correspondence to: Aleš Grošelj, M.D., Ph.D, Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre 
Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: ales.groselj@kclj.si
Disclosure: No potential conflicts of interest were disclosed.
Background. Electrochemotherapy (ECT) is a local cancer treatment based on electroporation where the electric 
field is used to enhance cell membrane permeability and thereby facilitating the transition of chemotherapeutic 
agents into the cell. For the treatment of non-melanoma skin cancer, a standard dosage of 15,000 IU/m2 bleomycin 
(BLM) is used. The aim of the present study was to evaluate the long-term ECT response in the group of elderly patients 
with non-melanoma skin cancer treated with a reduced dose of BLM in comparison to the outcome in the patients 
treated with the standard dose of BLM. 
Patients and methods. Twenty-eight patients older than 65 years, with a total of 52 non-melanoma skin lesions were 
included in the study. Twelve patients (24 lesions) in the experimental group received a reduced dose of BLM (10,000 
IU/m2), 16 patients (28 lesions) were treated with a standard dose of BLM (15,000 IU/m2). 
Results. No statistically significant difference in tumor control was observed between both groups. In the experimen-
tal group, tumors recurred in 39.0% of treated lesions in a median follow-up time of 28 months. In the control group, 
the recurrence rate of treated lesions was 15.4% in a median follow-up time of 40 months.
Conclusions. ECT with a reduced dose of BLM is a feasible treatment option for elderly patients with equal efficacy 
to standard dose treatment and should be considered as a treatment modality in advanced aged patients with 
comorbidities, where overall life expectancy is poor.
Key words: elect rochemotherapy; bleomycin; non-melanoma skin cancer
Introduction
Electrochemotherapy (ECT) is a local cancer treat-
ment modality with proven antitumor efficacy in 
various histological types of malignant tumors.1 
During an ECT procedure, electroporation is used 
to transiently increase cell permeability to a hydro-
philic chemotherapeutic agent such as bleomycin 
(BLM) and cisplatin.2 Currently, intravenous ad-
ministration of BLM is the most common way of 
drug administration utilized in ECT treatment.3,4
ECT acts through at least three different mecha-
nisms. The first mechanism is a direct cytotoxic ef-
fect driven by the transition of a chemotherapeutic 
agent into the tumor cells, which is enhanced by 
electroporation. ECT also has an impact on tumor 
blood vessels through sympathetic nerve stimula-
tion and subsequent vasoconstriction lasting sev-
Radiol Oncol 2020; 54(1): 79-85.
Jamsek C et al. / Long-term results of ECT with a reduced dose of bleomycin80
eral hours. Consequently, drug washout from the 
tumor is delayed. Additionally, the cytotoxic effect 
on endothelial cells of tumor blood vessels results 
in the late destruction of tumor vasculature by 
vascular disrupting effect. The third mechanism 
involves immune response provoked by immuno-
genic cell death and enhanced tumor antigen ex-
pression.5
In the ECT treatment of non-melanoma skin 
cancer (NMSC) compelling results were achieved 
when using standard dose (15,000 IU/m2) of intra-
venously administrated BLM.6 According to pub-
lished BLM pharmacokinetics study, an equally 
good antitumor response might be obtained with 
a reduced dose of BLM in the elderly population 
due to the slow elimination rate of BLM.7 Hence 
the updated SOP for ECT proposes de-escalation 
of standard dose due to high age and/or compro-
mised creatinine clearance.3 Till today only two 
clinical studies have been focused on ECT effects 
with a reduced dose of BLM. Both compared treat-
ment response two months after ECT and showed 
similar efficacy to the standard dose of BLM.8,9 
Even more, in one study authors observed faster 
healing time and favorable cosmetic outcomes 
when using the reduced dose.9
The aim of the present study was to evaluate the 
long-term ECT response in the group of elderly pa-
tients with NMSC treated with a reduced dose of 
BLM in comparison to the outcome in the patients 
treated with the standard dose of BLM. 
Patients and methods
Study summary
The study was conducted between June 
2014 and June 2019 at the Department of 
Otorhinolaryngology and Cervicofacial Surgery, 
University Medical Centre Ljubljana. The study 
protocol was approved by the Republic of Slovenia 
National Medical Ethics Committee (182/02/14 
and 0120-132/2015-2). Patients were selected ac-
cording to the inclusion and exclusion criteria 
listed in Standard Operating Procedures of ECT 
(SOP) and as previously reported.3,7,9 All patients 
had treatment naïve and biopsy-verified primary 
NMSC in the head and neck region. Each patient 
was presented to the multidisciplinary head and 
neck tumor board that confirmed indication. Prior 
to ECT procedure a written informed consent was 
obtained from all patients.
The study was conducted as a nonrandomized 
prospective study. Patients were grouped accord-
ing to BLM dose they received. The patients who 
were treated with a standard dose of BLM formed 
the control group and data from that group was 
used to determine BLM pharmacokinetics in el-
derly patients. 7 All subsequently treated patients 
older than 65 years received the reduced dose and 
formed the experimental group.
Procedure
ECT was performed under sedation or general or 
local anesthesia. BLM (Bleomycin medac; Medac, 
Wedel, Germany) was administered as intravenous 
bolus injection in 2 minutes at a dose of 15,000 IU/
m2 body surface area in the control group and at a 
dose of 10,000 IU/m2 body surface area in the ex-
perimental group (1,000 IU is equal to 1 mg of bleo-
mycin activity). In both groups, the electric pulses 
were applied 8 minutes after the injection of BLM 
by electrodes with fixed geometry (hexagonal, nee-
dle row, or plate electrodes). Electric pulses were 
generated by Cliniporator Pulse Generator (IGEA, 
s.r.l., Carpi, Italy), as described previously.9
Follow up
Response to the treatment was evaluated ac-
cording to Response Evaluation Criteria in Solid 
Tumors criteria, version 1.1.10 The two-month 
outcome has already been reported in 2018 in our 
previous publication.9 In this study we evaluated 
treatment outcome at 2, 4, 6, 12, 18, 24 months 
after ECT, and yearly thereafter. Minimal follow-
FIGURE 1. Kaplan-Meier curve of tumor control in experimental 
and control group.
Radiol Oncol 2020; 54(1): 79-85.
Jamsek C et al. / Long-term results of ECT with a reduced dose of bleomycin 81
up time of 6 months was required. Based on their 
presentation at three-year follow-up some patients 
were deemed disease free and were excluded from 
further follow-up at our institution. Those patients 
were referred to dermatologist for future yearly 
follow-up with instruction to report back in case 
of suspected recurrence of malignancy in treated 
area. 
Statistical analysis
Statistical comparison between the control and ex-
perimental group was performed using the Mann-
Whitney test (age of the patients and maximal tu-
mor diameter) and the Chi-square test (sex, histol-
ogy type, number of recurrent lesions and response 
to treatment). The results were analyzed using the 
PC SPSS, release 18.0 (SPSS, Chicago, IL) statistical 
package. All the tests were 2-sided, and the results 
were considered significant at a probability level of 
5%. Kaplan-Maier plots were drawn, and the log-
rang test was performed for the evaluation of long-
term tumor control.
Results
Twenty-eight patients, 65 years or older, with his-
tologically proven NMSC in the region of the head 
and neck, were included in the study. All the pa-
tients were treated by ECT, using intravenous 
bolus injection of BLM in standard (15,000 IU/m2 
body surface area) or reduced (10,000 IU/m2 body 
surface area) dose. There were no statistically sig-
nificant differences between both groups concern-
ing the patients (age and sex) and tumors (diam-
TABLE 1. Patients’ characteristics, treatment procedure and response to treatment of patients included in experimental group
Patient Gender Age (years)
Creatinine 
(μmol/L)
Total 
bleomycin 
dose (IU)
Electrodes 
used
Last follow 
up (months 
after ECT)
Histology
Maximum 
tumor size 
(mm)
Recurrence of 
tumor (months 
after ECT)
1 M 86 84 20,000 Needle row 30
BCC 20
BCC 8
2 M 67 108 24,000 Needle row 29
BCC 10
BCC 8
3 M 80 106 21,000 Needle row 20 BCC 30 10
4# M 82 66 20,000 Needle row 2 *
SCC 10
SCC 6
SCC 10
5 M 92 88 20,000 Needle row 25
BCC 25 25
BCC 15
BCC 15 25
6 M 79 67 20,000 Plate 34
BCC 80
24
BCC 20
BCC 20
BCC 10
7 F 78 83 20,000 Needle row 30 BCC 15
8# M 76 144 21,000 Needle row 6 *
SCC 20
SCC 27
SCC 35
9 F 86 74 17,500 Needle row 19 * BCC 25
10 M 80 81 21,000 Needle row 28 BCC 10 13
11 M 85 42 20,000 Needle row 24 * BCC 50 3
12 M 83 94 19,000 Needle row 28
BCC 7
SCC 7 4
BCC = basal cell carcinoma; ECT = electrochemotherapy; F = female; M = male; SCC = squamous cell carcinoma; * = patient deceased; # = excluded from analysis
Radiol Oncol 2020; 54(1): 79-85.
Jamsek C et al. / Long-term results of ECT with a reduced dose of bleomycin82
eter, histology type, and recurrent lesions) charac-
teristics (P > 0.05). Details of patients and tumors 
treated with reduced and standard BLM doses are 
presented in Tables 1 and 2.
The experimental group consisted of 12 patients 
(10 men and 2 women; median age 81 years; range 
67-92 years) with 24 lesions (17 BCCs, 7 SCCs), 18 
(75%) tumors were treatment naïve. The largest tu-
mor diameter ranged from 6 mm to 80 mm (medi-
an 21 mm). In control group 16 patients (8 men and 
8 women; median age 78 years; range 65-89 years) 
had 28 lesions (25 BCCs; 3 SCCs), 24 (86%) tumors 
were treatment naïve. The largest tumor diameter 
ranged from 4 mm to 50 mm (median 17 mm).
The complete response rates two months after 
ECT were observed in control and experimental 
in 96% and 100%, respectively.9 All patients were 
further followed up at regular visits. In the experi-
mental group, two patients died before six months 
follow up. One died due to the systemic dissemina-
tion of previously treated melanoma. The cause of 
death in another patient was an underlying disease, 
not related to skin cancer or ECT treatment. These 
two patients were excluded from the study. Out of 
TABLE 2. Patients’ characteristics, treatment procedure and response to treatment of patients included in control group
Patient Gender Age (years)
Creatinine 
(μmol/L)
Total 
bleomycin 
dose (IU)
Electrodes 
used
Last follow-
up (months 
after ECT)
Histology
Maximum 
tumor size 
(mm)
Recurrence of 
tumor (months 
after ECT)
1 M 65 68 30,000 Needle row 39 BCC 22
2 F 74 86 26,000 Needle row 55 BCC 15
3 M 83 129 28,000 Plate 19 * BCC 12
4 M 81 78 27,000 Needle row 37
BCC 32 7
BCC 10 7
BCC 10
BCC 5
BCC 6
5 F 82 73 24,000 Plate 41
BCC 4
BCC 9 6
BCC 5
BCC 11
6# M 88 142 30,000 Plate 2 BCC 39
7 F 69 84 23,000 Finger 46 BCC 15
8 F 82 DM 24,000 Hexagonal 41 BCC 50
9 F 89 69 23,000 Plate 48
BCC 7
BCC 20 18
BCC 6
BCC 5
BCC 6
10 M 65 DM 27,000 Plate 31 BCC 24
11# F 70 DM 27,000 Plate 4 BCC 7
12 M 78 DM 23,000 Plate 46 BCC 15
13 F 74 52 24,000 Needle row 38 BCC 15
14 F 89 54 25,000 Plate 48
BCC 21
SCC 22
15 M 67 DM 30,000 Plate 11 SCC 25
16 M 85 100 24,000 Needle row 15 * SCC 45
BCC = basal cell carcinoma; ECT = electrochemotherapy; F = female, M = male; SCC = squamous cell carcinoma; * = patient deceased; # = excluded from analysis
Radiol Oncol 2020; 54(1): 79-85.
Jamsek C et al. / Long-term results of ECT with a reduced dose of bleomycin 83
12 patients in the experimental group, 10 (83.0%) 
were evaluable at 6 months or longer. Median long-
term follow up was 28 months in the experimental 
group (average 24.9 ± 7.4 months). Tumor recurred 
in 6/10 (60.0%) patients and in 7/18 (39.0%) tumors 
in median recurrence time 18.5 months (average 
26.9 ± 9.0 months).
In the control group, 2/16 patients were ex-
cluded from the study. One died 4 months after 
the treatment due to other causes than cancer. The 
other patient did not come to a follow-up visit at 6 
months and was lost to further follow-up. Fourteen 
patients (88%) were evaluable at 6 months or long-
er. Median long-term follow up was 40 months (av-
erage 36.0 ± 14.5 months). The recurrence was ob-
served in 3/14 patients (21.4%) and in 4/26 nodules 
(15.4%) in a median time of 7.0 months (average 
9.4 ± 5.6 months). 
Overall, 6/28 (21%) patients included in the 
study died during follow-up due to other comor-
bidities. In neither of them the cause of death was 
related to NMSC or ECT treatment. After statisti-
cal analysis no significant difference in recurrence 
rate was observed between groups (Logrank test 
P=0,104).
No statistically significantly elevated levels of 
creatinine was detected neither in control (85.0 ± 
28.6 μmol/L) nor in experimental group (86.4 ± 25.6 
μmol/L, p > 0.1).
Discussion
Until now, only a few studies evaluated the long-
term efficacy of ECT treatment in NMSC in the 
head and neck region. Kristiansson et al. reported 
on 71% control rate in a case series of 7 patients 
with NMSC treated with ECT after a median fol-
low up of 119 months.11 In the most comprehensive 
study regarding long–term follow up after ECT 
treatment of BCCs, 5-year recurrence rate of local 
and locally advanced BCC was 20% and 38%, re-
spectively.12 It should be emphasized that ECT in 
these studies was performed according to the first 
version of SOP, thus standard dose (15,000 IU/m2) 
of intravenous administrated BLM was used.13 To 
the best of our knowledge, our clinical study is the 
only one where long-term effectiveness of ECT in 
NMSC in the head and neck region after the intra-
venous administration of a reduced dose of BLM 
was evaluated and was found to be equal to the ef-
fectiveness of ECT with standard dose.
The efficacy of a reduced BLM dose in elderly 
patients was confirmed in clinical studies after the 
identification of the main parameters of BLM phar-
macokinetics.7–9 Ageing is related to the impair-
ment of body functions, e.g., impaired renal func-
tion, and to a reduction in lean body mass. Both 
changes lead to reduced clearance of water-soluble 
drugs (such as BLM) and reduced volume of their 
distribution. Hence, the plasma concentration of 
BLM is higher than in younger adults. Thus, the 
use of the standard dose of BLM in elderly patients 
could lead to prolonged healing time and a more 
prominent inflammatory response, as a result of 
exceeded optimal concentrations of BLM. The ra-
tionale for dose de-escalation in elderly patients 
lays in diminishing possible systemic side effects 
(e.g., lung fibrosis), improving local healing and 
keeping total BLM dose as low as possible, espe-
cially in circumstances when multiple sessions of 
ECT are expected.8,9 According to our previous 
study complete response rate two months after 
ECT was almost 100% when using both standard 
(15,000 IU/m2) or reduced (10,000 IU/m2) BLM dose 
in elderly patients with NMSC.9 One of the major 
drawbacks of that study was too short observation 
time for adequate assessment of clinical response. 
This is especially important in BCCs because they 
are slow-growing tumors and it often takes months 
to years for a tumor to relapse after initial treat-
ment.14
After statistical analysis no significant differ-
ences were observed between control and experi-
mental groups regarding clinical or tumor param-
eters. In the control group, 4 of 26 tumors recurred 
in the median follow up time of 7.0 months. In 
the experimental group of patients, 7 out of 18 tu-
mors recurred in the median follow up time of 18.5 
months. After statistical analysis, no significant 
differences in long term tumor control between 
groups were observed (p=0.104). This confirms our 
hypothesis that long-term tumor control could be 
achieved with a lowered BLM dose. Our finding 
is in concordance with results of previous clinical 
trials on the elderly population, that suggest equal 
efficacy of reduced dose two months after the 
treatment even though the concentration of BLM 
around the tumor immediately after electropo-
ration is lower compared to the standard dose.8,9 
These findings can be explained with the pharma-
cokinetics of BLM in elderly patients, where higher 
concentrations are achieved due to reduced BLM 
clearance by the kidney and by the reduced vol-
ume of distribution.7 
Although differences in the long-term tumor 
control between both groups were not statisti-
cally significant, we observe a trend towards a re-
Radiol Oncol 2020; 54(1): 79-85.
Jamsek C et al. / Long-term results of ECT with a reduced dose of bleomycin84
currence of BCCs in the experimental group. We 
might speculate that further studies with a larger 
cohort of patients could show a lower tumor con-
trol of BCCs treated with reduced dose, as a result 
of reduced local inflammatory response. One of 
the antitumor mechanisms of ECT involves im-
mune response, provoked by immunogenic cell 
death and enhanced tumor antigen expression.5 
This might be especially important in the treat-
ment of BCCs since these tumors have the great-
est mutational burden among all human cancers.15 
Consequently, numerous tumor antigens provoke 
immune system, which is the most probable rea-
son for the less aggressive nature of BCCs.15 Taking 
these facts into consideration, less prominent local 
immune response after reduced dose ECT might 
lead to a lower tumor control of BCCs. 
The overall long-term tumor control rate at the 
end of the study was 79%. Deaths were correlated 
with underlying disease and not with NMSC pro-
gression or side effects after ECT. It is important to 
emphasize that although long term tumor control 
was not achieved in all patients, reducing possible 
side effects and consequent quality of life in pa-
tients with short life expectancy is of paramount 
importance. Thus, a reduced BLM dose in ECT 
should be considered as a treatment modality in 
elderly patients with comorbidities, where overall 
life expectancy is poor.
One of the future perspectives of ECT should 
be an orientation towards individual patients and 
tumors. For example, some studies have already 
shown that differences between tumor vasculari-
zation have an impact on BLM pharmacokinetics 
and therefore on antitumor response.16 The exact 
dose to achieve maximal antitumor response with 
minimal side effects should be determined accord-
ing to tumor histology and patients’ overall health. 
Hence, in Updated Standard Operating Procedures 
for ECT a compromised creatinine level was pro-
posed as a guide for using a reduced dose of BLM.3 
In our study average creatinine levels during ECT 
procedure were normal in both groups. It should be 
noted that the production of creatinine is decreased 
due to age-related reduction in skeletal muscle 
mass; thus, plasma creatinine level is an inaccurate 
indicator of glomerular filtration rate in the elderly 
population, where the reduction of lean body mass 
is prominent.7 We presume that creatinine is not a 
reliable marker in applying a reduced dose of BLM 
in the group of elderly patients and it must be in-
terpreted in concordance with other methods such 
as bioelectrical impedance analysis, which is used 
for body composition measurements.
We are aware that a low number of patients in 
our study is one of the drawbacks of the study. 
Even though this study raises some important clin-
ical questions, which need to be addressed. In the 
future, randomized studies with a larger cohort of 
patients, treated with reduced doses of BLM, are 
needed to evaluate the appropriate indications and 
clinical significance of de-escalated dose BLM in 
ECT treatment.
Acknowledgement
This research was funded by the Slovenian 
Research Agency, grant number P3-0003 and pro-
ject J3-9269.
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